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PubMed1993

[Fentanyl-TTS for postoperative pain therapy. A new alternative?].

Treatment of postoperative pain is often insufficient. It normally consists of systemic application of an analgesic drug or a regional technique of analgesia. Fentanyl-TTS may be a new approach for postoperative pain therapy. Fentanyl is incorporated into a transdermal system; after application to the skin continuous release of therapeutic doses is achieved for a period of 72 h. Serum peak levels are obtained 8-16 h after application; the serum half-life is about 16-21 h because of the dermal depot. Fentanyl-TTS was administered in several clinical studies for therapy of postoperative pain. The efficacy of this new form of application could be demonstrated. For the first 12 h the patients needed supplementary doses of analgesic drugs in the same range as the placebo groups because of the lag time of fentanyl-TTS. In the following 12 h the need for supplementary analgesics was significantly reduced. After removal of the patch, the need for analgesics was still reduced for 12 h. In 21 of 341 patients respiratory depression occurred under therapy with fentanyl-TTS; no respiratory depression was observed in the placebo groups. Thus, respiratory depression might occur in up to 9% of postoperative patients treated with fentanyl-TTS. Other adverse effects were nausea (62%), vomiting (26%), sedation (22%), urinary retention (11%), headache (5%), and dizziness (8%). Local reactions under the patch were erythema (39%) or pruritus (9%). These phenomena disappeared within a few hours. The pharmacokinetics of fentanyl-TTS have two major drawbacks: during the first 12-15 h the patients need supplementary analgesics, usually opioids.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMedDate not supplied

0.1% bupivacaine does not reduce the requirement for epidural fentanyl infusion after major abdominal surgery.

BACKGROUND AND OBJECTIVES: Although local anesthesia has been demonstrated to potentiate spinal morphine analgesia in animal studies, results comparing epidural local anesthesia/opioid mixtures with opioid alone are contradictory in clinical studies. The hypothesis was that, although the concentration of bupivacaine (0.1%) was low to minimize its adverse effects, if the infusion rate of a fentanyl/bupivacaine solution was closely adjusted according to need, the presence bupivacaine would reduce the requirement for epidural fentanyl. METHODS: Forty patients were randomly assigned to receive either fentanyl (10 micrograms/mL) or a fentanyl/bupivacaine (0.1%) mixture epidurally corresponding to the dermatome of the surgical incision in a double-blind fashion for the first 18 hours after major abdominal surgery. The infusion was titrated for each patient to the rate required for pain relief during forced inspiration (pain score < or = 2, maximum 10). Pain scores, the fentanyl doses required, plasma concentrations of fentanyl at 18 hours, and the incidence and severity of adverse effects were recorded. RESULTS: Patients reported similar median pain scores and were equally satisfied with pain relief in both groups. The mean required post-operative fentanyl infusion rate (57.7 +/- 19.5 micrograms/h) and the plasma concentrations (0.84 +/- 0.36 ng/mL) in the fentanyl group were comparable to the infusion rate (54.4 +/- 19.2 micrograms/h) and the plasma concentrations (0.86 +/- 0.36 ng/mL) in the fentanyl/bupivacaine group. Respiratory and cardiovascular functions were preserved, and the incidence of nausea, pruritus, and periods of drowsiness or sleep were similar in both groups. CONCLUSIONS: In low concentrations (0.1%), bupivacaine did not reduce the titrated dose of epidural fentanyl required for adequate pain relief during forced inspiration after major abdominal surgery. The incidence and severity of adverse effects were also comparable whether or not low-dose bupivacaine infusion was used.

Abdomen↗
PubMed1996

Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4.

The microsomal metabolism of fentanyl, a synthetic opioid commonly used in anesthesia, was investigated in human liver. Incubation of fentanyl with human hepatic microsomes fortified with NADPH resulted in the formation of a single major metabolite, namely norfentanyl, as determined by GC/MS. No evidence was obtained for the formation of either desproprionylfentanyl or N-phenylpropionamide, the latter arising via N-dealkylation of the fentanyl amide nitrogen. Kinetic analysis of microsomal fentanyl oxidation revealed a single K(m) of 117 microM and a Vmax of 3.86 nmol of norfentanyl formed/min/nmol of cytochrome P450 (P450). Studies using chemical inhibitors of human P450 enzymes revealed that only agents known to inhibit CYP3A4 (e.g. ketoconazole and erythromycin) were capable of strongly inhibiting (> or = 90%) microsomal fentanyl oxidation. Marked inhibition (> 90%) of norfentanyl formation by liver microsomes was also observed with polyclonal antibodies to CYP3A4, whereas antibodies to other human P450s were without effect. Furthermore, rates of norfentanyl production by 10 individual human liver samples were highly correlated (r2 = 0.876, F = 56.46 p < 0.001) with immunochemically determined levels of CYP3A4 present in the samples but not with levels of CYP2C8, CYP2C9, CYP2C19, or CYP2E1. Our results indicate that CYP3A4 is the major catalyst involved in fentanyl oxidation to norfentanyl in human liver. Alterations in CYP3A4 levels or activity, as well as the concomitant administration of other therapeutic agents metabolized by this P450 enzyme, could lead to marked perturbations in fentanyl disposition and, hence, analgesic response.

Analgesics, Opioid↗
PubMedDate not supplied

Pharmacokinetics of continuous infusion fentanyl in newborns.

Although fentanyl administration by continuous infusion in newborns during ventilatory support has increased, pharmacokinetic data are lacking. Our objective was to determine the pharmacokinetics of fentanyl continuous infusions for sedation/analgesia in newborns who had undergone mechanical ventilation. Fentanyl was administered per routine care in seven newborns who had undergone mechanical ventilation and had normal hepatic, renal, and cardiac function. Five blood samples were collected from each newborn's umbilical artery catheter. Sample 1 was obtained at > or = 36 hours after constant fentanyl was infused, and sample 2 was collected 12 hours later. Fentanyl was then discontinued and meperidine given. Additional samples were obtained 6, 12, and 24 hours after fentanyl was discontinued. Decanted plasma was stored at -20 degrees C until gas chromatography analysis was performed. Total body clearance (TBC), elimination half-life, and volume of distribution at steady state were determined. Patient weights were 1.88 +/- 1.12 kg (mean +/- SD) with postnatal age 16 +/- 9 days; the mean gestational age was 32 +/- 4 weeks. Mean final fentanyl dosage was 1.28 +/- 0.58 microgram/kg/hr (range 0.53 to 1.9 micrograms/kg/hr). Mean elimination half-life was 9.5 +/- 2.6 hours (range 5.7 to 12.7 hours), and volume of distribution at steady state was 17 +/- 9 L/kg (range 10.1 to 30.3 L/kg). Mean TBC was 1154 +/- 494 ml/kg/hr (range 565 to 2000 ml/kg/hr). Significant correlation between postnatal age and TBC occurred (r = 0.80; p = 0.03). Newborns were hemodynamically stable during the sampling period. We found an increased volume of distribution at steady state and prolonged elimination half-life compared with single-dose administration in newborns. TBC was similar to reported values for infants and young children but was higher than for older patients.

Anesthetics, Intravenous↗
PubMed1997

[Postoperative epidural fentanyl administration in patients for hysterectomy with para-aortic lymph node resection].

In our experience, continuous epidural administration of fentanyl in doses of 12.5 micrograms.h-1, has not been sufficient to relieve postoperative pain in patients after hysterectomy with para-aortic lymph node resection. Thus, a prospective, randomized, single-blind study was performed to compare the analgesic efficacy of fentanyl 25 micrograms.h-1 with 12.5 micrograms.h-1 in these patients for 48 hours after surgery. Twenty-one women undergoing hysterectomy with para-aortic lymph node resection were allocated into three groups; Group C (control, n = 7): fentanyl 12.5 micrograms.h-1, infusion rate 2 ml.h-1, Group S2 (double speed, n = 7): fentanyl 25 micrograms.h-1, infusion rate 4 ml.h-1, and Group C2 (double concentration, n = 7): fentanyl 25 micrograms.h-1, infusion rate 2 ml.h-1. At postoperative 0, 2, 6, 12, 24, and 48 hours, the degree of analgesia was evaluated by visual analogue scale (VAS) and verbal pain scores at both rest and movement. Groups S2 and C2 showed significantly lower VAS scores than group C at the postoperative 6- and 24-hour points. At movement, the analgesic efficacy was not sufficient in any groups, but, at rest, groups S2 and C2 experienced significantly less pain than the group C. The degree of pain relief was not different between groups S2 and C2. In conclusion, epidural fentanyl 25 micrograms.h-1 provided significantly superior analgesia compared with epidural fentanyl 12.5 micrograms.h-1.

Analgesia, Epidural↗
PubMed1997

Antagonistic modulation between the delta opioid agonist BW373U86 and the mu opioid agonist fentanyl in mice.

This study was performed to assess the interactions that occur between delta- and mu opioid receptors by studying effects of the systemically active nonpeptide delta agonist BW373U86 and the mu agonist fentanyl in mice. Concentrations of the compounds were varied, and analgesic responses were determined by 55 degrees C hot-plate assays. BW373U86 produced hot-plate antinociceptive activity along with convulsive side effects. These effects could be antagonized by the selective delta antagonist naltrindole. Fentanyl produced hot-plate antinociceptive activity with Straub tail and hyperactivity as side effects. When BW373U86 and fentanyl were coadministered, BW373U86 convulsive activity was attenuated by fentanyl in a dose-dependent manner and the fentanyl-induced Straub tail effect was antagonized by BW373U86, also in a dose-dependent manner. Hot-plate analgesic activity was additive between the two compounds. The delta antagonist naltrindole partially antagonized the ability of BW373U86 to block the fentanyl-induced Straub tail effect. The mu antagonist beta-funaltrexamine antagonized the fentanyl-induced blockade of the convulsive effects of BW373U86. These data suggest that complex inhibitory interactions take place between mu and delta receptors in mice. Future studies are clearly needed to study the neuromodulatory effects of mu and delta receptors. The widespread use of mu agonists in the clinic indicates that a large number of patients exist who could greatly benefit from the conjunctive use of delta pharmaceuticals.

Analgesics, Opioid↗
PubMed1997

[Prolongation of fentanyl-induced decreased arousal by clonidine].

Both fentanyl and clonidine lead to a reduction of vigilance. We tested the influence of clonidine on a fentanyl induced change of vigilance using a cross-out concentration test (b-cross-out test). With local ethics committee approval, we conducted a randomised double-blinded cross-over study with 10 healthy male subjects (25-35 years old). Each volunteer received intravenously at two separate sessions 1.5 micrograms/kg fentanyl and 1.5 micrograms/kg fentanyl plus 3 micrograms/kg clonidine. For testing the level of vigilance a concentration test (b-cross-out) was used. The number of correctly revised marks was evaluated prior to drug administration (TI), directly after application, one hour later and two hours later. Our data underwent a multiple analysis of variance. With fentanyl two hours after application the mean increase of correctly revised marks was 12% when compared to those prior to application (p < 0.024). This means that with fentanyl a learning effect was achieved as described in the literature. With fentanyl and clonidine two hours after application, a decrease in vigilance of 7 1/4 in comparison with TI was seen (n.s.). This reduction of vigilance should be considered during the postoperative course and especially with regard to ambulant anaesthesia when using clonidine.

Adult↗
PubMed1997

Comparison of intravenous retention of fentanyl and lidocaine on local analgesia in propofol injection pain.

BACKGROUND: With a tourniquet on arm for arresting venous blood flow, we evaluated the efficacy of intravenous (i.v.) retention of fentanyl and lidocaine in reducing the pain on i.v. propofol injection during general anesthesia. METHODS: One hundred and twelve patients were studied. Following a venous occlusion by a tourniquet inflated to 70 mmHg, patients in Group A (n = 38) received normal saline (NS) 3 ml, while those in Group B (n = 37) and in Group C (n = 37) respectively received fentanyl 150 micrograms or 3 ml and 2% lidocaine 3 ml (60 mg). The venous retention of drug was maintained for 1 min, followed immediately by tourniquet release and propofol 100 mg i.v. injection over 20 s. RESULTS: Both fentanyl and lidocaine treatments (Groups B and C) were significantly better than placebo (Group A) in reducing pain on propofol injection (p < 0.005). Lidocaine 60 mg was more effective than fentanyl 150 micrograms in reduction of pain associated with i.v. propofol (p < 0.001). Injection of fentanyl itself caused pain in 28% of patients as compared to 2% in the lidocaine group. Mild local skin erythema was noted in 14% of patients with fentanyl venous retention versus 0% of patients with lidocaine venous retention. CONCLUSIONS: Intravenous retention of fentanyl 150 micrograms, although less effective than that of lidocaine (p < 0.001), showed local analgesic effect in reducing the pain on propofol injection. The hypothetic mechanisms of action were speculated.

Adolescent↗
PubMed1998

Factors influencing quality of life in cancer patients: the role of transdermal fentanyl in the management of pain.

A transdermal fentanyl patch for the treatment of chronic cancer-related pain is available in four dosages (25, 50, 75, and 100 microg/hr). Fentanyl is released from a 72-hour reservoir by diffusion through a controlled-release membrane to the skin, through which it is absorbed into the microcirculation. The pharmacokinetics of fentanyl differ markedly as a function of the route of administration. Unlike intravenous administration, in which peak plasma levels occur within minutes and the plasma elimination half-life is 2 to 3 hours, after initial transdermal fentanyl patch application, peak levels occur within 14 hours and the elimination half-life exceeds 24 hours. When compared with oral morphine at doses effecting the same degree of pain relief, fewer gastrointestinal disturbances (nausea, vomiting, and constipation) and better alertness and sleep quality have been reported in two studies. The transdermal fentanyl patch is as effective as oral opioids in relieving cancer-related pain, with a safety and side effect profile equal to or better than that of oral opioids. The convenient, once-every-72 hours dosing regimen is easily adjusted to the individual's need for around-the-clock pain control, and provides stable and predictable therapeutic drug plasma concentrations. Patient acceptability is high and the cost is lower than other methods required to deliver parenteral opioids. The recent development of an oral transmucosal fentanyl citrate delivery system for the treatment of breakthrough pain will further expand the use of transdermal fentanyl patches for the treatment of chronic pain.

Administration, Cutaneous↗
PubMed1998

Physico-chemical stability of infusion solutions for epidural administration containing fentanyl and bupivacaine or lidocaine.

This study examines the physico-chemical stability of infusion solutions for epidural administration containing bupivacaine hydrochloride 0.06% or 0.125% or lidocaine hydrochloride 0.25% in 0.9% sodium chloride, each with fentanyl 0.0002%. The solutions were prepared in polyvinyl chloride (PVC) infusion bags and stored without overwrap at room temperature (25-30 degrees C) or refrigerated (4-8 degrees C). Over a period of 32 days stability was determined by visual inspection, pH measurement, and HPLC assay of drug concentrations. Admixtures of bupivacaine/fentanyl and lidocaine/fentanyl proved to be chemically stable over a 32 day period, but physical incompatibility (sorption) with PVC-bags was discovered. The stability of the admixtures was influenced by pH and storage temperature. In none of the tested admixtures with an initial pH value lower than 6, did the concentrations of fentanyl or the local anesthetic decrease under 90% of the initial concentrations. A solution of fentanyl and lidocaine with an initial pH of 6.7 exhibited a rapid decrease of drug concentrations. Supposing fentanyl loss was due to sorption, buffered single drug fentanyl solutions of pH 5.5, 5.8, 6.3, and 6.7 were prepared in glass and PVC containers and stored under the same conditions. All solutions in PVC bags showed relevant fentanyl loss which was more evident at higher pH, whereas fentanyl concentration remained unchanged in glass containers at any of the tested pH values.

Analgesics, Opioid↗
PubMed1993

Fentanyl antagonizes diazepam on carotid sinus baroreflex control of circulation in rabbits.

To investigate the effects of a combination of fentanyl and diazepam on carotid sinus baroreflex in conscious rabbits, we examined the responses of mean systemic arterial pressure (MAP), heart rate (HR) and total peripheral resistance (TPR) to bilateral carotid occlusion (BCO). Seven rabbits were given 0.5 mg.kg(-1) of diazepam i.v. followed by 10 mg.kg(-1) of fentanyl i.v. at 5 min intervals (group 1), and the drugs were given in the reverse order to 5 other rabbits (group 2). BCO was repeated in conscious state (control) and after each drug injection. MAP responses did not differ from control response in either group when both drugs were given. In group 1, however, diazepam decreased HR response to 71.4% of control, and increased TPR response by 36%. Fentanyl administration reversed diazepam-induced changes in BCO responses to the control level. In group 2, fentanyl decreased TPR response to 61.6% of control and increased HR response by 41.5%. Administration of diazepam following fentanyl restored HR and TPR responses to control levels. Carotid sinus baroreflex gain was 3.1 +/- 0.4 (mean +/- SEM) in control and 3.1 +/- 0.4 after administration of both drugs in 12 rabbits. The results suggest that a sedative dose of either fentanyl or diazepam antagonizes the other drug's action on the carotid sinus baroreflex. The combination of fentanyl and diazepam has little influence on carotid sinus baroreflex control of the circulation in rabbits.

Journal Article↗
PubMed1988

Wakefulness during the induction with high-dose fentanyl and oxygen anesthesia.

The purpose of this study was to investigate the state of wakefulness during the induction of anesthesia with high-dose fentanyl using the isolated forearm technique. Ten patients scheduled for elective cardiovascular surgery were premedicated with morphine (0.15 mg/kg) and scoploamine (0.3-0.4 mg) intramuscularly one hour before induction. The induction of anesthesia was performed by intravenous administration of 100 micro g/kg of fentanyl in 15 min or over. The pneumatic tourniquet applied on the left upper arm was inflated to 220-240 mmHg after 10 micro g/kg of fentanyl was given and then pancuronium was administered. Verbal commands were given to the patient after 25, 50, 75 and 100 micro g/kg of fentanyl was administered. Eight patients out of 10 responded to the verbal commands after administration of 25 micro g/kg of fentanyl. Six patients also responded after administration of 100 micro g/kg of fentanyl and diazepam 5 mg was given to prevent tachycardia and rigidity during endotracheal intubation. Muscle rigidity and tachycardia were noticed in three and four patients respectively. These complications disappeared by diazepam administration. It was noted that wakefulness frequently occurred during the induction by high-dose fentanyl and oxygen anesthesia. To prevent such wakefulness therefore, it is necessary to use anesthetic supplements which do not cause cardiovascular depression.

Journal Article↗
PubMed1993

Neonatal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section.

Epidural injection of opioids has been introduced to improve analgesia during labour and caesarean section. This study was designed to quantify placental transfer of fentanyl and to evaluate neonatal effects of adding fentanyl to 0.5% bupivacaine for epidural anaesthesia in women undergoing elective caesarean section at term. The parturients were randomly allocated to one of four groups of 20, who received either saline (control) or 50, 75 or 100 microg of fentanyl added to 20 ml of 0.5% bupivacaine. Apgar scores, time to sustained respiration and umbilical acid-base values did not differ among the groups. The median (interquartile range) umbilical artery to maternal vein fentanyl concentration ratio was 0.34 (0.26-0.48) when the fentanyl groups were taken together. Neurologic and adaptive capacity scores were evaluated at 2 and 24 h. Neonates whose mothers received fentanyl had lower scores with regard to supporting reaction at 2 h and active tone at 24 h, when compared to controls (P<0.05), but there were no differences among the groups with regard to the other test criteria in the neurobehavioural test. In conclusion, epidural injection of fentanyl 50-100 microg did not produce depression of the term neonate.

Journal Article↗
PubMed2002

Comparison of resource utilization by patients treated with transdermal fentanyl and long-acting oral opioids for nonmalignant pain.

OBJECTIVE: To quantify resource utilization and costs incurred for patients who received transdermal fentanyl as their first long-acting analgesic for non-malignant pain, and to compare these with utilization and costs for similar patients dispensed other long-acting oral opioids. DESIGN: A retrospective matched cohort study using medical claims data from a large New England Insurer. PATIENTS: We identified 478 patients without cancer who received transdermal fentanyl during 1995-1998. We selected patients who had no previous long-acting opioid dispensings and were enrolled during the 180 days before and 30 days following the initial dispensing. We used propensity scores to identify a matched comparison group of 478 long-acting oral opioid users. RESULTS: Transdermal fentanyl and matched long-acting oral opioid users incurred identical median costs for outpatient medical services and prescriptions during 2 years of follow-up. A larger proportion of transdermal fentanyl patients were still taking their initial opioid analgesic at the end of the 2-year follow-up than were patients initially taking other long-acting opioids. Use of short-acting opioids tapered off more slowly among transdermal fentanyl patients than among long-acting opioid patients. In the first 6 months, the transdermal fentanyl patients had more hospital discharges than the long-acting oral opioid patients, but this difference appeared to reflect preexisting conditions. CONCLUSIONS: Users of fentanyl transdermal system and other long-acting opioids experienced essentially identical evolution of health services utilization and costs over a 2-year period. The choice of long-acting opioid analgesia does not appear to be a determinant of future medical costs.

Journal Article↗
PubMed1990

Cerebrovasculr response to CO2 in edematous brain during either fentanyl or isoflurane anesthesia.

Cerebral blood flow response to changes in PaCO2 was studied in the edematous cerebral cortex of 19 patients with malignant supratentorial tumors using laser Doppler flowmetry technology. General anesthesia for craniotomy was induced with thiopental, 3-5 mg/kg i.v., and N2O, 60% in O2. In random sequence, 8 patients were assigned to receive fentanyl, 6 +/- 1.6 (SEM). mug/kg i.v.; the other 11 received isoflurane, 0.56% end-tidal + 0.07 (SEM). After a craniotomy bone flap was turned and the dura was opened, laser flowmetry probes were placed over surgically undisturbed cortex that was known to be edematous from preoperative CT and MRI scans. Flow index measurements were first made at hypocarbia (PaCO2 = 24.2 +/- 0.9 and 21.5 +/- 2.1 mm Hg for the fentanyl and isoflurane groups, respectively). Minute ventilation was then decreased and cortical flow index was remeasured with PaCO2 = 34.2 +/- 0.6 and 33.0 +/- 0.8 mm Hg for the fentanyl and isoflurane groups, respectively. Hypocarbia during fentanyl-supplemented N2O-O2 anesthesia resulted in a cortical flow index that was 70 +/- 8% of the flow index at near normocarbia (p <0.05). During isoflurane N2O-O2 anesthesia, however, there was a wide variety of responses to hypocarbia, including three patients whose flow indices increased markedly. The mean flow index during hypocarbia was significantly (p <0.05) lower during fentanyl-N2O anesthesia than it was during isoflurane-N2O anesthesia. There was no predictable relationship between the type of brain tumor and the CBF response to hypocapnia during isoflurane-N2O anesthesia. It is concluded that, in edematous brain, cerebral cortical blood flow response to hypocarbia is more likely to be preserved during fentanyl-supplemented N2O-O2 anesthesia than it is during isoflurane-supplemented N2O-O2 anesthesia. In neuropathologic states where hyperventilation is thought to be necessary to reduce cerebral blood flow and decrease brain bulk, isoflurane may be less satisfactory than fentanyl as a supplement to N2O-O2 anesthesia.

Journal Article↗
PubMed1989

Transdermal fentanyl: pharmacokinetics and preliminary clinical evaluation.

A new transdermal drug-delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72-hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero-order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.

Absorption↗
PubMed1984

Effects of drug-induced differences in reinforcement frequency on discriminative stimulus properties of fentanyl.

Rats were trained to discriminate between fentanyl (0.04 mg/kg) and saline in a two-lever procedure. Using a FR 10 schedule of food reinforcement, drug-induced differences between the number of reinforcers obtained under fentanyl and saline conditions were observed. The effect of eliminating these differences on the outcome of generalization tests was investigated by different manipulations. In one group (N = 10), the FR 10 schedule used during saline sessions was changed to FR 6 during drug sessions. In a second group (N = 12), saline sessions ended after the number of reinforcers obtained was equal to the number obtained during the preceding drug session. A control group (N = 10) was trained using a FR 10 schedule under both conditions. Elimination of differences in reinforcement frequency accelerated the acquisition of the discrimination, diminished response bias, flattened the slope and reduced the ED50 value of generalization gradients of fentanyl, morphine and sufentanil and increased the ED50 value of naloxone in antagonizing 0.04 mg/kg fentanyl. It is concluded that the unconditioned effects of 0.04 mg/kg fentanyl on response rate in a FR 10 procedure lead to differences between saline and drug sessions which contribute to the apparent discriminative stimulus properties of fentanyl.

Animals↗
PubMed1985

Distribution of fentanyl in rats: an autoradiographic study.

Unexpected respiratory depression reported to have occurred up to 2 h after neurolept analgesia with fentanyl has been proposed to be a redistribution phenomenon due to a gastro-entero systemic recirculation of fentanyl sequestered in the stomach. In the study presented here, this redistribution hypothesis was tested by employing whole-body autoradiography (WBAR) in two series of time-course experiments, designated to further elucidate the distribution of intravenously administered fentanyl which was radiolabelled in different parts of the molecule respectively. However, there was no evidence of a secondary accumulation of radioactivity in the brain. The possibility that fentanyl trapped in the stomach may be reabsorbed as it passes through the small intestines was investigated by intragastric administration of the drug. Its oral bioavailability was found to be only 1.5%. Also, evidence of a strong metabolic effect was obtained by analysis employing high performance thin-layer chromatography (HPTLC). In conclusion, the results obtained from this work do not support the hypothesis that the fentanyl rebound effect is due to a secondary rise in brain levels of the parent drug and its major metabolites, an event which could be brought about by reabsorption of fentanyl sequestered in the stomach.

Administration, Oral↗