Comparison of the efficacy and tolerability of a paracetamol/codeine fixed-dose combination with tramadol in patients with refractory chronic back pain.

Fifty-five patients suffering from refractory chronic back pain took part in a double-blind, multiple-dose, randomised, cross-over study to compare the efficacy and tolerability of a fixed-dose capsule preparation containing 500 mg paracetamol (CAS 103-90-2) and 30 mg codeine phosphate 1/2 H2O (CAS 41444-62-6) (talvosilen forte, test preparation) with a reference capsule preparation containing 50 mg tramadol hydrochloride (CAS 22204-88-2), in a regimen of two capsules 8-hourly. There were two treatment periods of up to 7 days each. Cross-over took place, without washout, at the end of 7 days, or sooner if patients were unable to tolerate the first treatment. The test preparation was at least as efficacious as the reference in the treatment of back pain (81% of patients experienced good or satisfactory pain relief). 81% of patients tolerated the test well compared to only 69% receiving the reference, as per protocol analysis. The results of this study suggest that the test product is at least as efficacious as tramadol in the treatment of patients with refractory chronic back pain, whilst being better tolerated.

Bioequivalence of controlled-release calcium antagonists.

In this review, several deficiencies of published bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care. A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test: reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made. With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. Some bioequivalence studies of calcium antagonists are deficient in this respect. To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. Some calcium antagonists, such as verpamil, show stereo-selective pharmacokinetics, so that enantiomers may have to be investigated. Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory.

Caffeine in sport. Urinary excretion of caffeine in healthy volunteers after intake of common caffeine-containing beverages.

The presence of a concentration of caffeine greater than or equal to 15 micrograms/ml in urine of athletes participating in competitive sport is a disqualifying factor. A study was conducted to establish how much caffeine needs to be ingested--in the form of coffee, tea or Coca-Cola--to approach or exceed this limit. Nine healthy volunteers participated in a randomised cross-over study and received caffeine in the form of these beverages, ingested within 15 minutes, in doses ranging from 1.52 mg/kg to 17.53 mg/kg. The latter dose is equivalent to nearly 8 cups of ordinary percolated coffee. The maximum caffeine concentration in urine recorded was 14 micrograms/ml, 3 hours after ingestion. A significant correlation was found between the caffeine dose and the maximum urinary concentration. The mean recovery of caffeine in urine was between 0.74% and 0.91% of the administered dose. The nature of the beverage did not appear to influence the degree of caffeine excretion. It is concluded that if a concentration of 15 micrograms caffeine/ml urine is recorded, it can safely be accepted that the athlete purposely ingested large amounts of the substance, in whatever form.