Caffeine: behavioral effects of withdrawal and related issues.

Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine. The prevalence of symptoms reported on withdrawal in different studies also covers a wide range from 11% or less to 100%. It is suggested that the evidence leads to the conclusion that non pharmacological factors related to knowledge and expectation are the prime determinants of symptoms and their reported prevalence on withdrawal of caffeine after regular consumption.

The effect of patient reminders on the use of screening mammography in an urban health department primary care setting.

Mammography screening continues to be under-utilized, especially among women from lower socioeconomic groups. In order to determine whether having direct access to health care services has an effect on mammography use among low income women, we conducted a randomized trial of two alternative letter reminders among 1,717 women who were enrolled at two locations of a multi-site inner city health department in Detroit. All participants were 39(1/2) years of age and older and were due for a screening mammogram at randomization. A physician-directed reminder form was placed in each of the participant's medical records at the beginning of the study. In addition participants were randomized to receive either a letter directing them to visit their primary care physician, a letter directing them to contact the clinic directly to schedule a mammogram, or no letter. Study participants were predominantly African-American, two-thirds of whom were over age 50, and who had minimal health insurance coverage. During the intervention year, mammograms were completed by 179 out of 967 study women at site one (18.5%), and 90 out of 750 study women at site two (12%). A multivariate model controlling for the simultaneous effect of age, insurance type, visit history and past mammography use, showed no significant independent effect of either type of letter reminder on mammography completion during the study year. In conclusion, letters targeted at women due for screening mammograms did not have a beneficial effect on mammography utilization above and beyond that of a physician medical record reminder.

The frequency of caffeine withdrawal in a population-based survey and in a controlled, blinded pilot experiment.

Reports of symptoms when regular caffeine consumption is stopped have appeared in the medical literature, but the frequency and significance of this phenomenon have remained controversial. The objective of this study was to collect information on the prevalence and severity of caffeine withdrawal in the general population and determine the incidence and type of symptoms reported on blind abrupt and gradual caffeine cessation among coffee drinkers reporting past episodes of caffeine-withdrawal symptoms. A community-based telephone survey was followed by a stratified, randomized, double-blind controlled study. Participants included 11,112 persons spontaneously calling to inquire about studies not related to caffeine and 57 regular caffeine users selected from among the callers because of self-reported caffeine-withdrawal symptoms. Gradual or abrupt withdrawal from caffeine was compared to continuation of the same caffeine level. In a survey of 11,112 persons, 61% reported daily caffeine consumption, and 11% of the caffeine consumers reported symptoms upon stopping caffeine. Among the regular caffeine users, only 0.9% of males and 5.5% of females reported symptoms significant enough to interfere with normal activities when they abruptly stopped caffeine. A group of those reporting withdrawal symptoms were randomly assigned to three subsamples. In the group subjected to abrupt withdrawal (N = 18), 6 (33.3%) reported symptoms (e.g., headaches and tiredness). Including decreases in functional ratings, a total of 7 of the 18 (38.8%) could be considered to have experienced caffeine withdrawal. The gradual withdrawal group (N = 20) reported minimal if any caffeine withdrawal symptoms. A third group (N = 18) was kept on a level dose of caffeine for comparison. When participants are unaware of the caffeine-withdrawal focus of the study, these results suggest that both the frequency and severity of caffeine-withdrawal symptoms are much lower than found in some previous reports and that clinically significant symptoms may be uncommon events among the general population.

How reminders given to patients and physicians affected pap smear use in a health maintenance organization: results of a randomized controlled trial.

BACKGROUND: Despite its effectiveness as a method of controlling cervical carcinoma, the use of Pap smear testing remains incomplete, and its promotion in the primary care setting provides an important opportunity for intervention. METHODS: The authors conducted a randomized controlled trial that involved three sites of a health maintenance organization (HMO) serving an urban minority population. Their aim was to evaluate the impact of reminders given to patients and physicians on site visitation by patients and Pap smear use. Eligible women (n=5801) were randomly assigned to 1 of 4 intervention combinations (in which reminders were given to either the patient or the physician, to both, or to neither). If they were ineligible for patient reminder intervention, patients were randomized only to physician reminder intervention (the presence or absence of it). The letter of reminder mailed to the patient invited women due for Pap smears to visit the HMO site, and the reminder for physicians was a medical record notice that a Pap smear was due. Logistic and survival analyses were used to investigate the correlation of intervention status with visitation, interval of time to a visit, and Pap smear use. RESULTS: In the primary intent-to-treat analysis, there was no significant effect of either patient or physician reminder interventions on rates of visitation or Pap smear completion. The secondary efficacy analyses demonstrated no overall effect of either patient or physician reminders, but effects among subgroups of women at individual HMO sites were noted. At Site 3, there was an apparent increase in time to the next visit among the subgroup of women with a chronic illness (16 weeks with intervention vs. 9 weeks without). With the physician reminder, the odds that a Pap smear would be given during the study year were increased among women without a previous Pap smear at Site 1 (adjusted odds ratio=1.39) and those with a chronic illness at Site 2 (adjusted odds ratio=3.38). CONCLUSIONS: Reminders given to patients and physicians had a limited impact on visitation by patients to the HMO sites or Pap smear completion. Although some subgroups of women may benefit, the authors also observed a possibly unfavorable impact among other subgroups. These results emphasize the importance of identifying more effective interventions, targeting them to women most likely to benefit, and not overlooking the possibility that preventive intervention will have an unanticipated adverse effect.

The effect of patient and physician reminders on use of screening mammography in a health maintenance organization. Results of a randomized controlled trial.

BACKGROUND: Despite its demonstrated efficacy in reducing breast carcinoma mortality, screening mammography remains underutilized and its promotion in the primary care setting provides an important opportunity for intervention. METHODS: A randomized controlled trial was conducted in two sites of a health maintenance organization (HMO) serving an urban, minority population to evaluate the impact of patient and physician reminders on site visitation and mammography use. Eligible women (n = 2368) were randomly assigned to 1 of 4 intervention combinations (patient and physician reminders individually, together, or neither). The patient reminder letter invited mammography-due women to visit. The physician reminder was a notice placed in the medical record of mammography-due women. Logistic analysis and survival analysis were used to investigate the relationship of intervention status to visitation, time to a visit, and mammography use. RESULTS: The patient reminder intervention had no effect upon rates of study year visitation or mammography at either site. However, among HMO Site 2 enrollees with entitlement insurance, the median time to the next visit was reduced from 12 to 9 weeks in association with assignment to patient reminder intervention. The physician reminder intervention was also effective in increasing the rate of completed mammography at Site 2 among all assignees (36% vs. 22% for those with vs. those without physician reminders) and among assignees who visited (59% vs. 43%). CONCLUSIONS: Patient reminder letters had limited impact on visitation in this setting. Physician reminders are more effective but sites vary in their responsiveness. Further improvement in mammography utilization will require a better understanding of the determinants of patient and physician behavior.

Activity anorexia: An interplay between basic and applied behavior analysis.

The relationship between basic research with nonhumans and applied behavior analysis is illustrated by our work on activity anorexia. When rats are fed one meal a day and allowed to run on an activity wheel, they run excessively, stop eating, and die of starvation. Convergent evidence, from several different research areas, indicates that the behavior of these animals and humans who self-starve is functionally similar. A biobehavioral theory of activity anorexia is presented that details the cultural contingencies, behavioral processes, and physiology of anorexia. Diagnostic criteria and a three-stage treatment program for activity-based anorexia are outlined. The animal model permits basic research on anorexia that for practical and ethical reasons cannot be conducted with humans. Thus, basic research can have applied importance.

Stereotypy and asymmetry in mice.

Mice ran in a circular runway. Number and direction of circuits were recorded. Most control mice ran about the same number of circuits in each direction. After 100 mumols/kg cocaine there were 3.5 times as many circuits and most mice ran most circuits in one direction. Some mice ran strongly in one direction after a first dose of cocaine and strongly in the other direction after a second dose. Hence, the primary influence toward unidirectional running is stereotypy rather than asymmetry.

Extrapolation by proximate inference.

Scientific extrapolation, as in astronomy, is different from legal or regulatory extrapolation, as in arriving at acceptably safe levels of agents. Scientific and technological information is required in the latter process, but scientists fail to contribute when they respond to legal and regulatory questions by attempting purely scientific extrapolation.

Directional running in mice: effects of cocaine and chlorpromazine.

Mice ran in a circular runway. Some received milk at every third circuit in a designated direction, clockwise or counterclockwise, in daily 1000-s sessions. Under control conditions, about 10 times as many circuits were made in the reinforced direction as in the non-reinforced direction. Cocaine (10, 30, 100 microM/kg) had little effect on the total number of circuits, but progressively increased the number in the non-reinforced direction. Chlorpromazine (1, 3, 10, 30 microM/kg) caused a monotonic decrease in total number of circuits and in number in non-reinforced direction. At the highest doses the proportion in the non-reinforced direction was increased. Mice, untrained in the runway and with no reinforcement of circuits in either direction, made many fewer total circuits than when running was reinforced and about equal numbers were in clockwise and in counterclockwise directions. Cocaine greatly increased the total number of circuits. As in the subjects whose running was reinforced, cocaine led to a much higher tendency for mice to run in a single direction. The similarities between the tendency to run in one direction after cocaine and the rotational behavior of rodents seen after cocaine and amphetamine suggest a common mechanism.

Behavioral toxicology of volatile organic solvents. I. Methods: acute effects of toluene.

Behavioral toxicity of toluene has been assessed in mice. Because of its small size the mouse can be confined in a 20 l hermetically sealed chamber for several hours. Toluene was introduced through a port and volatilized by a hot-plate. Samples of chamber air for analysis were taken through another port. A smaller mesh cage held the mouse within the larger chamber. Schedule-controlled responding was developed by arranging that a response, breaking a beam of light, was followed by milk under an Fl 60 sec schedule. Responding was much more rapid in the presence of stimuli correlated with the Fl schedule than when the schedule was not operating. Standard sessions consisted of alternating series of 8 consecutive Fl 60 sec and inter-series 30 min time-outs. Toluene disappeared from the atmosphere of the unopened empty chamber at the rate of 0.2%/hr. When the mouse cage was in the chamber the disappearance was 1.5%/hr and when a mouse was also present it was 3.7%/hr. Concentration-effect curves were determined by exposing a mouse to incremental additions of toluene at 30 min intervals. Toluene increased the rate of responding in most mice at levels of about 700 ppm. Higher concentrations progressively reduced responding. The ED50 (the concentration reducing responding by 50%) averaged 1657 ppm in 10 mice. In the appendix, principles for the assessment of hazard from results of this type are presented. It is estimated that there is a 1/1000 chance of the responding of a mouse being reduced by as much as 10% by a concentration of toluene of 69 ppm.

Effects of drugs on schedule-controlled running of mice in a circular runway.

Partially food deprived mice ran in a 1-m circular runway. Every 30 circuits, diluted evaporated milk was delivered. Under control conditions mice averaged 0.18 circuits/s for 1 h. The rate was reduced to 0.11 circuits/s 1 h after gavage of Tylose (cellulose derivative) vehicle. Amphetamine, chlordiazepoxide and pentobarbital increased the rate of responding over some dose range, but chlorpromazine, clozapine, imipramine and morphine caused only decreases in responding at effective dose levels. The results are generally similar to reports of effects of the drugs on responses of much briefer duration occurring at similar rates.

Behavioral effects of caffeine, (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse.

The effects of caffeine (1-100 mg/kg, IP), (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA) (0.01-1 mg/kg, IP), and of the two drugs in combination were studied in mice responding under a mult FR30 FI600 s schedule of food presentation. The lowest dose of caffeine, 1 mg/kg, had no effect on responding under either component of the mult schedule. Intermediate doses of caffeine (3 and 10 mg/kg) slightly increased responding under the FI component, while higher doses decreased responding. Caffeine only decreased responding, at doses above 30 mg/kg, under the FR component. PIA decreased responding under both components of the mult schedule in a dose-dependent, and similar, manner. In most cases, the rate-increasing effect of caffeine on FI responding was diminished when combined with a rate-decreasing dose of PIA. However, when 0.01 mg/kg PIA, a dose that had no effect alone, was combined with 3 mg/kg caffeine, the increase in rate exceeded that of caffeine alone. Rate-decreasing effects of PIA were antagonized by caffeine; with larger doses of PIA, larger doses of caffeine were required for antagonism. Thus, while the rate-increasing effects of caffeine can be either enhanced or diminished, when combined with different doses of PIA, the rate-decreasing effects of PIA are clearly antagonized by caffeine in a dose-dependent manner.