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PubMed1999

Uptake of fentanyl in pulmonary endothelium.

Fentanyl is a basic amine shown to have extensive first-pass pulmonary uptake. To evaluate the role of the pulmonary endothelium in this uptake process, the simultaneous pharmacokinetics of [3H]fentanyl and two marker drugs, blue dextran, and [14C]antipyrine, were evaluated in a flow-through system of pulmonary endothelial cells. Fentanyl equilibrium kinetics were determined in a static culture system. The flow-through system consisted of monolayers of bovine pulmonary artery endothelial cells cultured on solid microcarrier beads placed in a chromatography column and perfused at 1.0 ml/min (37 degreesC). Fentanyl and the markers were injected into the perfusate at the top of the column and samples were collected from the eluate at 9-s intervals for 10 min. The pharmacokinetic analyses were based on determinations of mean transit time and flow. Fentanyl was partitioned into the pulmonary endothelial cells 60 times more than the tissue water space marker antipyrine. In the static system, monolayers of bovine pulmonary artery endothelial cells were cultured in 3.8-cm2 wells to which were added 0 to 946 micromol (0-500 microgram/ml) of unlabeled fentanyl citrate and 0.14 micromol of [3H]fentanyl. After a 10-min incubation, solubilized cells were assayed for [3H]fentanyl. Pulmonary endothelial cells contained a higher relative fentanyl concentration at lower fentanyl supernatant concentrations than would be expected if uptake occurred by diffusion alone. These observations can be explained with a model of fentanyl uptake that includes both passive diffusion and saturable active uptake. This suggests that the extensive first-pass pulmonary uptake of fentanyl observed in vivo is due largely to vascular endothelial drug uptake by both a passive and a saturable active uptake process.

Animals↗

PubMed1991

Evaluation of receptor mechanism mediating fentanyl analgesia and toxicity.

In the present study the antagonism of fentanyl pharmacodynamics was studied in the mouse and the receptor populations mediating the analgesic and lethal effects of fentanyl were examined. Both 1 and 8 days following implantation (s.c.) of a 15 mg naltrexone pellet there was a significant shift to the right of the fentanyl dose-response curves for analgesia and lethality. The analgesia dose-response curves were shifted significantly more (80- to 264-fold) than the lethality curves (13- to 16-fold) in the presence of naltrexone. In addition, acute naloxone (0.1 mg/kg s.c.), antagonized fentanyl analgesia more than lethality. Consequently, the relative safety ratio of fentanyl (LD50/ED50) was decreased in the presence of opioid antagonists. Pretreatment with naloxonazine (35 mg/kg s.c.) 24 h prior to testing effectively inhibited fentanyl-induced analgesia, but not fentanyl-induced lethality. However, pretreatment with beta-funaltrexamine (beta-FNA) (20 mg/kg, s.c.) 24 h prior to testing inhibited both fentanyl-induced analgesia and lethality. Implantation (s.c.) of a 75 mg morphine pellet for 72 h resulted in cross-tolerance to both fentanyl analgesia and lethality. However, the degree of the cross-tolerance was 1.8-fold for analgesia and 4.5-fold for lethality. Displacement studies of [3H]naltrexone by fentanyl in mouse brain homogenate indicated two populations of binding sites. Taken together, the pharmacodynamic studies and the binding studies suggest that fentanyl exerts its analgesic and lethal effects through different receptor populations.

Analgesics↗

PubMed1996

Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain.

Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrome beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.

Administration, Cutaneous↗

PubMed2004

Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses.

It is known that morphine has a negative impact on the immune responses. The potent opioids fentanyl and buprenorphine have recently become available as transdermal preparation for the treatment of chronic pain. We analyze the effect of fentanyl and buprenorphine on splenic cellular immune responses in the mouse. The parameters evaluated were lymphoproliferation, natural killer cell activity and interleukin-2 and interferon-gamma production. Drugs were administered acutely at the equianalgesic doses of 0.25 mg/kg for fentanyl and 5 mg/kg for buprenorphine, or delivered continuously with osmotic pumps for 24 h, 3 and 7 days at the rate of 7.5 microg/h per mouse (fentanyl) and 12.5 microg/h per mouse (buprenorphine). After acute administration, a significant decrease of lymphoproliferation is observed in fentanyl-treated animals only. After 24 h of fentanyl administration all the parameters were significantly reduced. After 3 days of fentanyl infusion NK activity had returned to normal values, while all the other parameters were still significantly reduced. In 7 day fentanyl-treated animals immunological tolerance had developed, since no differences with controls were present. In contrast no immune alterations were ever present in buprenorphine-treated animals. No tolerance to the antinociceptive effect of drugs had yet developed. After 1 week of infusion with fentanyl and buprenorphine, new pumps were implanted releasing double amounts of drugs. Neither fentanyl nor buprenorphine-treated animals showed altered immune responses at any time considered. These results indicate that fentanyl and buprenorphine exert different immune effects. Opioid-induced immunosuppression is less relevant in chronic administration than in acute or short-time administration.

Administration, Cutaneous↗

PubMed1999

Analgesic doses of fentanyl impair oxidative metabolism of neonatal hepatocytes.

BACKGROUND/PURPOSE: Studies in human surgical neonates have shown that intraoperative fentanyl analgesia results in greater fall in perioperative body core temperature compared with morphine analgesia. The aim of the study was to compare in a neonatal animal model the biochemical effect of fentanyl and morphine on hepatocyte oxidative metabolism. METHODS: Hepatocytes were isolated from suckling rats and the oxygen consumption from palmitate was measured polarographically. In experiment A, fentanyl and morphine within the respective analgesic serum ranges were added to hepatocytes to assess the effect on oxygen consumption. In experiment B, fentanyl was added to hepatocytes in the presence of inhibitors of mitochondrial respiration to investigate its site of action. In experiment C, hepatocytes were incubated with either fentanyl or morphine, centrifuged, and then examined ultrastructurally by electron microscopy. RESULTS: In experiment A, fentanyl inhibited oxygen consumption by up to 40% (P < .01). Morphine inhibited oxygen consumption to a maximum of 25% (P < .01). In experiment B, in the presence of oligomycin, fentanyl increased the inhibition of oxygen consumption; however, in the presence of myxothiazol, no further inhibition by fentanyl occurred. In experiment C, mild ultrastructural alterations to hepatocytes were observed after incubation with fentanyl but not with morphine. CONCLUSIONS: This study demonstrates that therapeutic doses of two commonly used analgesic drugs impair neonatal hepatic oxidative metabolism. Fentanyl exerts a greater effect than morphine by diminishing liver oxygen consumption by up to 40%. The inhibitory effect of fentanyl occurs directly on the mitochondrial respiratory chain, either on substrate oxidation or on the thermogenic proton leak. The findings of this study are relevant to the perioperative management of surgical neonates.

Analgesics, Opioid↗

PubMed1998

Effect of current density on pharmacokinetics following continuous or intermittent input from a fentanyl electrotransport system.

The pharmacokinetics of fentanyl were determined in two open-label crossover studies following 24-h periods of delivery by an electrotransport transdermal system (E-TRANS [fentanyl] system) in young healthy male volunteers. A direct current was applied continuously in study 1 (at 50, 100, and 200 microA; surface area = 5 cm2; n = 8), but in study 2 it was limited to the first 20 min of each hour (at 150, 200, and 250 microA; surface area = 2 cm2; n = 12). The opioid effects of fentanyl were blocked with naltrexone administered every 12 h. With increasing electrical current, the increase in serum fentanyl concentration, amount absorbed, and AUC values were proportional in study 2 but not in study 1. It is hypothesized that the lack of proportionality in study 1 is due to lower current density (microA/cm2) in this study. It appears that for fentanyl, the current density should be about 75 microA/cm2 or greater for a linear relation between current and amount absorbed as seen in study 2. Compared with intravenously infused fentanyl, the serum concentrations resulting from E-TRANS (fentanyl) system application revealed a slightly dampened rate of increase (stratum-corneum barrier effect) and decrease in serum concentrations, and a similar intersubject variability in fentanyl AUC values. Fentanyl pharmacokinetics with either E-TRANS (fentanyl) or intravenous infusion were time-invariant over a 24-h application period, with similar mean half-life values (about 15-18 h). E-TRANS (fentanyl) administration (either continuous or intermittent input) was safe and well tolerated. Adverse effects were mild to moderate; they consisted mainly of local erythema and pruritus (which resolved in most patients within 24 h after system removal) and occasional opioid effects.

Adult↗

PubMed2005

Effectiveness of eutectic mixture of local anesthetic cream and occlusive dressing with low dosage of fentanyl for pain control during shockwave lithotripsy.

BACKGROUND AND PURPOSE: To investigate the effect and usefulness of Eutectic Mixture of Local Anesthetic (EMLA) applied with an occlusive dressing and used simultaneously with a low dose of fentanyl during shockwave lithotripsy (SWL). PATIENTS AND METHODS: One hundred sixty patients with kidney stones, aged between 19 and 68 years, were randomly divided into seven groups that were treated as follows: group 1: fentanyl 1 microg/kg by intravenous infusion (IV); group 2: IV fentanyl 0.25 microg/kg; group 3: occlusive dressing and IV fentanyl 0.25 microg/kg; group 4: placebo cream and IV fentanyl 0.25 microg/kg; group 5: EMLA cream and IV fentanyl 0.25 microg/kg; group 6: placebo cream and IV fentanyl 0.25 microg/kg with an occlusive dressing; and group 7: EMLA cream and IV fentanyl 0.25 microg/kg with an occlusive dressing. The mean arterial pressure (MAP), heart rate, ventilatory rate, and oxygen saturation (SpO(2)) were recorded on all patients. A visual analog scale 0-100 mm (VAS) was used for the evaluation of pain. The skin integrity was inspected to detect any lesions after SWL. RESULTS: The SpO(2) in group 1 was lower statistically than in the other groups. The VAS score in group 7 was clearly lower than in the others in the first, tenth, and twentieth minutes and at the end of SWL. In groups 6 and 7, additional fentanyl doses were lower than in the other groups, but only in group 7 was the total fentanyl dosage low. Skin lesions were not seen only in groups 3, 6, and 7. CONCLUSION: Use of EMLA and an occlusive dressing with low doses of fentanyl during SWL provides appropriate analgesia with minimal morbidity.

Administration, Topical↗

PubMed2003

Fentanyl use, misuse, and abuse: a summary of 23 postmortem cases.

We report the rapidly increasing finding of fentanyl in medical examiner cases in southwestern Virginia. During the past 3 years, fentanyl cases have increased from 3 in 2000 to 12 in 2002. The first medical examiner case of 2003 was a fentanyl poisoning. Nineteen of 23 cases were attributed to fentanyl misuse or abuse of fentanyl transdermal patches. Routes of administration were transdermal, transmucosal/oral, intravenous, and combinations of routes of administration. Fentanyl was identified using a solid-phase extraction basic drug screen in blood and/or urine followed by full scan gas chromatography-mass spectrometry (GC-MS) in the electron impact ionization mode. Fentanyl quantitation was performed using selected ion monitoring GC-MS. The method was linear from 1 to 50 microg/L with a limit of quantitation of 1 microg/L. Fentanyl blood concentrations ranged from 2 to 48 microg/L with a mean concentration of 18 microg/L. The age range of the decedents was 16-53 with an average age of 37. Southwestern Virginia is currently a "hot spot" for misuse and abuse of oxycodone and methadone. The rapid rise in the number of fentanyl cases over the past three years, the increasing availability of fentanyl patches, and the large number of case histories indicating misuse or abuse suggest that fentanyl is rapidly becoming an additional desired opioid similar to oxycodone and methadone.

Adolescent↗

PubMed1998

The effect of fentanyl on electrophysiologic recovery of CA 1 pyramidal cells from anoxia in the rat hippocampal slice.

UNLABELLED: Fentanyl is widely used in conditions in which the brain is at risk of ischemic or anoxic injury. We evaluated the effect of fentanyl on anoxic injury to CA 1 pyramidal cells in the rat hippocampus. These neurons are extremely sensitive to anoxic injury and are densely populated with opioid receptors. We prepared hippocampal slices from adult Sprague-Dawley rats and evoked a postsynaptic population spike in the CA 1 pyramidal cell region by stimulating the Schaffer collateral pathway. The amplitude of this response was used to evaluate the effect of fentanyl on anoxic injury. Pretreatment with fentanyl (50 or 500 ng/mL) did not alter the amplitude of the CA 1 population spike before anoxia, nor did it alter the recovery of this response after 5,6, or 7 min of anoxia. After 5 min of anoxia, the population spike recovered to 76% of its preanoxic level in the control group and to 87% in the group treated with 500 ng/mL of fentanyl. After 6 min of anoxia, recovery was 45% in the control group, 57% in the group treated with 50 ng/mL of fentanyl, and 58% in the group treated with 500 ng/mL of fentanyl. After 7 min of anoxia, recovery was 5% in the control group and 4% in the group treated with 50 ng/mL of fentanyl. We conclude that fentanyl does not affect the recovery of the electrophysiological response in rat hippocampal neurons subjected to an anoxic insult. IMPLICATIONS: Because fentanyl is used in large doses during surgical procedures in which the brain is at increased risk of ischemic or anoxic injury, it is important to determine its effect on such injury. Using the rat hippocampal slice model, we found fentanyl to be neither neurotoxic nor protective against anoxic injury to neurons when used in concentrations comparable to those produced in clinical practice.

Analgesics, Opioid↗

PubMed1979

Pharmacokinetics of 3H-fentanyl in the dog anesthetized with enflurane.

Fentanyl is often used as an anesthetic supplement for short procedures because it has a rapid onset and brief duration of action. However, persistence of ventilatory depression several hours following the last dose has been seen. The authors studied the pharmacokinetics of fentanyl in the dog to find an explanation for the occasionally prolonged duration of action. 3H-fentanyl citrate, 10 or 100 microgram/kg, was injected intravenously in dogs anesthetized with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl and for total 3H radioactivity. Kinetic indices were derived by nonlinear least-squares analysis of log concentration (ng/ml) vs. time relationships. Initially, the elimination of fentanyl from plasma was very rapid, and 98 per cent of the amount administered was removed from plasma in the first 5 min after an intravenous injection. However, the terminal elimination phase was prolonged (t1/2 = 199 +/- 17 min). The apparent volume of distribution was large (9.81/kg) and independent of dose. Repetitive doses produced an accumulation of fentanyl. 3H-labelled metabolites of fentanyl were present in the earliest samples of plasma, and accounted for the major portion of the total 3H radioactivity in both plasma and urine. Urine collected for six hours contained 36 per cent of the total 3H radioactivity administered, but only 4 per cent of fentanyl administered was excreted as unchanged fentanyl. The authors conclude that most of a single dose of fentanyl is rapidly eliminated from the body by biotransformation and leads to accumulation of the drug when administered in very large or repeated doses. Under these circumstances the slow release of drug from tissues results in persistent plasma levels of fentanyl and a prolonged duration of action.

Anesthesia, Inhalation↗

PubMed1983

Dose-response suppression of noxiously evoked activity of WDR neurons by spinally administered fentanyl.

The present study examined the influence of spinally administered fentanyl on the spontaneous and noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of decerebrate, spinal cord-transected cats. This work was performed in order to evaluate the dose-response relationship, time course, and naloxone reversibility of fentanyl suppression of neurons that are involved with the transmission of information about pain. Extracellular single neuron recordings were obtained from 18 WDR neurons in the lumbar enlargement. These neurons were activated by a radiant heat stimulus on the footpads of the hindpaw. Fentanyl (10, 15, 25 micrograms in 0.5 ml of physiologic saline) was placed on the spinal cord following control studies of each neuron and the effect was observed. In 12 cats, 31 min after fentanyl administration, naloxone (0.1 mg) was administered intravenously, and its effect on the fentanyl suppression was determined. All three doses of fentanyl suppressed both the spontaneous and evoked activity of all the neurons studied. Thirty minutes after fentanyl the mean evoked activity was reduced to 47, 23, and 11% of control values by 10, 15, and 25 micrograms, respectively. The spontaneous activity was reduced to similar levels. Intravenous naloxone (0.1 mg) caused a significant reversal of the fentanyl suppression. The results of the present study indicate that fentanyl causes a naloxone-reversible, dose-dependent suppression of noxiously evoked WDR neuron activity. Such results support the concept that fentanyl is acting through a specific drug-receptor interaction. The onset of neuronal suppression occurred more rapidly, and the duration of the suppression was longer following fentanyl than that seen following spinal morphine. The onset and duration of this suppression correlates well with human clinical data, providing further evidence that alterations of WDR neuronal activity may be important in the production of spinal opioid analgesia.

Action Potentials↗

PubMed1985

Computer-assisted continuous infusions of fentanyl during cardiac anesthesia: comparison with a manual method.

The design and implementation of a computer-assisted continuous infusion (CACI) system to rapidly attain and maintain a constant plasma fentanyl concentration (PFC), as well as a CACI system that allowed the anesthesiologist to change the plasma level of fentanyl during cardiac anesthesia, were developed. In 30 patients (three groups of 10 patients each) these two automated methods of fentanyl infusion were compared with a manual fentanyl administration method. There was excellent agreement in the measured/predicted PFC ratios with the CACI stable fentanyl level system (ratio = 0.99, n = 91) and in the CACI variable fentanyl level system (ratio = 1.08, n = 79). The stable fentanyl level group of patients received significantly more (P less than 0.05) fentanyl than did the other groups. The CACI variable fentanyl level group of patients had greater hemodynamic stability, required significantly (P less than 0.05) fewer adjuvant drug interventions and experienced significantly (P less than 0.05) fewer hypotensive and hypertensive episodes than the manual, bolus fentanyl (control) group. These data show that a computer-assisted automated infusion of fentanyl is safe and as good as manual methods. CACI has greater potential as a new method of intravenous anesthesia administration.

Adult↗

PubMed1990

A randomized double-blind comparison of epidural versus intravenous fentanyl infusion for analgesia after cesarean section.

The authors conducted a randomized double-blind controlled study comparing groups of patients receiving iv or epidural fentanyl infusions to determine whether, at comparable levels of analgesia, 1) the severity of side effects was different; and 2) plasma fentanyl concentrations differed between the two groups. Twenty-eight ASA physical status 2 women scheduled to undergo elective cesarean section were randomized into two groups to either receive fentanyl intravenously and saline epidurally or fentanyl epidurally and saline intravenously. After delivery of the infants under epidural anesthesia, each patient received a bolus of fentanyl 1.5 microgram/kg either intravenously or epidurally, and a fentanyl infusion was begun via the same route. Concurrently, a saline bolus and infusion were given via the alternate route. The rates of the fentanyl and saline infusions were adjusted until each patient was comfortable. Patients rated their pain, nausea, and pruritus on visual analogue scales. Sedation was evaluated by an observer. Respiratory depression was evaluated by end-tidal PCO2. Data were analyzed by unpaired two-tail t tests. Plasma fentanyl concentrations were measured at 12 and 24 h. Three patients in the iv group were dropped from the study because of inadequate pain relief. For the remaining 25 patients, similar infusion rates of fentanyl were required to produce similar levels of analgesia at 12 and 24 h. The severity of nausea, pruritus and sedation, and end-tidal PCO2 were similar for both groups. The plasma concentrations of fentanyl were significantly greater in those who received iv fentanyl at 12 h but not at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Isoflurane minimum alveolar concentration reduction by fentanyl.

BACKGROUND: Isoflurane is commonly combined with fentanyl during anesthesia. Because of hysteresis between plasma and effect site, bolus administration of fentanyl does not accurately describe the interaction between these drugs. The purpose of this study was to determine the MAC reduction of isoflurane by fentanyl when both drugs had reached steady biophase concentrations. METHODS: Seventy-seven patients were randomly allocated to receive either no fentanyl or fentanyl at several predetermined plasma concentrations. Fentanyl was administered using a computer-assisted continuous infusion device. Patients were also randomly allocated to receive a predetermined steady state end-tidal concentration of isoflurane. Blood samples for fentanyl concentration were taken at 10 min after initiation of the infusion and before and immediately after skin incision. A minimum of 20 min was allowed between the start of the fentanyl infusion and skin incision. The reduction in the MAC of isoflurane by the measured fentanyl concentration was calculated using a maximum likelihood solution to a logistic regression model. RESULTS: There was an initial steep reduction in the MAC of isoflurane by fentanyl, with 3 ng/ml resulting in a 63% MAC reduction. A ceiling effect was observed with 10 ng/ml providing only a further 19% reduction in MAC. A 50% decrease in MAC was produced by a fentanyl concentration of 1.67 ng/ml. CONCLUSIONS: Defining the MAC reduction of isoflurane by all the opioids allows their more rational administration with inhalational anesthetics and provides a comparison of their relative anesthetic potencies.

Adult↗

PubMed1993

Epidural versus intravenous fentanyl for reducing hormonal, metabolic, and physiologic responses after thoracotomy.

BACKGROUND: Previous attempts to prevent all the unwanted postoperative responses to major surgery with an epidural hydrophilic opioid, morphine, have not succeeded. The authors' hypothesis was that the lipophilic opioid fentanyl, infused epidurally close to the spinal-cord opioid receptors corresponding to the dermatome of the surgical incision, gives equal pain relief but attenuates postoperative hormonal and metabolic responses more effectively than does systemic fentanyl. METHODS: Forty patients were randomly assigned to receive either fentanyl epidurally and saline intravenously, or fentanyl intravenously and saline epidurally, in a double-blind fashion for the first 20 h after thoracotomy. For each patient, the fentanyl infusion was titrated to the rate required for pain relief (pain score < 3, maximum 10). Postoperative changes in blood pressure, heart rate, rectal temperature, and blood concentrations of adrenocorticotrophic hormone, beta-endorphin immunoreactivity, cortisol, growth hormone, prolactin, glucose, and leukocytes were assessed. RESULTS: Patients reported similar median pain scores, but the epidural group required about 40% less fentanyl than the intravenous group. Four hours postoperatively, the beta-endorphin immunoreactivity concentrations were less in the epidural than in the intravenous group. Plasma cortisol increased in a similar manner in both groups within 4 h of surgery, but the increase persisted to the next morning only in patients receiving intravenous fentanyl. Adrenocorticotropin, growth hormone, and prolactin responses were similar in both groups. The postoperative hyperglycemic response, leukocytosis, and blood pressure were greater, and mean rectal temperature was lower, in the intravenous than in the epidural fentanyl group. CONCLUSIONS: The authors' results indicate that some aspects of the hormonal response to surgery are blocked more completely with epidural than with intravenous fentanyl. Adequate pain relief with epidural fentanyl, with a smaller mean dose, led to a smaller increase of some hormonal, metabolic, and physiologic responses after thoracotomy than in association with the adequate pain relief provided by intravenous fentanyl.

Adrenocorticotropic Hormone↗

PubMed1995

Effect of fentanyl on the minimum alveolar concentration of isoflurane in swine.

BACKGROUND: Fentanyl is used in anesthetic protocols for swine, but there are no reports on its potency in this species. This study measured the extent to which fentanyl reduces the minimum alveolar concentration of isoflurane (MACISO) in swine. METHODS: Sixteen swine were randomly assigned to four groups. For each group, baseline MACISO was determined, and three groups received two of three fentanyl infusions as follows: 50 micrograms.kg-1.h-1 intravenously followed by 100 micrograms.kg-1.h-1, 50 micrograms.kg-1.h-1 followed by 200 micrograms.kg-1.h-1, or 100 micrograms.kg-1.h-1 followed by 200 micrograms.kg-1.h-1 (n = 8 for each dosage). A loading dose of fentanyl preceded each infusion. Each infusion was maintained for 60 min before initiating minimum alveolar concentration determination. The infusions were maintained throughout the period of minimum alveolar concentration determination. Plasma fentanyl samples were obtained after 30 min of each infusion, and plasma fentanyl and hemodynamic parameters were obtained immediately before stimulating swine for the final isoflurane concentration used in determining minimum alveolar concentration. A fourth group, control animals, received saline infusions. After each infusion, the MACISO was redetermined. Minimum alveolar concentration was determined using incremental changes in isoflurane concentrations until gross purposeful movement resulted when using a hemostat stimulus applied for 1 min to a rear dewclaw. RESULTS: MACISO for controls was 2.19 +/- 0.17% (mean +/- SEM) and changed minimally over time (-0.13 +/- 4.77%). MACISO decreased significantly (P < or = 0.01) 24.5 +/- 3.2%, 29.9 +/- 4.8%, and 45.9 +/- 5.5% with fentanyl dosages of 50, 100, and 200 micrograms.kg-1.h-1, respectively. Corresponding plasma fentanyl concentrations were 14 +/- 1 ng/ml, 26 +/- 3 ng/ml, and 59 +/- 5 ng/ml, respectively. A ceiling effect on reduction of MACISO was not observed. Changes over time or between groups were not observed for arterial blood gas tensions, blood pressure, heart and respiratory rate, or body temperature. CONCLUSIONS: These fentanyl dosages are larger than those commonly used in humans and other species. Anesthetic protocols using fentanyl for swine should be designed with the knowledge that a fentanyl infusion of 200 micrograms.kg-1.h-1 contributes approximately a 50% MACISO equivalent.

Animals↗

PubMed1998

The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision.

BACKGROUND: Fentanyl produces a minimal reduction in the minimum alveolar concentration of sevoflurane to prevent response to a verbal command in 50% of patients (MAC[awake]) at low but analgesic plasma concentrations. The reduction in MAC(awake), however, is still unknown at higher fentanyl concentrations. The reduction in the MAC of sevoflurane by fentanyl has not been described accurately. The purpose of this study was to determine the MAC(awake) and MAC reduction of sevoflurane by fentanyl. METHODS: Ninety-two patients were randomly allocated to seven fentanyl concentration groups (target plasma concentrations of 0, 1, 1.5, 3, 6, 10, and 14 ng/ml). Responses to verbal command were observed for MAC(awake) assessment at predetermined sevoflurane concentrations. Thereafter, in patients whose target fentanyl concentration was 0 to 10 ng/ml, responses to skin incision were observed for MAC assessment at new steady-state sevoflurane concentrations. The reduction in the MAC(awake) and MAC of sevoflurane by the measured fentanyl concentration was calculated. RESULTS: There was an initial steep reduction in the MAC of sevoflurane by fentanyl, with 3 ng/ml resulting in a 59% MAC reduction. A ceiling effect was observed, with 10 ng/ml providing only a further 17% reduction in MAC. The initial reduction in MAC(awake) was not as steep as that in MAC. Fentanyl reduced MAC(awake) by approximately 24% at a plasma concentration of 3 ng/ml. Although the reduction curve of MAC(awake) was parabolic, no manifest ceiling effect was observed at concentrations administered in the present study. CONCLUSIONS: The reduction in sevoflurane requirements for loss of consciousness and skin incision by fentanyl was determined. Fentanyl reduced both requirements, but the mode of the reduction was not comparable.

Adult↗

PubMed1999

Bupivacaine augments intrathecal fentanyl for labor analgesia.

BACKGROUND: fentanyl has been shown to be an effective analgesic for labor; this study investigated the analgesic effect of low-dose bpivacaine added to intrathecal fentanyl for labor analgesia METHODS: Ninety parturients in active labor who requested regional analgesia were randomized to receive an intrathecal injection of either fentanyl, 25 microg; bupivacaine, 1.25 mg, with fentanyl, 25 microg; or bupivacaine, 2.5 mg, with fentanyl, 25 microg, as part of a combined spinal-epidural technique. Visual analog pain scores were recorded before and at intervals after injection until the patient requested further analgesia. Maternal blood pressure and fetal heart rate were recorded before and at intervals after injection. Lower-extremity muscle strength was tested before and 30 min after injection; anesthetic level to cold sensation and the presence and severity of pruritus were recorded. RESULTS: Duration of analgesia was longer in the group receiving bupivacaine, 2.5 mg, and fentanyl, 25 microg, than the group receiving plain fentanyl (108 vs. 92 min; P < 0.05). Onset of analgesia was faster in both groups receiving bupivacaine compared with plain fentanyl (P < 0.05). No differences in muscle strength after injection were found in any group, although anesthetic levels to cold were documented in all patients in the bupivacaine groups, and 21 of 30 in the plain fentanyl group. Baseline fetal heart rates did not change after injection in any group, and maternal blood pressure was unchanged. CONCLUSIONS: The addition of 2.5 mg isobaric bupivacaine to 25 microg fentanyl for intrathecal labor analgesia modestly increases duration and speeds onset of analgesia compared with plain intrathecal fentanyl.

Adult↗