No abstract

AimsIt is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. MethodsEleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 m g, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS). Pharmacokinetic parameters were calculated by noncompar tment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. ResultsThe data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 m g) for dose adjusted AUC ( F = 0.42, P = 0.6660), dose adjusted C max ( F = 0.08, P = 0.9206) and Tmax ( F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100 m g) in dose adjusted AUC from the three-period crossover analysis was -0.016 min·ng/ ml ( t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t max increased from 39.7 ± 17.4 to 48.7 ± 26.3 and 56.7 ± 24.6 min for the 100, 200 and 400 m g doses, respectively. Adverse events were few and did not increase with increasing dose.B. Lennernäs et al. 25059 :2 Br J Clin Pharmacol ConclusionWith this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

The concurrent validity of questionnaires in population studies on drug use was tested by comparing information from registers and interviews in two populations of young people from Gothenburg. The questionnaire items' sensitivity and specificity according to criteria and their capacity for prediction of drug use and no drug use and correct classification were calculated. Considering criteria weaknesses and other sources of errors, the validity of the questionnaire items was good. This conclusion is basic to longitudinal population studies which aim at clarifying the prognosis of drug abuse among young people.

Mortality in young drug users in Gothenburg was studied, by following up, for about a decade, two unselected groups (ninth grade pupils and military conscripts), and selected groups of abusers from the files of the health and social welfare authorities. In the unselected groups, cannabis smoking predominated. Solvents, LSD, and central stimulants taken orally or intravenously also occurred, particularly in the selected groups. Polydrug abuse including alcohol was common, opiate abuse was rare. Observed mortality was compared with expected mortality in the same age groups. The mortality rate was significantly increased in several of the selected groups, 2.4-6.9 times in men and 1.3-7.9 times in women. Among pupils with high-frequency drug use it was increased 5.5 times in boys and not significantly increased in girls. Among pupils with low-frequency drug use it was not significantly increased in boys and increased 4.7 times in girls. Among registered pupils the mortality was increased 4.2 and 8.2 times in boys and girls respectively. Military conscripts did not display an increased mortality. The proportion of unnatural deaths was over 90%, which was significantly higher than in the population. About half of the deaths were suicides and undetermined suicides. The proportion of undetermined suicides was high among men. Two of the male deaths were homicides. In about one third of the deaths alcohol was involved. Dextropropoxyphene was present in five of the 14 intoxications among men. Although mortality was increased it is lower than in other Scandinavian studies. This may be explained by the relative youth of the abusers and the rare occurrence of opiate abuse.

In the Gothenburg year cohort of 1953 1% of the men and 0.2% of the women were registered for chronic drug abuse through 1979. An early début and a polydrug abuse with emphasis on intravenous abuse of central stimulants but not opiates were found. Compared with matched individuals who were unregistered for drug abuse, chronic drug abusers had a large over-consumption of psychiatric and social care. Their registered criminality was higher, they were more often sick-listed and had lower incomes than the controls. The prevalence and overall impairment of chronic abusers are similar to those of schizophrenics.