Caffeine is an effective analgesic adjuvant because it increases the antinociceptive effect of NSAIDs while reducing the probability of side effects. The mechanism by which caffeine increases the antinociceptive action of NSAIDs does not appear to include a pharmacokinetic interaction. The potentiation appears to be due to a pharmacokinetic mechanism including actions at the central and the peripheral levels. Because caffeine shifts the effect-compartment concentration-effect relation of NSAIDs to the left and this relationship is sigmoidal, there is no potentiation if the NSAID concentrations are too high or too low with respect to EC(50). The best potentiation can be observed if the NSAID doses used yield effect-compartment concentrations in the vicinity of EC(50). Therefore further investigation of the PK/PD relations of caffeine-NSAID combinations for different pain states and intensities is needed to optimize the therapeutic use of these mixtures

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations

OBJECTIVE: To assess whether codeine and caffeine enhance the analgesic effect of aspirin in post-operative pain. METHOD: Systematic overview of the literature and meta-analysis of published randomized controlled trials (RCTs). RESULTS: Codeine 60 mg leads to a small increase in the analgesic effect of 650 mg of aspirin when total pain relief score (TOTPAR%) is used as a efficacy end-point. This increased effect was not seen when sum of pain intensity (SPID%) and proportions of patients responding with moderate to excellent pain relief were used as outcome measures. Caffeine did not enhance the analgesic effect of aspirin. CONCLUSION: Codeine 60 mg may produce a small increase in the analgesic effect of aspirin 650 mg. However, this effect is not clinically meaningful. Caffeine has no adjuvant analgesic effect. At over-the-counter (OTC) doses, caffeine and codeine are not useful in aspirin formulations

Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than ten reports of OC/drug interactions were found involving antihistamines, thyroid hormone, vitamin C, antacids, ulcer medication, or diuretics. These may represent a set of OC/drug interaction problems that need to brought into medical awareness. Pregnancy is the first event reported when OCs appear to interact with another drug. However, menstrual disturbances are reported more often. BTB is the most frequently reported menstrual disturbance: it has been considered a warning signal that OC efficacy may be compromised. In such circumstances, contraceptive backup may be warranted. Reports of interference with OC efficacy have been most common for drugs used to treat tuberculosis, epilepsy, and depression, so patients and their physicians should be aware of potential problems. However, the average woman is more likely to encounter antibiotics, analgesics, and antihistamines, and current package inserts contain appropriate warnings. In recent years, prescriptions for low-estrogen OCs have outnumbered those for high-dose preparations. Many physicians became concerned that there was an increased risk of OC drug failure with the low-dose products. The database does not seem to suggest that this has happened. The dose of estrogen is not correlated with total adverse experience reports, time of appearances of the first adverse experience reports, or rate of reporting of the interactions. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributed to OC/drug interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of OCS on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 13 healthy males, nine healthy females taking no OCS, and nine healthy females on OCS. The t1/2 (beta) was significantly prolonged in women on OCS (10.7 +/- 3.0 hr vs. 6.2 +/- 1.6) (p less than 0.001) as compared to women taking no OCS. Women on OCS had a significantly lower total plasma clearance (0.79 +/- 0.21 ml/min/kg vs. 1.3 +/- 0.35) and free clearance (1.12 +/- 0.28 ml/min/kg vs. 1.97 +/- 0.57) that women not taking OCS. Volumes of distribution and plasma binding were similar in both groups of females. When women taking no OCS were compared with men, all pharmacokinetic parameters were similar except for volume of distribution, which was significantly larger in the women (p less than 0.05). We conclude that OCS impair the elimination of caffeine.

The effect of chronic (greater than 3 months) administration of low-dose oestrogen-containing (less than 50 micrograms oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.7501/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 micrograms/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users

There is considerable variation in opinion about the importance of drug interactions between the combined oral contraceptive pill (COCP) and broad-spectrum antibiotics. Clinical practice varies widely, especially between doctors in Europe and those in the US. Rifampicin and griseofulvin induce hepatic enzymes and do appear to have a genuine interaction with the COCP, leading to reduced efficacy. The situation with the broad-spectrum antibiotics is less clear. There are relatively few prospective studies of the pharmacokinetics of concurrent COCP and antibiotic use and few, if any, demonstrate a convincing basis for any reduced contraceptive efficacy. There is evidence, however, that variable contraceptive steroid handling could make some women, at some times, more susceptible to COCP failure. Given the serious consequences of unwanted pregnancy, the cautious approach of using additional or alternative contraception during short courses of broad-spectrum antibiotics and the initial weeks of long-term antibiotic administration may be justified to safeguard the few unidentifiable women who may be at risk. Conflicting opinion and advice is potentially confusing to both professionals and patients, and instructions for additional precautions during and after concurrent COCP and antibiotic use are complicated. Many women are ignorant of, or confused about, the circumstances that can cause OC to fail. Health professionals who prescribe the COCP must continue to strive to educate women about the mode of action and about the times when there is the greatest danger of failure. Professionals who feel that concurrent antibiotic use represents a real threat to contraceptive efficacy of the COCP should be prepared to present the advice for additional contraceptive precautions in a simple and consistent way, backed up with written information and reinforced at regular intervals

Oral contraceptive steroids increased the residence time of caffeine in 9 young women by a factor of 2. The effect was already manifested during the first cycle 2 weeks after starting oral contraceptive steroids (OCS) and was slightly increased in the second cycle, after 6 weeks on OCS. Toxic effects attributed to oral contraceptive steroids may in part be indirect and due to prolonged retention of absorbed toxic agents to which women are exposed

OBJECTIVE: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. METHODS: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2-6 post-onset of menses), ovulatory (days 13-16 post-onset of menses) and luteal (days 22-26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. RESULTS: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration-time curve (AUCinf) was 93.01 mg 1(-1) x h and the absorption rate constant (ka) was 2.88 h(-1) during the ovulatory phase, 83.0 mg 1(-1) h and 2.06 h(-1), respectively, during the luteal phase and 84.7 mg 1(-1) x h and 1.84 h(-1), respectively, during the follicular phase. CONCLUSIONS: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine

This study investigated the role of genetic factors (CYP1A2) in caffeine metabolism. The CYP1A2 activity was determined in 378 Danish twins following oral intake of a single dose of 200 mg caffeine and subsequent determination of the caffeine ratio (AFMU+1MU+1MX)/17DMU in a 6-h urine sample. The mean (+/- SD) caffeine ratio was 5.9 +/- 3.4. The caffeine ratio was statistically significantly higher in men compared to women, in smoking men and women compared to non-smoking persons of the same gender and in women not taking oral contraceptives compared with women on oral contraceptives. Thus, we confirmed that CYP1A2 is more active in men than in women, that it is induced by smoking and inhibited by oral contraceptives. In the subsequent analysis of heritability, we included 49 monozygotic twin pairs and 34 same gender dizygotic twin pairs concordant for non-smoking and non-use of oral contraceptives. The intraclass correlation coefficient was 0.798 (95% confidence interval, 0.696-0.900) and 0.394 (95% confidence interval, 0.109-0.680) in the monozygotic and dizygotic twins, respectively. The correlation was statistically significantly higher (P = 0.0015) in the former compared with the latter. A biometrical model for the caffeine ratio including only additive genetic factors and unique environmental factors was the overall best fitting model. Estimates based on this model gave a heritability estimate of 0.725 (95% confidence interval 0.577-0.822). Unique environmental effects seem to account for the remainder 0.275 (95% confidence interval, 0.178-0.423). Our study shows that the CYP1A2 activity is mainly governed by genetic factors

BACKGROUND AND OBJECTIVES: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP 1A2 activity is not clear. METHODS: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean +/- SD) 27.8 +/- 3.8 years, body mass index 23.8 +/- 3.8 kg x m-2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 +/- 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. RESULTS: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day -9 to -4 prior to onset of the next menses) to the follicular phase (days 5-10) was (n = 13, point estimate) 1.03 (90% CI 0.95-1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. CONCLUSIONS: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates