Caffeine withdrawal,sleepiness, and driving performance: What does the research really tell us?

Abstract

As a psychostimulant, caffeine is thought to reduce road accidents by keeping drivers alert and wakeful. Studies have found that caffeine can improve performance on vigilance tasks and in driving simulators under normal sleeping conditions and after sleep restriction or deprivation. However, there is increasing evidence that these beneficial effects of caffeine are due to withdrawal reversal. Studies comparing the effects of caffeine versus placebo on driving performance have tested habitual caffeine consumers deprived of caffeine from the evening before the test day. The conclusion from this review is, therefore, that improvements in driving performance and alertness after caffeine are likely to represent withdrawal reversal rather than a net beneficial effect of caffeine. Further research using designs that control for caffeine withdrawal are necessary and, accordingly, advice given to the public on use of caffeine as an antidote to tiredness and impaired performance should be reviewed.     

ALCOHOLIC WITHDRAWAL SYNDROME AND SEIZURES

A study of 72 alcoholics, hospitalized for alcohol withdrawalsyndrome, was undertaken to determine the incidence of seizures,their relationship with other withdrawal symptoms, the presenceof brain atrophy and the relationship of this last with withdrawalintensity severity. Sixty-seven (93%) were male and the meanage was 44.9±1.3 (mean±SEM) years. Thirty-three(46%) of the 72 patients had seizures at admission, 10 of thesedeveloped minor withdrawal symptoms, in 18 delirium tremensensued and 5 showed no symptoms of withdrawal. Thirty-nine (54%)had withdrawal syndrome without seizures. Twenty-one of thesedeveloped minor withdrawal syndrome and 18 delirium tremens.Seizures showed no relationship with the other withdrawal manifestations,and in all the cases preceded them. Our findings also show thatalcoholics with seizures due to withdrawal are more prone tosuffer seizures in their future withdrawal episodes, and thatalcoholics who suffer morning withdrawal symptoms are proneto develop delinum tremens. In 46 patients a CT scan was performed.Though the alcoholics showed ventricular and sulcal enlargement,brain atrophy was similar when the seizure and non-seizure groupsor those with and without delirium tremens were compared. However,cortical and ventricular     

Challenging the stereotypes: men, withdrawal, and reproductive health in Lebanon

In Lebanon, coitus interruptus or withdrawal remains a widely practiced method of family planning. Our research sought to understand the role of men in reproductive health in Lebanon by focusing on this common practice. Our main questions were: Why is it that the practice persists when more effective modern methods of family planning are available? How is the decision taken to practice withdrawal? When is withdrawal practiced and with whom? And, finally, does the practice of withdrawal affect sexual pleasure and the sexual relationship more generally?To answer these questions, we embarked on a small exploratory study using in-depth interviews with 16 open-ended questions. We found that the most important reason for the continuing practice of withdrawal is fear of side effects from other methods. Men and women expect pleasure and fulfillment in sexual relations, but they are willing to limit their pleasure to limit their fertility by means they consider safe. No one prototypical practice of withdrawal seems to exist, and this may explain whether or not the method fails to prevent pregnancy.     

TIAPRIDE AND CHLORMETHIAZOLE IN ALCOHOL WITHDRAWAL: A DOUBLE-BLIND TRIAL

Sixty-eight patients undergoing withdrawal from alcohol wererandomly allocated to treatment with tiapride, which is a dopamineblocking drug, chlormethiazole or placebo. The placebo groupwas discontinued early in the trial because of the high rateof major complications, a finding which supports the need foractive treatment in withdrawal. Tiapride was less effectivein preventing hallucinosis but was more successful in alleviatinggastrointestinal and psychological distress. Our findings supplementother work suggesting a disturbance of dopaminergic transmissionin alcohol dependency and withdrawal.     

Comparative effects of long-term ethanol consumption and forebrain lesions on maze learning and active avoidance behavior in rats

Male rats consumed a liquid diet containing 10.7% ethanol as their only source of food and fluid for 6.5 months, beginning at 2 months of age. During withdrawal, there were no differences between the alcohol group and their pair-fed or free-fed controls on EEG, body temperature, irritability and tremor measures. In behavioral tests begun 4-5 weeks after withdrawal, the rats that had consumed alcohol acquired accurate spatial behavior in a cross maze task more slowly than controls, but were unimpaired in shuttle-avoidance learning. In concurrent studies with groups of rats that had sustained lesions of the dorsal hippocampus, the mamillary bodies (MMB), or the mediodorsal thalamus, the pattern of behavioral deficits after MMB lesions was found to be qualitatively similar to that observed after the cessation of long-term alcohol consumption. These findings provide renewed hope that a useful rodent model for studying the neuropsychology of cognitive deficits associated with human alcoholism can be developed.     

CHILDREN,YOUTH, AND MOBILE COMMUNICATION

Exposure to online risks does not necessarily result in harm, but some groups of children prove to be less resilient than others when facing a potentially harmful situation online. The aim of this article is to better understand and explain which children under which social conditions are more likely to be more or less resilient. Children with low self-efficacy and more psychological difficulties are more vulnerable online as they experience stronger negative feelings and are more likely to go offline for a while or simply hope the problem would go away. A higher level of digital literacy is related to the use of online coping strategies aimed at solving the problem and protecting the child from further harm. Girls and younger children are more susceptible to sexual risks. Parental mediation and monitoring do not result in more online resilience. Mediation from peers and teachers has rather ambigous outcomes.     

Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study.

The use of more than 130 drugs and drug combinations against the alcohol withdrawal syndrome reflects the fact that views on its treatment are far from being unequivocal. Benzodiazepines are the first choice treatment but it should not be disregarded that they have side effects and, above all, a varying risk of dependency themselves. In recent years many trials have focused on carbamazepine in this respect. Its efficacy was proven in various open and double-blind studies, most of them using concomitant sedative drugs, thereby diminishing the reliability of the results. In a double-blind study we compared the efficacy of carbamazepine with that of oxazepam, in 60 in-patients suffering from alcohol withdrawal syndrome. The main rating instrument was the Clinical Institute Withdrawal Scale--Alcohol (CIWA-A). The 7-day trial showed equal efficacy of carbamazepine and oxazepam during the first 5 days and a statistically significant superiority of carbamazepine on days 6 and 7. Four patients in each group had to be dropped from the study due to side effects or after having withdrawn informed consent. There was no decrease in white blood counts under carbamazepine. The experiences with carbamazepine up to now suggest a more widespread use, especially in non-delirious withdrawal states.     

Human milk inactivates pathogens individually, additively, and synergistically

Breast-feeding can reduce the incidence and the severity of gastrointestinal and respiratory infections in the suckling neonate by providing additional protective factors to the infant's mucosal surfaces. Human milk provides protection against a broad array of infectious agents through redundancy. Protective factors in milk can target multiple early steps in pathogen replication and target each step with more than one antimicrobial compound. The antimicrobial activity in human milk results from protective factors working not only individually but also additively and synergistically. Lipid-dependent antimicrobial activity in milk results from the additive activity of all antimicrobial lipids and not necessarily the concentration of one particular lipid. Antimicrobial milk lipids and peptides can work synergistically to decrease both the concentrations of individual compounds required for protection and, as importantly, greatly reduce the time needed for pathogen inactivation. The more rapidly pathogens are inactivated the less likely they are to establish an infection. The total antimicrobial protection provided by human milk appears to be far more than can be elucidated by examining protective factors individually.     

Effects of calcium channel blockers on pentylenetetrazol drug discrimination in rats.

The effects of the dihydropyridine L-type calcium channel blockers nitrendipine and nimodipine on the pentylenetetrazol (PTZ) drug discrimination, an operant model of anxiety, were investigated. Male Long-Evans rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline. Both nitrendipine (5.0-25 mg/kg, i.p.) and nimodipine (5.0-25 mg/kg, i.p.) partially substituted for the PTZ discriminative stimulus. However, pretreatment with nitrendipine (25 mg/kg, i.p.) or nimodipine (25 mg/kg, i.p.) produced no change in the PTZ dose-effect function. Rats were given a nutritionally balanced liquid diet containing 6.5% ethanol for 10 days. Rats selected the PTZ drug lever during withdrawal. Subchronic coadministration of nitrendipine (1.25-5.0 mg/kg, i.p., b.i.d.) with ethanol failed to dose-dependently reduce PTZ-lever responding, but it did reverse withdrawal signs. Acute administration of nitrendipine (5, 10, and 20 mg/kg, i.p.) produced marked suppression of lever responding, but it failed to significantly reduce levels of PTZ-lever responding. Although calcium channel blockers reduce signs of ethanol withdrawal, they also markedly reduce rates of behavior and produce no clear effects on anxiety-like behaviors induced by ethanol withdrawal.     

Caffeine withdrawal, sleepiness, and driving performance: what does the research really tell us?

As a psychostimulant, caffeine is thought to reduce road accidents by keeping drivers alert and wakeful. Studies have found that caffeine can improve performance on vigilance tasks and in driving simulators under normal sleeping conditions and after sleep restriction or deprivation. However, there is increasing evidence that these beneficial effects of caffeine are due to withdrawal reversal. Studies comparing the effects of caffeine versus placebo on driving performance have tested habitual caffeine consumers deprived of caffeine from the evening before the test day. The conclusion from this review is, therefore, that improvements in driving performance and alertness after caffeine are likely to represent withdrawal reversal rather than a net beneficial effect of caffeine. Further research using designs that control for caffeine withdrawal are necessary and, accordingly, advice given to the public on use of caffeine as an antidote to tiredness and impaired performance should be reviewed.     

PAYMENTS,PROMOTION, AND THE PURPLE PILL

Understanding competition in the US drug market requires knowing how sensitive demand is to prices. The relevant prices for insured consumers are copayments. There are many studies of copayment elasticity in the health literature, but they are of limited applicability for studies of competition. Because of a paucity of data, such studies typically control for neither competitor copayment nor advertising. Whereas previous studies examined copayment sensitivity when copayments for branded drugs move in unison, this study examines copayment sensitivity when copayments diverge. This study uses unique panel data of insurance copayments and utilization for 77 insurance groups, as well as data on advertising. The results indicate that demand can be much more sensitive to copayment than previously recognized. Manufacturers selling drugs with higher copayments than branded competitors can lose substantial market share. Manufacturers can offset the loss of demand by increasing advertising to physicians, but it is costly. Copyright © 2013 John Wiley & Sons, Ltd.     

Platelet and erythrocyte membrane fluidity changes in alcohol-dependent patients undergoing acute withdrawal.

This study tested the hypothesis that membrane fluidity may alter during the alcohol-withdrawal syndrome. Platelet membranes of alcohol-dependent patients (n = 7) were significantly more rigid than controls (n = 7) at the start of alcohol withdrawal (mean fluorescence anisotropy 203.1 x 10(-3) vs 195.5 x 10(-3) respectively, P = 0.03), but were significantly more fluid when withdrawal was complete (191.4 x 10(-3) vs 199.2 x 10(-3), P = 0.03). Consequently platelet membranes of patients adapted to the known acute fluidizing effect of alcohol by becoming more rigid, but underwent a marked fluidization during withdrawal. There were no significant changes in erythrocyte membrane fluidity during withdrawal.     

EFFECTS OF CHRONIC ADMINISTRATION AND SUBSEQUENT WITHDRAWAL OF ETHANOL-CONTAINING LIQUID DIET ON RAT LIVER TRYPTOPHAN PYRROLASE AND TRYPTOPHAN METABOLISM

An investigation of the effects of chronic administration ofethanol by the liquid diet procedure and its subsequent withdrawalon tryptophan (Trp) metabolism and disposition was performedin rats. Treatment with the control liquid diet caused an enhancementof liver Trp pyrrolase activity and mRNA abundance. These effectsare not due to the starvation associated with this feeding procedure,because they occur in rats maintained on the liquid diet adlibitum. Chronic ethanol administration in the liquid diet didnot further influence the above increased expression of Trppyrrolase mRNA but caused inhibition of pyrrolase activity incompetition with the effects of the diet. The control liquiddiet decreased liver Trp concentration, but exerted no significanteffects on other aspects of Trp disposition. The most strikingand robust finding was a highly significant elevation in bothTrp pyrrolase activity and mRNA expression at 7 h followingdiscontinuation of ethanol availability, at which time therewere demonstrable behavioural signs of ethanol withdrawal. Theincrease in Trp pyrrolase mRNA during alcohol withdrawal maybe caused by corticosterone. whose circulating concentrationwas also increased. The changes in Trp pyrrolase activity duringethanol withdrawal were associated with significant alterationsin Trp disposition including decreased brain Trp concentrationand 5-hydroxy-tryptamine synthesis and turnover. These alterationsmay play a pivotal role in the behavioural manifestations ofethanol withdrawal including the hyperexcitement underlyingaudiogenic seizures. We suggest that rat Trp pyrrolase generegulation may be an important biological determinant of theethanol withdrawal syndrome and requires further study, andthat the use of the liquid diet procedure in Trp metabolic studiesrequires inclusion of adequate controls and special attentionto the effects of the liquid diet itself.     

Diet composition,alcohol utilization,and dependence

Experiments were carried out in which a nutritionally balanced liquid diet previously used in this laboratory was modified as to total calorie content and high or low carbohydrate and fat concentration. Ethanol was added at 4.5% and 6.2% of diet weight and provided either 27% or 34–37% of total calories depending upon the changes in nutrient content. Measurements included 8-day food/calorie and ethanol consumption, plasma ethanol level, liver alcohol dehydrogenase (ADH) activity, and rate of audiogenic-induced withdrawal seizures. The original liquid diet with 4.5% ethanol was consumed in significantly lesser amounts than the alcohol-free diet, and essentially no body weight gain occurred, regardless if the major nonalcohol, nonprotein calorie source was fat or carbohydrate. When the calorie content of the diet was boosted through the addition of extra carbohydrate or fat (at the expense of water), appreciable weight gain was noted; in the case of the higher calorie diet boosted with more carbohydrate (maltodextrin) calories, growth was similar to that observed on the alcohol-free control diet. On this latter diet ethanol calories appeared to be utilized close to their theoretical value of 7 kcal/g. Blood alcohol levels were significantly higher on the lower calorie diets and were lowest on the high-calorie, high-carbohydrate, 4.5% ethanol diet. This diet also allowed for the lowest rate of withdrawal seizures despite an ethanol intake that was as high as on the lower calorie diets. Essentially, no differences were noted among ADH activities for the dietary treatments studied and thus, did not explain the differences observed among blood ethanol levels. When the alcohol concentration in the high-carbohydrate, high-calorie diet was raised to 6.2% from 4.5% to provide 34% of total calories, the rats responded by decreasing their food (and alcohol) intake to the same level as did the animals receiving a much lower calorie diet, but with 37% of caloric alcohol content. This suggests that at a diet alcohol concentration of 34–37%, one or more nutrient metabolites become limiting in the utilization of ethanol, resulting in food intake adjustments that maintain similar amounts of alcohol consumption.     

COFFEE DRINKING AND PEPTIC ULCER DISEASE

Caffeine is a well known stimulant of gastric acid secretion. Both instant coffee and decaffeinated coffee are equal and more potent stimulants of acid secretion and they reduce esophageal pressure contraction more than can be explained by the caffeine they contain.     

Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption.

Both acamprosate and naltrexone have demonstrated clinical utility in reducing relapse to alcohol use in recovering alcoholics. The present experiments examined the effects of acamprosate and naltrexone, either alone or in combination, on basal ethanol consumption in a limited-access model with the use of outbred Wistar rats. Naltrexone, 0.1 mg/kg, significantly reduced ethanol consumption as previously reported. Acamprosate, 50 mg/kg, did not significantly reduce ethanol consumption when administered alone and provided no evidence of additive or synergistic effects when combined with naltrexone. Acamprosate, 200 mg/kg, produced a modest reduction in ethanol consumption when administered alone but no evidence of additive or synergistic effects when combined with naltrexone. From these findings, it is suggested that a combination approach of these drugs may not be any more effective than monotherapy.     

不同剂量米非司酮治疗子宫肌瘤106例临床观察

目的:比较12.5 mg/d和25 mg/d两组剂量的米非司酮治疗子宫肌瘤的疗效及其副作用,以及评估停药后肌瘤反跳生长的情况。方法:选取106例确诊为子宫肌瘤的患者,分别予米非司酮12.5 mg/d和25 mg/d,连续服用3个月。用药前后用B超测量子宫肌瘤的三维径线,同时评估患者血清中血红蛋白浓度、临床症状改善情况及子宫内膜情况,并对患者进行1年随访,观察子宫肌瘤反跳生长情况。结果:两组剂量米非司酮均明显改善子宫肌瘤患者相关的临床症状,提升血红蛋白及缩小子宫肌瘤体积,两组间差异无统计学意义(P>0.05)。停药后分别比较两组3个月、6个月和9个月的反跳率,差异均无统计学意义(P>0.05)。米非司酮12.5 mg/d组发生子宫内膜不规则增生率显著低于25 mg/d组(P<0.05)。结论:米非司酮治疗子宫肌瘤25 mg/d和12.5 mg/d两个剂量均能缩小肌瘤体积、改善临床症状,但以12.5 mg/d剂量更为安全。米非司酮治疗子宫肌瘤后反跳率高,建议最好作为术前用药。     

Neurobiological mechanisms of nicotine craving.

Nicotine induces craving, but the degree of craving is believed to be milder than that with other abused drugs. In this article, the neurobiological mechanisms of craving for nicotine and other drugs are reviewed, focusing especially on three factors that can be involved in the development of craving. The first factor is the affective symptoms of withdrawal, the neural basis of which may involve neuroadaptations (desensitization) within the reward systems. Affective symptoms experienced during withdrawal from nicotine are milder than those experienced in withdrawal from other drugs, probably because of its mode of action on the reward systems, which is similar to that of natural rewards. The second factor is the conditioning process, in which environmental stimuli can gain properties of a secondary reinforcer. Nicotine has weak but reliable conditioning effects, and the brain region mediating those effects of nicotine involves the ventral tegmental area. The third factor is a cognitive (memory) process, but little is known about this area.