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.

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.

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.

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 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. It was found that adding incremental doses of 10 micrograms sufentanil up to a maximum of 30 micrograms reduced the incidence of instrumental deliveries from 36 to 24% (P less than 0.01) and significantly improved quality and duration of analgesia without depressing the neurobehavioral status of the baby. No other benefits from adding sufentanil were found. The only side effect that occurred more frequently after sufentanil was pruritus. We conclude that epidural injection of 10-30 micrograms sufentanil added to 0.125% bupivacaine with epinephrine (1:800,000) improved the quality of analgesia during labor and reduced the incidence of instrumental deliveries without jeopardizing the safety of the baby.

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.

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. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the IV group were sedated versus only two in the intranasal group (P less than 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5 and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUC0-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.

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. Additional 1-mg bolus doses of alfentanil were administered as required. Plasma samples were assayed for alfentanil using radioimmunoassay. Pharmacokinetic parameters were estimated by a model-independent approach and by curve-fitting. Regression analysis showed no statistical relationship between T 1/2 beta, Cl or Vd and the duration of the infusion, total dose or body weight. We found no significant correlation between age and T 1/2 beta of alfentanil for patients younger than 40 yr. For patients older than 40 yr, T 1/2 beta increased linearly with age. There was no significant decrease in Cl with age, although the lower values for Cl (100-200 ml min-1) were generally found in subjects older than 60 yr. The present study demonstrated that a 100-micrograms kg-1 loading dose and a 1-micrograms kg-1 min-1 infusion may be appropriate for analgesia in general surgical procedures.

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.

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.

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 0.5 mg per ml alfentanil or 0.05 mg per ml fentanyl, for induction of anaesthesia. After positioning the patient, a 3-4 ml bolus dose of the analgesic was administered and occasional increments were given thereafter. There were significantly fewer responses to intubation in the 'alfentanil patients' than in the 'fentanyl patients'. Extubation time, although of little clinical importance, was significantly shorter in the alfentanil group. 12 Patients who were treated with alfentanil and 10 patients who were treated with fentanyl required the administration of an analgesic after mean time intervals of 65 and 64 min, respectively. Recovery of consciousness was similar in the two groups, but alertness 45 min after completion of the operation was significantly better in the alfentanil group: 52% were fully awake, as compared with 30% after administration of fentanyl.

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. All patients in both groups were pain-free after 30 min. Analgesia lasted for 450 +/- 46 min in Group 1 and 690 +/- 92 min in Group 2 (P less than 0.05). Coughing and active movement was possible with little pain for 6 h post-operatively in Group 1 and 7 h in Group 2. The respiratory rate was significantly decreased from 15 min to 1 h after injection in Group 1 compared with Group 2 (P less than 0.05) and in three patients in Group 1 it was necessary to stimulate the patients verbally to maintain adequate respiration. PaCO2 increased significantly in both groups over the first 2 h. The patients in Group 1 showed more marked sedation 1 h after injection. Changes of HR and MAP were similar in both treatment groups. Side-effects were observed more frequently in Group 2, although the differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.