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.

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.

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.

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.

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.

The effects of the addition of sufentanil to 0.125% bupivacaine on the quality of analgesia during labor and on the incidence of instrumental deliveries.

In a double-blinded, randomized, prospective multi-center study of 695 women, we investigated whether epidural injection of sufentanil added to 0.125% bupivacaine with epinephrine (1:800,000) reduces the total amount of local anesthetic required, resulting in less motor blockade and reduced incidence of instrumental deliveries, and improves the quality of analgesia provided by this low concentration of local anesthetic without jeopardizing the safety of the baby. In addition, other potential benefits of sufentanil (such as decrease in the incidence of shivering) and side effects were examined.

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.

Comparison of intravenous and intranasal sufentanil absorption and sedation.

The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 micrograms sufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations.

Pharmacokinetics of alfentanil during and after a fixed rate infusion.

Twenty-nine patients (age range 14-81 yr) undergoing orthopaedic surgery received alfentanil 100 micrograms kg-1 given as two i.v. boluses followed by a fixed rate infusion of 1 micrograms kg-1 min-1 for 44-445 min.

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.

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.

A comparison of alfentanil and fentanyl in short surgical procedures with special reference to postoperative effects.

A comparison of alfentanil and fentanyl was made with special reference to their postoperative effects. The study was performed double-blind in one hundred patients of either sex, undergoing elective surgery for hernia nuclei pulposi. All patients received thiopental, pancuronium, droperidol and 1-2 ml of a randomly selected ampoule, containing either 0.

Epidural sufentanil for post-operative pain relief: effects of adrenaline.

The analgesic, respiratory and haemodynamic effects of epidural sufentanil 75 micrograms (Group 1) or sufentanil 75 micrograms with adrenaline 75 micrograms (Group 2) were studied in 20 patients following abdominal surgery in a double-blind randomized trial. Pain relief, assessed on a linear analogue scale, sedation, heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and arterial carbon dioxide tension (PaCO2) were recorded before, and for 12 h after, injection. Good post-operative pain relief was obtained after 4 min in Group 1 and 6 min in Group 2.

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.

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.

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.

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.

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.

Alfentanil kinetics in renal insufficiency.

Alfentanil 100 micrograms/kg was administered as an i.v. bolus to 9 patients with severe chronic renal dysfunction (creatinine clearance 1.

Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma.

Maternal and umbilical venous plasma was obtained at delivery from 8 mothers and their neonates after an i.v. bolus injection of alfentanil, and from 6 mothers and their neonates after epidural administration of sufentanil.

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.

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.

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.