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PubMed2005

Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain[ISRCTN83088383].

BACKGROUND: Despite preclinical evidence suggesting a synergistic interaction between ketamine and opioids promoting analgesia, several clinical trials have not identified dosing regimens capable of eliciting a benefit in the co-administration of ketamine with opioids. METHODS: Ten healthy volunteers participated in a double blinded, randomised, placebo controlled, crossover laboratory study in order to determine whether a low dose of ketamine potentiated the antinociceptive effect of fentanyl without causing an increase in sedative effects. A battery of tests was used to assess both nociception and sedation including electrical current, pressure, thermal stimuli, psychometric tests, and both subjective and objective scores of sedation. Target controlled infusions of the study drugs were used. Ketamine and fentanyl were administered alone and in combination in a double-blinded randomised crossover design. Saline was used as the control, and propofol was used to validate the tests of sedation. Cardiovascular and respiratory parameters were also assessed. RESULTS: The electrical current pain threshold dose response curve of fentanyl combined with ketamine was markedly steeper than the dose response curve of fentanyl alone. While a ketamine serum concentration of 30 ng/ml did not result in a change in electrical pain threshold when administered alone, when it was added to fentanyl, the combination resulted in greater increase in pain threshold than that of fentanyl administered alone. When nociception was assessed using heat and pressure stimuli, ketamine did not potentiate the anti-nociceptive effect of fentanyl. There was no difference between the sedative effect of fentanyl and fentanyl in combination with ketamine as assessed by both subjective and objective measures of sedation. Cardiovascular and respiratory parameters were unaffected by the study drugs at the doses given. CONCLUSION: A serum concentration of ketamine that did not alter indices of sedation potentiated the antinociceptive effect of fentanyl. This potentiation of antinociception occurred without an increase in sedation suggesting that low steady doses of ketamine (30-120 ng/ml) might be combined with mu opioid agonists to improve their analgesic effect in a clinical setting. (296 words).

Journal Article↗
PubMed1981

Determination of plasma fentanyl by GC-mass spectrometry and pharmacokinetic analysis.

GC-mass spectrometry was used to measure extremely low levels of fentanyl in dog plasma. Deuterated fentanyl was synthesized for use as an internal standard. Fentanyl was hydrolyzed to despropionyl fentanyl by 20% DCl in in deuterium oxide. Mass spectrometric analysis of the product revealed that the molecular ion was three mass units higher than that of the authentic despropionyl fentanyl, indicating that the deuterium exchange reactions occurred at this stage. Deuterated despropionyl fentanyl was reesterified by propionyl chloride to fentanyl-d3. The drug was assayed in biological fluids by extraction into ethyl acetate followed by analysis with GC-chemical-ionization mass spectrometry. The lowest measurable plasma fentanyl level is 500 pg/ml. The method is highly selective and is suitable for monitoring the time course of plasma drug levels. Evaluation of pharmacokinetic data from experiments using nine dogs revealed a triphasic phenomenon. No measurable amounts of the major metabolites, depropionyl fentanyl and norfentanyl, were detected.

Animals↗
PubMed1996

Effect of fentanyl citrate anesthesia on protein turnover in patients with esophagectomy.

The objectives of this study were to determine whether high doses of fentanyl anesthesia reduced the surgical stress level and to elucidate the effect of fentanyl anesthesia on protein turnover after esophagectomy. Seventeen male patients with esophageal cancer were divided into two groups, conventional anesthesia (CA) and fentanyl anesthesia (FA). The FA patients received 134.0 +/- 15.3 microg/kg fentanyl citrate and the CA patients 15.7 +/- 7.4 microg/kg fentanyl during the surgery. Protein turnover was measured by the method of bolus infusion of [15N]glycine (1 g). High dose of fentanyl anesthesia reduced cortisol levels during the surgery (CA 38.0 +/- 13.8 pg/ml vs FA 13.5 +/- 2.4, P < 0.05) and interleukin-6 levels in the plasma after the surgery (P < 0.02). The postoperative nitrogen retention was greater with fentanyl anesthesia than with conventional anesthesia. Both protein synthesis and breakdown rates were increased with fentanyl anesthesia, while they were unaltered in CA patients. Postoperative fibrinogen synthesis rate was greater with FA than with CA (CA 51.1 +/- 9.2%/day vs FA 100.9 +/- 14.0, P < 0.01). The protein turnover and fibrinogen synthesis data suggested a shorter duration of shock phase in FA patients than in CA patients. We concluded that a high dose of fentanyl anesthesia reduced surgical stress levels and shortened the postoperative shock phase, resulting in a nitrogen-sparing effect.

Acute-Phase Proteins↗
PubMed1996

Intratracheal administration of fentanyl: pharmacokinetics and local tissue effects.

OBJECTIVE: To study the pharmacokinetics and local tissue effects resulting from the intratracheal administration of preservative-free fentanyl. DESIGN: Prospective, randomized, blinded and controlled animal study. SETTING: University research laboratory. SUBJECTS: Eighteen adult male New Zealand rabbits. INTERVENTIONS: Preservative-free fentanyl citrate or normal saline was administered by the intratracheal (i.t.) and intravenous (i.v.) routes to randomized groups of rabbits. The animals were killed at 24, 48 and 72 h following administration. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of fentanyl were measured before administration and at 2, 5, 10, 30, 60 and 120 min following administration by a specific radioimmunoassay. A detailed histological examination of the lung and tracheal tissue was performed to identify local side effects. There were no significant differences in the plasma fentanyl concentrations resulting from the i.v. or i.t. route of administration. In both groups, the concentrations of fentanyl were within the therapeutic range (i.t. 2.37 ng/ml, i.v. 2.53 ng/ml) by 2 min after injection and reached a maximum concentration within 5 min. The bioavailability of i.t. fentanyl was 71%. Microscopic examination of the respiratory system did not show significant differences between the two random groups overall. However, in the sub-group of animals killed at 24 h, more animals in the i.t. group showed signs of inflammation in the lung parenchyma. CONCLUSIONS: There is rapid absorption of fentanyl following i.t. administration. Pharmacokinetic parameters for fentanyl were not significantly altered by the route of administration. Although there were no signs that i.t. administration of preservative-free fentanyl produces lung injury, a transient and mild inflammatory response was detected at 24 h after administration.

Analgesics, Opioid↗
PubMed1996

Effects of the delta opioid against BW373U86 in pigeons trained to discriminate fentanyl, bremazocine and water in a three-choice drug discrimination procedure.

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01-10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1-10 mg/kg) but not by the mu selective antagonist naloxone (0.1-30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED50 values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1-1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.

Analgesics↗
PubMed1989

Haemodynamic responses to laryngoscopy and tracheal intubation in geriatric patients: effects of fentanyl, lidocaine and thiopentone.

The haemodynamic responses to laryngoscopy and intubation after induction of anaesthesia with thiopentone alone or in combination with 1.5 mg.kg-1 lidocaine and/or 1.5 or 3.0 microgram.kg-1 fentanyl were measured in 150 patients over 64 years of age to determine whether lidocaine, fentanyl or both lidocaine and fentanyl attenuated the pressor response. Fentanyl reduced the rises in systolic, diastolic and mean arterial pressures, heart rate, and rate pressure product and lidocaine decreased the rises in arterial blood pressure and rate pressure product (P less than 0.05). Fentanyl decreased the incidence of marked fluctuations in haemodynamic variables, often seen in geriatric patients (P less than 0.05). The haemodynamic effects of lidocaine and fentanyl were independent of each other. Complications occurred in all groups. Lidocaine-treated patients had fewer cardiac dysrhythmias (P less than 0.05) and 34 per cent of them had tinnitus. Fentanyl-treated patients had a higher incidence of hypotension (P less than 0.05). Respiratory depression developed in only one per cent of the fentanyl-treated patients. Both lidocaine and fentanyl are recommended adjuncts to induction of anaesthesia with thiopentone in geriatric patients.

Aged↗
PubMed2002

Validation of fentanyl pharmacokinetics in patients undergoing coronary artery bypass grafting.

PURPOSE: The current emphasis on more rapid recovery and earlier tracheal extubation after cardiac surgery requires greater precision in administering opioids to reap their benefits while minimizing the duration of postoperative respiratory depression. Therefore, we aimed to define a pharmacokinetic model that accurately predicts fentanyl concentrations before, during, and after cardiopulmonary bypass (CPB) in patients undergoing coronary artery bypass grafting (CABG). METHODS: Parameters for two-compartment and three-compartment models were estimated by applying population pharmacokinetic modelling to fentanyl concentration vs time data measured in 29 patients undergoing elective, primary CABG. The ability of these models to predict fentanyl concentrations in a second series of ten patients undergoing CABG was then assessed. RESULTS: A simple, three-compartment model had excellent predictive ability, with a median prediction error (PE = ([Fentanyl]meas - [Fentanyl]pred)/[Fentanyl]pred x 100%) of -0.5%, and a median absolute PE (APE = /PE/) of 14.0%. In comparison to the two-compartment models, linear regression of measured:predicted concentration ratios indicated that the three-compartment model was free of systematic and time-related changes in bias (P < 0.05). The parameters of this three-compartment model are: V1 15.0 l, V2 20.0 l, V3 86.1 l, Cl1 1.08 L x min(-1), Cl2 4.90 L x min(-1), and Cl3 2.60 L x min(-1). CONCLUSIONS: Our pharmacokinetic model provides a rational foundation for designing fentanyl dose regimens for patients undergoing CABG. When combined with previously published information regarding intraoperative fentanyl pharmacodynamics, dose regimens that reliably achieve and maintain desired fentanyl concentrations throughout the intraoperative period can be designed to achieve specific therapeutic goals.

Aged↗
PubMed2003

Remifentanil with morphine transitional analgesia shortens neurological recovery compared to fentanyl for supratentorial craniotomy.

PURPOSE: To compare the recovery profiles, efficacy and safety of remifentanil and morphine for transitional analgesia with fentanyl in patients undergoing elective craniotomy for supratentorial mass lesions. METHODS: Ninety-one patients were enrolled in this prospective, randomized, multicentre study. Anesthesia was induced with thiopental and remifentanil (1.0 micro g x kg(-1) bolus and a 1 micro g x kg(-1) x min(-1) infusion) or fentanyl (1 micro g x kg(-1) bolus and a 1.0 micro g x kg(-1) x min(-1) infusion). The opioid infusion continued until the level of anesthesia was deemed appropriate for intubation. Anesthesia was maintained with N(2)O/O(2), isoflurane 0.5 MAC and remifentanil 0.2 micro g x kg(-1) x min(-1) or fentanyl 0.04 micro g x kg(-1) x min(-1). At bone flap replacement, either morphine 0.08 mg x kg(-1) (remifentanil group) or saline (fentanyl group) was given. RESULTS: Systolic blood pressure was greater in those receiving fentanyl during induction (145.6 +/-17.5 mmHg vs 128.8 +/-18.3 mmHg; P = 0.006) and intubation (126.9 +/-17.1 vs 110.9 +/-16.5 mmHg; P < 0.001). Median time to tracheal extubation was similar but less variable in the remifentanil group (remifentanil = 8 min: range = 2-44 min; fentanyl = 8 min: range = 1-732 min). The fentanyl patients required a longer time to achieve the first normal neurological score (fentanyl = 38.0 min; remifentanil = 26.0 min; P = 0.035). Both the anesthesiologists and the recovery room nurses rated remifentanil better with respect to level of consciousness. Analgesics were required earlier in patients receiving remifentanil; median time 0.5 vs 1.08 hr, P < 0.001. CONCLUSIONS: Remifentanil is a suitable alternative to fentanyl in supratentorial craniotomy. Time to preoperative neurological recovery is faster and morphine provides some transitional analgesia without compromising the quality of recovery.

Adult↗
PubMed2000

Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids.

RATIONALE: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. OBJECTIVES: In vivo apparent pA(2) analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. METHODS: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA(2) analyses were used to evaluate receptor mechanisms of stimulus control. RESULTS: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA(2) values of 7. 6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA(2) values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. CONCLUSIONS: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.

Analgesics, Opioid↗
PubMed1994

Effects of the neuroleptanalgesic fentanyl-fluanisone (Hypnorm) on spike-wave discharges in epileptic rats.

Effects of fentanyl-fluanisone (Hypnorm), a combination often used as a neuroleptanalgesic and anaesthetic, were investigated on spike-wave discharges of epileptic WAG/Rij rats. Fentanyl-fluanisone has stimulating effects on the amount of spike-wave discharges, but not in a dose-dependent manner. A low dose of 0.01 mg/kg fentanyl with 0.5 mg/kg fluanisone causes a large increase in epileptic activity. This effect is larger than with a middle dose of 0.1 mg/kg fentanyl and 5 mg/kg fluanisone and much larger than with a high dose of 0.2 mg/kg fentanyl with 10 mg/kg fluanisone. The last two doses cause a prolonged anaesthetic state in rats. The frequency of the spikes in the spike-wave discharges was decreased by the mixture of fentanyl-fluanisone; this decrease was dose-dependent. Administration of fentanyl alone in the same doses as in the combination abolishes spike-wave activity during the anaesthetic phase but causes a moderate increase after this phase. It also causes a lowering in spike frequency, which is of the same order as with fentanyl-fluanisone. The mechanisms of action of fentanyl are not completely clear, but the opposite effects of mu- and kappa-opioid receptors on spike-wave discharges may play a role in this biphasic effect. Fluanisone alone in the same doses as in the mixture induces a large dose-dependent increase in spike-wave activity, with only a small effect on spike frequency. This might be caused by the antagonistic action of this drug at dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The noradrenergic component contributing to spinal fentanyl-induced antinociception is supraspinally mediated.

1. Male Sprague-Dawley rats were fitted with intrathecal (i.t.) and intracerebroventricular (i.c.v.) catheters. Fentanyl was injected either i.t. or i.c.v., and the antinociceptive efficacy of fentanyl was evaluated using the tail-flick analgesiometric assay. 2. Fentanyl dose-dependently elevated tail-flick latency (TFL) following i.c.v. or i.t. administration. The antinociceptive effects of fentanyl were reversed by naltrexone. 3. Experiments were also designed to evaluate the effects of serotonin and alpha-adrenoceptor antagonists on i.t. or i.c.v. fentanyl-induced elevations in TFL. 4. Phentolamine administered i.t. reversed both the spinal and supraspinal antinociceptive effects of fentanyl, whereas i.t. methysergide did not significantly alter the i.t. or i.c.v. effects of the mu agonist. 5. These data suggest that fentanyl-induced antinociception does not rely on local serotonergic neuronal activation. Due to the highly lipophilic nature of fentanyl, it is possible that the noradrenergic component contributing to spinal fentanyl-induced analgesia is supraspinally-mediated.

Adrenergic Antagonists↗
PubMed1992

Transdermal fentanyl: long-term analgesic studies.

Alternative routes of drug delivery have particular relevance for use in chronic pain. When the pain experience is constant or nearly constant, a continuous infusion of drug is an ideal way to achieve effective pain relief. Early experience with the transdermal application of fentanyl in chronic cancer pain suggests that it is a safe, noninvasive, effective method of managing pain. The first experience with the use of transdermal fentanyl in cancer pain was reported by Miser and colleagues in 5 patients. They demonstrated that steady-state blood concentrations of fentanyl were linearly related to the transdermal fentanyl dose. The terminal elimination half-life was approximately 34 hr. Zech and colleagues studied 13 patients with chronic cancer pain. Pain relief was obtained and was correlated with plasma fentanyl levels. The largest experience so far was reported in 39 patients in a multicenter trial conducted by Simmonds and colleagues. The median fentanyl dose was 100 micrograms/hr (range, 25-525 micrograms/hr). The initial dose of fentanyl from morphine conversion (6:1) was adequate in 50% of patients and titrated upward by 72 hr for the remaining 50%. Patients wore the system for a median of 84 days (range, 5-365 days). Median supplementary daily dose of morphine was 105 mg/day (range, 0-720 mg/day). The system was able to be maintained through a variety of concomitant events. This experience demonstrated the safety and clinical effectiveness of transdermal fentanyl. The transdermal therapeutic system (fentanyl) is a promising advance in achieving noninvasive, continuous drug administration for the management of chronic cancer pain.

Administration, Cutaneous↗
PubMedDate not supplied

Continuous administration of fentanyl for postoperative pain: a comparison of the epidural, intravenous, and transdermal routes.

STUDY OBJECTIVES: To evaluate the influence of the route of administration [epidural, intravenous (IV), or transdermal] on onset and quality of analgesia and to evaluate the pharmacokinetics of continuous administration of fentanyl. DESIGN: Randomized, open, single-dose, prospective study. SETTING: Postanesthesia care unit of a university hospital. PATIENTS: 54 ASA physical status I-III patients scheduled for lower major abdominal, gynecologic, or urologic surgery. INTERVENTIONS: Patients were assigned to 1 of 3 comparable groups, to receive, for 72 hours postoperatively, an IV (Group IV) or epidural (Group EP) constant-rate infusion of fentanyl (loading dose 1.5 micrograms/kg, infusion rate 1 micrograms/kg/hr), or a transdermal patch (Group TTS), applied preoperatively, delivering fentanyl 75 micrograms/hr. MEASUREMENTS AND MAIN RESULTS: Pain intensity, vital signs, blood gas status, and plasma fentanyl concentration (Cp) were measured for up to 96 hours postoperatively. Onset of analgesia was delayed in Group TTS. Analgesic efficacy was similar for all 3 routes of administration except during the first 4 hours in Group TTS. Initially, the patients in Groups TTS and IV needed significantly more rescue morphine than those in Group EP. The time course for fentanyl Cp in Groups TTS and IV evolved to similar plateau levels. However, fentanyl Cp continued to rise throughout the study period in Group EP, reaching concentrations that elicited hypoxemia after 48 hours. A significant negative relationship existed between fentanyl Cp and oxygen saturation in this group. All 3 routes of administration showed similar frequencies of side effects (i.e., nausea, vomiting, pruritus, and ileus). CONCLUSIONS: The epidural, transdermal, and IV administration of identical doses of fentanyl given at a constant rate provided almost equivalent degrees of analgesia. But continuing epidural administration produced a steady rise in systemic fentanyl concentrations into the ventilatory-depressant range, affecting the hypoxemic regulation of breathing.

Administration, Cutaneous↗
PubMed2003

Hyperglycolysis is exacerbated after traumatic brain injury with fentanyl vs. isoflurane anesthesia in rats.

Despite common use of narcotics in the clinical management of severe traumatic brain injury (TBI), in experimental models rats treated with fentanyl have exhibited worse functional outcome and more CA1 hippocampal death than rats treated with standard isoflurane anesthesia. We hypothesized that greater post-traumatic excitotoxicity, reflected by cerebral glucose utilization (CMRglu), may account for detrimental effects of fentanyl vs. isoflurane. Rats were anesthetized with either isoflurane (1% by inhalation) or fentanyl (10 mcg/kg iv bolus then 50 mcg/kg/h infusion). 14C-deoxyglucose autoradiography was performed 45 min after controlled cortical impact (CCI) to left parietal cortex (n=4 per anesthetic group) or in uninjured rats after 45 min of anesthesia (n=3 per anesthetic group). Uninjured rats treated with fentanyl vs. isoflurane showed 35-45% higher CMRglu in all brain structures (p<0.05) except CA3. After TBI in rats treated with isoflurane, CMRglu increased significantly only in ipsilateral CA1 and ipsilateral parietal cortex (p<0.05 vs. isoflurane uninjured). Conversely, after TBI in rats treated with fentanyl, CMRglu increased markedly and bilaterally in CA1 and CA3 (p<0.05 vs. fentanyl uninjured), but not ipsilateral parietal cortex. In contralateral CA1, CMRglu was nearly two times greater after TBI in fentanyl vs. isoflurane treated rats (p<0.05). Hyperglycolysis was exacerbated in CA1 and CA3 hippocampus after TBI in rats treated with fentanyl vs. isoflurane anesthesia. This post-traumatic hyperglycolysis suggests greater excitotoxicity and concurs with reports of worse functional outcome and more CA1 hippocampal death after TBI with fentanyl vs. isoflurane anesthesia.

Anesthesia↗
PubMed2006

LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems.

Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. A 78-year-old woman with a history of cancer was found dead in bed. She was lying on her back. The external examination revealed 10 Durogesic transdermal therapeutic systems (100 microg/h fentanyl) on the body. Liquid-liquid extraction and liquid chromatography tandem mass spectrometry with electrospray source in positive ionization mode was applied for the quantitation of fentanyl and its major metabolite norfentanyl in the post-mortem samples. Fentanyl-d5 and norfentanyl-d5 were used as internal standards. Multiple reaction monitoring was used for specific detection. Calibration was performed by addition of standard solutions to drug-free matrix (blood, urine and liver) prior to extraction. The method showed good linearity for fentanyl and norfentanyl over a concentration range of 5-150 microg/L in reconstituted extracts with coefficients of determination equal or greater than 0.998. Percent mean within-day precision and accuracy of 0.9-1.0% and 99.4-101.1% for fentanyl and 2.0-4.5% and 93.1-101.0% for norfentanyl were obtained. Mean extraction recoveries varied between 95.5% and 100.3% for fentanyl and 39.2-57.4% for norfentanyl. The following fentanyl (norfentanyl) concentration in the post-mortem samples were measured; 28.6 microg/L (3.0 microg/L) in right and 28.2 microg/L (3.5 microg/L) in left subclavian blood, 21.3 microg/L (<2 microg/L) in right and 20.9 microg/L (<2 microg/L) in left femoral blood, 37.6 microg/L (4.2 microg/L) in right and 33.9 microg/L (4.4 microg/L) in left ventricular blood, 282.9 microg/L (121.2 microg/L) in urine, 688.2 microg/L in stomach contents, 122.5 microg/L (25.4 microg/L) in bile, 19.5 microg/L (< 2 microg/L) in vitreous humour, 203.0 microg/kg (26.6 microg/kg) in liver and 78.6 microg/kg (46.3 microg/kg) in kidney. We concluded that the woman's death was caused by acute intoxication with fentanyl. The manner of death was presumed to be suicide due to excessive administered Durogesic transdermal therapeutic systems.

Administration, Cutaneous↗
PubMed2005

Recovery and cognitive function after fentanyl or remifentanil administration for carotid endarterectomy.

STUDY OBJECTIVE: To compare recovery and restoration of cognitive function after fentanyl-propofol or remifentanil-propofol anesthesia administration in patients undergoing carotid endarterectomy. DESIGN: Randomized, double-blind, prospective study. SETTING: Department of Anesthesiology, University hospital. PATIENTS: Seventy patients with ASA physical statuses II and III (53 men and 17 women) undergoing elective carotid endarterectomy. INTERVENTIONS: Anesthetic technique and drugs were identical in the 2 groups, with the exception of remifentanil and fentanyl administration. Induction of anesthesia was obtained with a bolus dose of propofol (1-2 mg/kg), maintenance was achieved with a propofol infusion according to hemodynamics and nitrous oxide/oxygen (FIO(2), 0.50). Muscle relaxation was achieved with rocuronium. The remifentanil group received 1 microg/kg of remifentanil as a single dose during the induction of anesthesia and 0.5 microg/kg per minute as an infusion throughout the procedure. The fentanyl group received 2 microg/kg of fentanyl as a single dose during the induction of anesthesia. MEASUREMENTS: Intraoperative hemodynamic adverse events were recorded. All patients were also evaluated with regard to their recovery and the restoration of their cognitive function, recording the immediate recovery times and using the Aldrete score 15 and 60 minutes after surgery and the Hasegawa scale 6 hours after surgery. For evaluation of postoperative pain, the Numeric Pain Scale (0-10) was used. MAIN RESULTS: Patients receiving remifentanil had significantly (P < .05) fewer episodes of intraoperative hypertension and needed nitroglycerine administration less frequently (P < .05) than those receiving fentanyl. Immediate recovery was significantly earlier (P < .05) with remifentanil (eye opening, 5.1 +/- 1.3 [remifentanil] and 7.2 +/- 3.7 [fentanyl] minutes; extubation time, 5.4 +/- 1.9 [remifentanil] and 7.8 +/- 4.1 [fentanyl] minutes). The Hasegawa Dementia Scale scores 6 hours after surgery and Aldrete scores 15 and 60 minutes after surgery did not differ significantly between the 2 groups. Pain levels were also similar for patients taking remifentanil and fentanyl. CONCLUSIONS: Although intraoperative hemodynamics were better preserved and immediate recovery was more rapid with remifentanil, overall postoperative recovery and restoration of cognitive functions as well as postoperative pain intensity seem to be similar for patients receiving remifentanil and for those receiving fentanyl combined with propofol for carotid endarterectomy operations.

Aged↗
PubMed2005

Enhancement of fentanyl antinociception by subeffective doses of nitroparacetamol (NCX-701) in acute nociception and in carrageenan-induced monoarthritis.

We have reported that subanalgesic doses of new generation non-steroidal anti-inflammatory drugs (NSAIDs) enhance the antinociceptive activity of the mu-opiate fentanyl, and the duration of its effect, in acute nociception. Since this therapy is intended for situations of hyperalgesia, we have compared the antinociceptive activity of fentanyl in the absence and in the presence of subeffective doses of NCX-701 (nitroparacetamol) in normal animals and in animals with carrageenan-induced monoarthritis. Subanalgesic dose of NCX-701 did not modify any of the nociceptive responses on its own but reduced the ID50 of fentanyl more than two-fold in both the normal and sensitized states. When administered alone, full recovery from fentanyl was always observed within 15 to 20 minutes, however, full recovery was not observed in the presence of NCX-701. Naloxone was unable to reverse the effect, suggesting a possible reduction of other opiate-mediated secondary effects. We therefore studied the possibility that combining administration of fentanyl and nitroparacetamol (NCX-701) would reduce the development of acute tolerance to fentanyl in behavioral experiments. Acute tolerance to fentanyl in behavioral nociceptive reflexes was developed within 72 h after the constant infusion of the drug, whereas in animals treated with small doses of NCX-701 tolerance was not observed. In summary, our results, both in normal animals and in animals with hyperalgesia, show that fentanyl antinociception can be strongly potentiated with subanalgesic doses of the NSAID NCX-701 and that the development of acute tolerance to fentanyl in normal animals is prevented by this combination of drugs.

Acetaminophen↗
PubMed1991

Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion.

Tolerance to opioid-induced sedation has been reported in neonates sedated with fentanyl by continuous infusion while undergoing extracorporeal membrane oxygenation. We undertook a prospective analysis of eight newborn infants sedated with fentanyl during extracorporeal membrane oxygenation therapy for respiratory failure. We recorded daily mean fentanyl infusion rate, measured serial plasma fentanyl concentrations, and documented the occurrence of spontaneous motor activity or respiratory effort. Mean fentanyl infusion rate increased steadily during the period of infusion from a mean of 9.2 +/- 1.9 (SEM) micrograms/kg per hour on day 1 to a mean of 21.9 +/- 4.5 micrograms/kg per hour by day 6. Mean plasma fentanyl concentrations increased steadily during the period of fentanyl infusion from 3.1 +/- 1.1 (SEM) ng/ml on day 1 to 13.9 +/- 3.2 ng/ml on day 6. All infants exhibited movement in response to gentle tactile stimulation throughout the period of infusion, and seven of eight infants manifested spontaneous movement of the extremities and eye opening. Our results indicate that when fentanyl is used for sedation in neonates, the plasma concentrations required for satisfactory sedation steadily escalate, possibly indicating the rapid development of tolerance to the sedating effects of fentanyl.

Extracorporeal Membrane Oxygenation↗