Alfentanil kinetics in the elderly.

Alfentanil disposition after an intravenous bolus of 50 micrograms/kg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two-compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; means), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/min/kg) than in young adults (6.5 ml/min/kg), whereas terminal plasma t1/2 was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long-term infusions are required.

Fentanyl delivery from an electrotransport system: delivery is a function of total current, not duration of current.

This open-label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E-TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E-TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 microA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 microA for 26 hours plus 4 additional doses at 1,200 microA over 2.5 minutes during hour 1 (group E); or 500 microA for 0.5 hours and 100 microA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1-3 ng/mL) were attained in treatments using the E-TRANS (fentanyl) system with basal current of 100 microA for 26 hours. There were no safety issues after treatment with E-TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E-TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant-current fentanyl delivery.

Investigation of the pharmacokinetics and analgesic effects of an intramuscular injection of sustained-release sufentanil for postoperative pain: an open study.

STUDY OBJECTIVES: To investigate the pharmacokinetics after an intramuscular (IM) injection of sufentanil in thin vegetable oil in postsurgical patients and to determine whether sustained-release IM sufentanil can provide safe and sufficient analgesia of long duration in these patients. DESIGN: Open study. SETTING: University hospital. PATIENTS: 10 ASA physical status I and II patients aged 18 to 65 years who were scheduled for elective surgery. INTERVENTIONS: All patients were premedicated with lorazepam and anesthetized with a general anesthetic technique containing nitrous oxide, fentanyl, and isoflurane. As soon as significant pain [visual analog scale score of 5 or greater (range, 0 = no pain to 10 = worst pain imaginable)] occurred during the early postoperative period, the patient received an IM injection of sustained-release sufentanil. MEASUREMENTS AND MAIN RESULTS: During the first 48 hours following surgery, blood samples were taken for determination of plasma sufentanil concentrations. Blood pressure, heart rate, respiratory rate, pain scores, and sedation scores were documented at the same time. The IM administration of sufentanil in thin vegetable oil provided sufficient pain relief, although the onset of analgesia was rather slow (+/- 1 hour). The analgesic effect was still apparent 48 hours later. Plasma concentration of sufentanil at the different time points varied from 0.021 to 0.142 ng/ml, with a mean maximal peak concentration of 0.103 ng/ml. The plasma concentration 48 hours after injection varied from 0.026 to 0.074 ng/ml. CONCLUSIONS: Although an IM injection of sufentanil in thin vegetable oil is effective for postoperative pain relief, it is associated with wide interindividual variability in plasma concentration of sufentanil and long duration of action.

General anesthesia with etomidate, alfentanil and droperidol for caesarean section.

Seventy-two pregnant women, all of them admitted for caesarean section were given etomidate and succinylcholine for induction of anesthesia. Ventilation was done with N2O/O2. Once the baby was delivered, droperidol 5 mg was injected as an anti-emetic and alfentanil 50 micrograms/kg for analgesia. At the same time an alfentanil infusion was started at a rate of 1 microgram/kg/min. The combination of etomidate, N2O/O2 and a muscle relaxant was adequate in all patients until delivery. The alfentanil infusion of 1 microgram/kg/min. appeared to be sufficient in 82% of the patients. The remaining patients needed a temporary increase of the infusion rate, which was able to abolish all stress responses immediately. Cardiovascular parameters remained quite stable, except during the period in which no alfentanil was given. Recovery was fast, patients being alert within a few minutes after surgery. Postoperative vomiting occurred in 2 patients only.

Low dose sufentanil for major intracranial surgery.

The use of intravenous sufentanil in a single dose of 3 to 5 micrograms/kg body weight, was evaluated in 41 patients anesthetised for major intracranial surgery. It was assessed in a technique of balanced anesthesia which allowed controllable alteration in cardiovascular parameters and rapid postoperative recovery and neurological evaluation. It was concluded that the 4 micrograms/kg dose was superior regarding peroperative stability and recovery. The delayed recovery in aneurysm and fossa posterior surgery should be explained by several factors not involving the anesthetic technique.

Partial versus full agonists for opioid-mediated analgesia--focus on fentanyl and buprenorphine.

In contrast to other opioids, fentanyl and buprenorphine share a number of physicochemical properties that render both agents potentially suitable for transdermal delivery. However, there are significant differences between them in terms of their pharmacological profiles, as fentanyl is a full mu opioid receptor agonist capable of exerting a maximal response in certain tissues, while buprenorphine is a partial agonist unable to exert this maximum effect even at high doses. This review examines the hypothesis that partial opioid agonists would confer a number of benefits over full agonists, namely effective analgesia with a better tolerability and a lower propensity for addiction, with respect to fentanyl and buprenorphine. An attempt is also made to correlate clinical differences between these drugs with their respective agonist profiles and other differential pharmacokinetic/pharmacodynamic properties. Despite a dearth of directly comparative trials, the pharmacology of fentanyl and buprenorphine is well documented. Considerable data concerning buprenorphine suggest that the advantages initially espoused for partial opioid agonists are not borne out in clinical practice. Indeed, it may be postulated that full mu opioid agonists, particularly those with high selectivity and potency such as fentanyl, have a superior clinical profile and fulfill the above criteria more closely. Relative receptor binding, selectivity, potency and intrinsic efficacy of the opioids appear to be key determinants of their individual pharmacological profiles, contributing significantly to the heterogeneity of this class of analgesics.

Opioid tolerance and dependence: an inevitable consequence of chronic treatment?

Although opioids provide effective analgesia, largely unsubstantiated concerns about opioid-induced tolerance, physical dependence and addiction have limited their appropriate use. As a consequence, many patients receive inadequate treatment for both malignant and non-malignant pain. However, it has been shown that analgesic tolerance develops less frequently during chronic opioid administration in a clinical context than in animal experiments, and that instituting an appropriate dosing regimen can minimise withdrawal symptoms. Early studies had suggested that addiction might result from chronic opioid therapy, though more recent data indicate a low risk in patients with no history of drug abuse. New treatment regimens may also reduce the risk of tolerance, physical dependence and addiction. Long-acting preparations, such as transdermal fentanyl and possibly some forms of other slow release opioids, which maintain constant opioid concentrations in the plasma, minimise the occurrence of the 'between-dose' symptoms such as withdrawal and opioid-induced euphoria. This review discusses the development of tolerance, physical dependence and addiction during opioid therapy, and the influence of these factors on the choice of treatment.

Effects of adrenaline, an alpha 2-adrenoceptor agonist, the volume of injection, and the global pain state of the animal on the activity of epidural sufentanil.

A study was made of the effects of different volumes of injection product, adrenaline, the alpha 2-adrenoceptor-agonist medetomidine and Mycobacterium butyricum on epidural sufentanil in the rat. Increasing the volume of epidural sufentanil, and similarly decreasing the concentration of the injection product, resulted in a potentiation of the analgesic properties of epidural sufentanil without affecting the effects of the drug on the pinna and cornea reflexes and on muscle tonus. An analogue effect was observed if rats were tested for epidural analgesia during a chronic pain phase after inoculation with Mycobacterium butyricum. Adding adrenaline to epidural sufentanil also resulted in an increased analgesia but there was also a minor potentiation of all other behavioural parameters measured. The alpha 2-adrenoceptor-agonist medetomidine, clearly potentiated all behavioural effects induced by epidural sufentanil. As a consequence, there was no gain in specificity for epidural analgesia. Medetomidine, however, clearly reversed the normally observed skeletal muscle rigidity into a muscle hypotonia. Globally, these results thus indicate that manipulations of the volume of injection, the additional treatment with other drugs and the pain state of the animal can alter the activity of epidural sufentanil. Therefore, it might be concluded that the differences in the duration of analgesia observed with epidural sufentanil between human and animal studies can be partially explained in terms of differences between the experimental conditions.

Total intravenous anesthesia with etomidate, alfentanil and droperidol.

Forty-six women admitted for gynecologic surgery, were given alfentanil 1 mg, droperidol 2.5 mg and etomidate 0.3 mg/kg body weight intravenously for induction. Anesthesia was maintained using etomidate infused at a rate of 0.1 mg/kg/min for 5 minutes and at 0.01 mg/kg/min afterwards. Analgesia was achieved with a bolus injection of alfentanil prior to surgery, supplemented with additional injections of alfentanil as needed. Controlled ventilation was done with a mixture of air/oxygen. Anesthesia was uneventful in all but two patients. Blood pressure and heart rate remained stable during the entire operative period. Recovery from anesthesia was smooth, although the combination with etomidate and droperidol appears to prolong the recovery time.

Alfentanil used in the aged: a clinical comparison with its use in young patients.

The clinical effects of an i.v. bolus dose of 50 micrograms kg-1 alfentanil were studied during surgical anaesthesia in 10 elderly patients and compared with those of the same dosage in nine young adults. Plasma samples, to determine alfentanil concentrations, were taken at regular intervals during the first hour following injection. Cardiovascular changes were minor. A transient fall in systolic blood pressure shortly after the alfentanil administration was seen in both groups but was more pronounced in the elderly patients. The quality of initial intra-operative analgesia was good in all patients. The duration of action of 50 micrograms kg-1 alfentanil, as judged by the occurrence of signs of insufficient analgesia, was longer in the elderly patients (mean: 36 min) than in young patients (mean: 22 min). The alfentanil plasma levels extrapolated for these time points were similar. Hence, the difference in duration of action must be due to the slower elimination from the body in the elderly patient, rather than an increased sensitivity. On these grounds, age should be one of the criteria for selecting the appropriate dose of alfentanil.

Effect of etomidate on cortisol biosynthesis: site of action after induction of anaesthesia.

To determine the site of inhibition of etomidate on cortisol biosynthesis, plasma cortisol, aldosterone, 17 alpha-hydroxyprogesterone, 11-deoxycortisol and ACTH levels were measured in healthy women before and after the administration of a single dose of either 0.20 mg kg-1 etomidate (mean value, n = 10) or 3.15 mg kg-1 thiopental (n = 9) for induction of anaesthesia in a randomized trial. Etomidate produced a smaller increase in plasma cortisol and had a later onset of action than thiopental. Plasma ACTH levels, however, rose higher in the etomidate-induced patients to reach peak levels 6 h after drug administration. In the same group, plasma aldosterone remained below the control levels but still within the normal range, whereas it rose about 2-fold in the thiopental group. Plasma levels of 17 alpha-hydroxyprogesterone and 11 beta-deoxycortisol were hardly modified after thiopental but increased significantly and remained high for 6 h after etomidate injection. This marked rise in precursors together with a blunted and delayed cortisol response to high ACTH levels, and slightly lowered plasma aldosterone concentration indicates a blockage of 11 beta-hydroxylation in adrenal cortisol synthesis after induction of anaesthesia with etomidate.

Hydroxypropyl-beta-cyclodextrin can modulate the activity of spinally administered sufentanil.

Hydroxypropyl-beta-cyclodextrin increased the effectiveness of sufentanil after epidural and intrathecal administration in rats, both in terms of a longer duration of analgesia after a fixed dose of sufentanil, and in a reduction of the lowest ED50s to produce analgesia. There was also an increase in specificity, as indicated by the greater dissociation between the ED50s for analgesia and for supra-spinal side-effects. Maximal activity was measured after inclusion complexation of sufentanil in 10% hydroxypropyl-beta-cyclodextrin. At higher concentrations of hydroxypropyl-beta-cyclodextrin, both the activity and the specificity were attenuated. The increased safety of sufentanil in 10% hydroxypropyl-beta-cyclodextrin after spinal administration was also confirmed in terms of opioid-induced deviations in arterial PO2, PCO2 and oxygen saturation. At a dose of twice the ED50 for deep surgical analgesia, the sufentanil/hydroxypropyl-beta-cyclodextrin complex produced no changes in these parameters. With sufentanil alone at comparable analgesic doses, significant shifts in all three parameters were present immediately after drug administration. At higher concentrations of sufentanil in hydroxypropyl-beta-cyclodextrin changes in the three blood gases were present but the deviations were always smaller than those observed with comparable doses of plain sufentanil. These results support the notion that after complexation sufentanil is present longer at the spinal level after spinal administration. As a consequence, there is less free sufentanil available for redistribution into lipid tissue and into the circulatory system, producing less systemic side-effects.

The pharmacokinetic basis of alfentanil infusion.

Owing to the rapid blood:brain equilibration and the short duration of action, alfentanil is well suited for use in infusion techniques. A pharmacokinetic basis is given for alfentanil infusion schemes in patients undergoing routine surgery. Practical schemes can be worked out according to the general principle of a loading dose followed by a maintenance infusion. The loading dose of 100 micrograms kg-1 may be given as a short infusion, as two incremental doses, or as a combination of a single dose and short infusion. The maintenance infusion rate of approximately 1 microgram kg-1 min-1 results in steady-state plasma levels in the therapeutic range in most patients. Application of small extra doses, in addition to the maintenance infusion and modification of the infusion rate, might result in an appropriate and safe anaesthetic technique in most patients and surgical situations.

Practical aspects of alfentanil infusion.

The administration of alfentanil by infusion appears to present advantages for the induction and maintenance of anaesthesia during general surgery lasting over 1 h. The following dosage scheme is proposed: a loading dose of 100 micrograms kg-1, given either in one or two doses, or as a fast infusion administered over 10 min, followed by a maintenance infusion at a rate of 1 microgram kg-1 min-1. During maintenance anaesthesia, the infusion rate should be the lowest possible compatible with adequate analgesic effect, and should be further decreased 15-20 min before the projected end of surgery. Fine control of the opioid effect can be achieved with small increments of 7-15 micrograms kg-1 or by alterations of the alfentanil infusion rate. Breathing should be carefully monitored during the post-operative phase. Dedicated syringe pumps have been designed to avoid laborious calculations of the infusion rates and allow simple, rapid changes of the infusion rate.

Extradural bupivacaine with sufentanil for vaginal delivery. A double-blind trial.

The combination of sufentanil with bupivacaine plus adrenaline given extradurally for pain relief during labour was studied in a double-blind trial. One hundred and twenty patients were randomly divided into three groups and received a 10-ml extradural injection of sufentanil 15 micrograms + bupivacaine 12.5 mg + adrenaline 12.5 micrograms, sufentanil 7.5 micrograms + bupivacaine 12.5 mg + adrenaline 12.5 micrograms, or bupivacaine 12.5 mg + adrenaline 12.5 micrograms (control group). A second injection, which was given upon request, was identical to the first. Subsequently, patients received a further 10 ml of bupivacaine + adrenaline, if required. The addition of sufentanil significantly decreased the latency, and increased the duration, of the analgesia. Moreover, the quality of analgesia was better and less bupivacaine was required, resulting in less motor blockade at delivery. There were no differences between the three groups in regard to Apgar scores. The only side effect of sufentanil was pruritus.

Intrathecal sufentanil as a supplement to subarachnoid anaesthesia with lignocaine.

The combination of low-dose sufentanil with lignocaine for subarachnoid anaesthesia was studied in a double-blind comparative trial in 40 urological patients. Patients were allocated randomly to two groups and received 5% heavy lignocaine 1.5 ml together with either 1.5 ml of sufentanil 5 micrograms ml-1, or physiological saline 1.5 ml. No statistically significant differences were observed between the two groups with respect to analgesia or anaesthesia. The only clear benefit of the addition of a low dose of sufentanil to lignocaine was the significantly longer period of postoperative analgesia. There was no significant difference in the number of patients requiring supplementary analgesics. Side-effects were similar in both groups.

Epidural sufentanil for cancer pain control in outpatients.

Fifteen patients with cancer pain refractory to other methods of pain control were treated with epidural sufentanil. They all suffered from very severe or unbearable pain but had expressed the wish to spend the last period of their lives at home. On the first day of hospitalization, an epidural catheter and a portal catheter were implanted under local anesthesia. Sufentanil was delivered by a portable infusion pump into the portal catheter. The patients remained a further 2-3 days in hospital to titrate the infusion rate to their specific needs and to monitor pain relief and possible side effects. In the home situation, the patients were supervised by their general practitioners. Nine patients had epidural sufentanil as their sole analgesic till they died; six patients needed adjunctive nonepidural medications. There were no epidural- or portal-catheter related infections or cases of respiratory depression. After 1651 patient treatment days, we have found continuous epidural sufentanil infusion to be a safe and effective method for cancer pain control in outpatients.

Epidural sufentanil for postoperative pain relief.

An open pilot study was undertaken to evaluate the analgesic properties of epidurally administered sufentanil in the early postoperative period. After orthopaedic surgery of the lower extremity, four different groups of five adult patients each received either 15 micrograms (group 1), 30 micrograms (group 2), 50 micrograms (group 3) or 75 micrograms (group 4) sufentanil via an epidural catheter previously used for the surgical procedure. Results were satisfactory in groups 3 and 4 with very good relief of pain and a mean duration of action of 372 and 307 minutes respectively. Dosage above 50 micrograms did not seem to improve the quality or duration of pain relief, although the onset of action was faster with 75 micrograms. Sedation was always present in patients with effective analgesia. In the present study respiratory depression was not evident, but three patients complained of itching and two of urinary retention.

Intranasal sufentanil for pre-operative sedation.

Sufentanil, a short-acting and potent narcotic agent, was studied as a premedicant administered by the nasal route. A total dose of 5 micrograms appeared to be too low, while either 10 or 20 micrograms was very effective in producing sedation. Side effects were minor. There appeared to be no differences between nose drops and spray. In a further study, sufentanil nose drops were compared with saline 0.9% in a double-blind fashion. Sedation of rapid onset but of limited duration was observed in the majority of patients who received sufentanil.