International opioid consumption.

The aim of the present study was to analyse the opioid consumption in the 10 most opioid-consuming countries in relation to the Danish consumption. The results revealed, that the total opioid consumption has increased in all of the 10 most opioid consuming countries (range 26-1423%). In Denmark, the total opioid consumption increased 353% from 1981 to 1993, exceeding 1.45 million defined daily doses per 1 million inhabitants in 1993, which is the highest in the world. Of these, morphine accounted for 39%, methadone 22%, ketobemidone 21% and buprenorphine 14%. The consumption of long-acting opioids (morphine sustained release, methadone, buprenorphine) and short acting opioids (others) increased 1427% and 105%, respectively. Analysis of a sample of 1854 prescriptions made by general practitioners for opioids revealed, that less than 10% of the prescriptions were issued for cancer pain conditions. In conclusion of other countries consider Denmark as worthy of imitation concerning opioid treatment in cancer pain, attention should be paid to the pattern of the Danish opioid consumption, which is outstanding with respect to quantity.

[Opioid analgesics in the treatment of non-malignant chronic pain]. / Opioide analgetika i behandlingen af kroniske smerter af ikkecanceroprindelse.

Opioid sensitivity, residual pain, development of tolerance, physical and psychological dependence are described and discussed in relation to long-term opioid therapy. Based on this, guidelines for long-term opioid administration are established for chronic pain conditions of non-cancer origin. The indication must be well-considered--a life-long treatment may be instituted. Prior to final initiation of the treatment, a testing of the selected drug and method of administration should be performed. Due to the compliance-reasons, only long acting opioids should be used (controlled release morphine preparations, methadone, buprenorphine) and the route of administration should always be oral. The treatment must be individualised, covering 24 hours a day. The single dosages should be identical and administered with identical time intervals, which are determined by the duration of action of the drug in use. P.r.n.-administration should not be allowed. Only one physician should be responsible for the treatment and for the prescription of the opioid analgesic drugs.

Total intravenous anaesthesia for direct laryngoscopy: propofol infusion compared to thiopentone combined with midazolam and methohexitone infusion.

Total intravenous anaesthesia for direct laryngoscopy was investigated in 40 patients, randomized into four groups of 10 patients each. First, propofol infusion was compared to thiopentone combined with midazolam. Next, a comparison of propofol infusion with methohexitone infusion was undertaken. The propofol group showed significantly lower peroperative blood pressure compared to the thiopentone/midazolam group. The second propofol group required significantly less alfentanil to stabilize the blood pressure, compared to the methohexitone group. Completeness of recovery, assessed by means of a coin counting test, was faster in the propofol group compared to the thiopentone/midazolam group, while no difference could be demonstrated between the second propofol group and the methohexitone group. It is concluded that propofol seems to be superior to both thiopentone/midazolam and methohexitone with respect to the stability of peroperative blood pressure. Concerning recovery, propofol is superior to thiopentone/midazolam, but offers no advantage over methohexitone.

Absorption profiles of rectally administered midazolam estimated by deconvolution.

UNLABELLED: An algebraic deconvolution procedure adopted from the literature has been used to estimate the absorption profiles of rectally administered midazolam (0.3 mg/kg) in 8 healthy subjects. The extent of absorption estimated by the conventional AUC approach has previously been published and was compared to the deconvolution results. In the original study the sampling period was 840 min. When a deconvolution approach is used there may be no need to sample after the absorption is completed. Thus in this communication only samples drawn within the first 120 min and 300 min were used. The bioavailability estimated by the AUC ratio (mean 0.52 +/- SDrel 16%) is compared to the deconvolution results obtained using only data points within 120 (0.46 +/- 22%) (p = 0.02) and 300 min (0.51 +/- 20%) (p = 0.6) after drug administration. The absorption is almost complete after 120 min. Regarding the absorption rates 40% (range 27.55%) of the dose is absorbed after 60 min. The relative (normalised) absorption profiles showed that 79% (range 63-90%) of the maximum absorbed amount is absorbed within 60 min. IN CONCLUSION: Information regarding the rectal absorption of midazolam can be obtained from a sampling period of approximately 5 hours using the deconvolution approach. The algorithm used is relative easy to implement and is very easy to use with polyexponential parameters obtained by curve fitting as input.

The effect of the benzodiazepine antagonist, flumazenil, on psychometric performance in acute ethanol intoxication in man.

The effect on cognitive and psychomotor performance of the benzodiazepine (BZD) antagonist, flumazenil, in antagonising the central effect, of ethanol in man has been investigated. Eight healthy adult male volunteers, aged 23 to 32 years, participated in the study. Following a loading infusion, stable blood ethanol levels with a mean value of 1.6 g x l-1 were produced by a maintenance infusion. When stable blood levels of ethanol were reached, 5.0 mg flumazenil/placebo was administered intravenously, and after 15 and 75 min a test battery evaluating psychomotor and cognitive functions was applied. The test battery was sensitive to the test model, but no significant improvement in the test scores could be demonstrated following the administration of flumazenil. It is concluded that flumazenil has no influence on psychomotor functions in acute ethanol intoxication.

Rectal administration of midazolam versus diazepam for preanesthetic sedation in children.

Sixty children were included in the trial. Each subject received midazolam 0.4 mg/kg body weight of diazepam 0.75 mg/kg body weight rectally in a double-blind randomized order. The degree of sedation of the children was assessed on arrival in the operating unit and during the induction of anesthesia. Adequate sedation on arrival in the operating unit and during induction of anesthesia was obtained in 84% and 67%, respectively, following administration of midazolam compared with 80% and 70% in the diazepam group. No side effects were noted. It is concluded that rectally administered midazolam 0.4 mg/kg is comparable to diazepam 0.75 mg/kg with respect to preanesthetic sedation in children.

Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration.

1. In an open cross-over trial, plasma concentrations of midazolam were measured in eight healthy male volunteers following administration of 0.3 mg kg-1 body weight given by the rectal and intravenous routes. 2. Maximum plasma concentrations of 92-156 ng ml-1 (mean 118 ng ml-1) were recorded from 20 to 50 min (mean 31 min) after rectal application. The rectal bioavailability was 40-65% (mean 52%) and the terminal half-life was 114-305 min (mean 161 min). 3. A substantial first-pass hepatic effect was observed following rectal administration. 4. No systemic or local intolerance was noted. 5. In conclusion, the rectal route of administration provides a rapid and reliable absorption of midazolam.

Hypokalemia and ventricular arrhythmias in acute myocardial infarction.

In the present study, 408 patients with acute myocardial infarction were included. The serum concentration of potassium was assessed on admission. Episodes of ventricular fibrillation and/or ventricular tachycardia within the following 6 hours were registered. A significant positive correlation between hypokalemia and the incidence of malignant ventricular arrhythmias was demonstrated. Ongoing treatment with diuretics at the time of admission did not appear to be of any significance for the development of ventricular fibrillation or ventricular tachycardia. Out of 100 hypokalemic patients, only 33 were treated with diuretics. The main reason for hypokalemia in the early phase of an acute myocardial infarction is most likely an activation of the sympathetic nervous system leading to an influx of potassium from the extracellular to the intracellular body fluid compartment.

Ro 15-1788 for postoperative recovery. A randomised clinical trial in patients undergoing minor surgical procedures under midazolam anaesthesia.

In a double-blind randomised study, 100 women who underwent induced abortion under midazolam anaesthesia were given the benzodiazepine antagonist Ro 15-1788 or placebo after termination of anaesthesia. Recovery was assessed by means of a modified Steward coma scale. Following incremental doses of Ro 15-1788, 56% of the patients were fully awake within 3 minutes and 92% after 5 minutes, which was significant compared to the placebo group. The median duration of amnesia was 91 minutes after Ro 15-1788 compared to 121 minutes in the placebo group (p less than 0.001). The median dose of Ro 15-1788 was 0.4 mg. A slight positive correlation between total dose of Ro 15-1788 and total amount of midazolam was found. Nausea and/or vomiting were found to be more frequent in the Ro 15-1788 group, but otherwise we found no differences between groups with regard to either side effects or cardiorespiratory function. Ro 15-1788 is evidently an effective antagonist to the sedation induced by midazolam.