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PubMed1998

Fentanyl infusion preserves cerebral blood flow during decreased arterial blood pressure after traumatic brain injury in cats.

Hypotension after traumatic brain injury (TBI) has been associated with significant reductions in cerebral blood flow (CBF) in experimental animals. In humans, posttraumatic hypotension is associated with significantly worsened outcome, possibly because of cerebral hypoperfusion. The existence of opioid receptor-mediated cerebrovascular dilatory effects in humans has been theorized. We studied the systemic and cerebral vascular effects of fentanyl after fluid-percussion injury (FPI) TBI in isoflurane-anesthetized cats. In an approved protocol, 17 fasted cats were anesthetized, mechanically ventilated with 1-1.5% isoflurane in 70% N2O/30% O2, and prepared for FPI. Electroencephalogram (EEG) and intracranial pressure (ICP) were monitored. Cerebral blood flow and cardiac output were measured with radiolabelled microspheres. Animals received moderate FPI (2.2 atm) followed by 15 min of stabilization. Cats were then randomized to control (isoflurane anesthesia plus saline placebo) or fentanyl (isoflurane anesthesia plus fentanyl 50 microg x kg(-1) h(-1)) groups. CBF, EEG, and ICP were recorded at baseline (Baseline), 15 min post-FPI (post-FPI), and at 15, 75, and 135 min after beginning fentanyl or saline placebo infusions (INF 15, INF 75, INF 135). EEG, ICP, PaCO2, PaO2, pH, and temperature were similar between groups. Mean arterial pressure was significantly lower than in the control group after fentanyl administration, while total CBF was not significantly different from control values. In a previous study, decreasing MAP to 80 mm Hg after TBI in isoflurane-anesthetized cats resulted in a 30% decrease in CBF. In this study, fentanyl after TBI significantly decreased MAP but not CBF. Fentanyl administration was associated with preservation of CBF despite hypotension. Further research is necessary to evaluate the effects of fentanyl on cerebral autoregulation after TBI.

Animals↗
PubMed2000

Isoflurane improves long-term neurologic outcome versus fentanyl after traumatic brain injury in rats.

Despite routine use of fentanyl in patients after traumatic brain injury (TBI), it is unclear if it is the optimal sedative/analgesic agent. Isoflurane is commonly used in experimental TBI. We hypothesized that isoflurane would be neuroprotective versus fentanyl after TBI. Rats underwent controlled cortical impact (CCI) and received 4 h of N2O/O2 (2:1) and either fentanyl (10 microg/kg i.v. bolus, 50 microg/kg/h infusion) or isoflurane (1% by inhalation) with controlled ventilation. Shams underwent identical preparation, without CCI. Functional outcome (beam balance, beam walking, Morris water maze [MWM] tasks) was assessed over 20 days. Lesion volume and hippocampal neuron survival were quantified on day 21. Additional rats underwent identical CCI and anesthesia with intracranial pressure (ICP) monitoring, and brain water content was assessed. Motor and MWM performances were better in injured rats treated with isoflurane versus fentanyl (p < 0.05). CA1 hippocampal damage was attenuated in isoflurane-treated rats (p < 0.05). Fentanyl-treated rats had higher mean arterial blood pressure after injury (p < 0.05); however, ICP and brain water were similar between groups. Isoflurane improved functional outcome and attenuated damage to CA1 versus fentanyl in rats subjected to CCI. Isoflurane may be neuroprotective by augmenting cerebral blood flow and/or reducing excitotoxicity, not by reducing ICP or brain water content. Alternatively, fentanyl may be detrimental. Isoflurane may mask beneficial effects of novel agents tested in TBI models. Additionally, fentanyl may not be optimal early after TBI in humans.

Analgesics, Opioid↗
PubMed1991

Comparison of sufentanil-nitrous oxide anaesthesia with fentanyl-nitrous oxide anaesthesia in geriatric patients undergoing major abdominal surgery.

We have measured haemodynamic changes and plasma concentrations of catecholamines during sufentanil-nitrous oxide and fentanyl-nitrous oxide anaesthesia in a controlled, randomized, double-blind study of 20 geriatric patients (age 65-86 yr) undergoing major abdominal surgery. Fentanyl 7 micrograms kg-1 followed by infusion of 3 micrograms kg-1 h-1 was compared with sufentanil 1 micrograms kg-1 followed by 0.4 micrograms kg-1 h-1. The opioid was supplemented with 60-67% nitrous oxide in oxygen. Haemodynamic changes, plasma concentrations of catecholamines (by high pressure liquid chromatography) and opioids (by radioimmunoassay), and myocardial lactate extraction were measured in the awake state, and at defined times during anaesthesia and surgery. Haemodynamic state was stable during induction and tracheal intubation in both groups, while during stressful operative periods there were increases in mean arterial pressure (17% in the fentanyl group; 11% in the sufentanil group), heart rate (fentanyl 20%, sufentanil 14%) and plasma concentrations of catecholamines (adrenaline: fentanyl 316%, sufentanil 86%; noradrenaline: fentanyl 78%, sufentanil 186%) in both groups. Sufentanil was similar to fentanyl in attenuating the haemodynamic and hormonal responses to surgical stimulation. In two patients in the fentanyl group and three in the sufentanil group, myocardial lactate production was observed temporarily, indicating myocardial ischaemia caused by surgical stress.

Abdomen↗
PubMed1994

Effect of fentanyl on awakening concentration of sevoflurane.

This study was designed to determine if fentanyl altered MAC-awake (the end-tidal concentration of sevoflurane associated with eye opening to verbal command) in 30 healthy, ASA I patients. During anaesthesia, no other anaesthetics or drugs were given with the exception of sevoflurane. After surgery, end-tidal anaesthetic concentration was maintained constant for at least 15 min. If patients failed to respond to command, the end-tidal concentration was decreased and again maintained constant for 15 min. The anaesthetic concentration midway between the value permitting the response and that just preventing the response was recorded as MAC-awake. Fentanyl was administered at predicted plasma concentrations of 1 and 2 ng mg-1 using a computer-controlled continuous infusion and plasma concentrations of fentanyl were measured at the time of MAC-awake measurements. MAC-awake of the control group in which fentanyl was not administered was mean 0.67 (SD 0.12)% or 0.36 (0.03) MAC, being significantly higher than that of the fentanyl 2-ng ml-1 group (0.57 (0.09)% or 0.30 (0.04) MAC). In the fentanyl 1-ng ml-1 group, MAC-awake (0.65 (0.10)% or 0.34 (0.05) MAC) did not differ from that in the control group. Logistic regression analysis showed that increasing plasma concentration of fentanyl and increasing age significantly reduced the MAC-awake of sevoflurane. Because the reduction was very small relative to the overall scatter of the MAC-awake, a low plasma concentration of fentanyl did not significantly reduce the MAC-awake of sevoflurane.

Adult↗
PubMed1996

Patient-controlled extradural analgesia with bupivacaine, fentanyl, or a mixture of both, after Caesarean section.

In this randomized, double-blind study of 60 patients, we have assessed the analgesic efficacy of extradural bupivacaine and extradural fentanyl, either alone or in combination, after Caesarean section. Patients received 0.1% bupivacaine (group B), fentanyl 4 micrograms ml-1 (group F) or 0.05% bupivacaine combined with fentanyl 2 micrograms ml-1 (group BF) by patient-controlled extradural analgesia (PCEA). Adding fentanyl to bupivacaine reduced the dose of bupivacaine by up to 68%, improved analgesia at rest and decreased PCEA use. Motor and sensory block were decreased, but there was more pruritus. Overall patient satisfaction was increased. Adding bupivacaine to fentanyl reduced the dose of fentanyl by up to 57% without altering pain scores or PCEA use. Sensory block increased but pruritus did not decrease. Bupivacaine 0.05% produced clinically significant leg weakness in three patients. Overall patient satisfaction was not altered. There was a significant additive analgesic effect between 0.05% bupivacaine and fentanyl but no clinical benefit was demonstrated from using the combination compared with fentanyl alone for this group of postoperative patients.

Adult↗
PubMed2003

Lumbar epidural fentanyl: segmental spread and effect on temporal summation and muscle pain.

BACKGROUND: Despite extensive use, different aspects of the pharmacological action of epidural fentanyl have not been clarified. We applied a multi-modal sensory test procedure to investigate the effect of epidural fentanyl on segmental spread, temporal summation (as a measure for short-lasting central hyperexcitability) and muscle pain. METHODS: Thirty patients received either placebo, 50 or 100 micro g single dose of fentanyl epidurally (L2-3), in a randomized, double-blind fashion. Heat pain tolerance thresholds at eight dermatomes from S1 to fifth cranial nerve (assessment of segmental spread), pain threshold to transcutaneous repeated electrical stimulation of the sural nerve (assessment of temporal summation) and pain intensity after injection of hypertonic saline into the tibialis anterior muscle (assessment of muscle pain) were recorded. RESULTS: Fentanyl 100 micro g, but not 50 micro g, produced analgesia to heat stimulation only at L2. Surprisingly, no effect at S1 was detected. Both fentanyl doses significantly increased temporal summation threshold and decreased muscle pain intensity. CONCLUSIONS: The findings suggest that a single lumbar epidural dose of fentanyl should be injected at the spinal interspace corresponding to the dermatomal site of pain. Increased effect on L2 compared with S1 suggests that drug effect on spinal nerve roots and binding to opioid receptors on the dorsal root ganglia may be more important than traditionally believed for the segmental effect of epidurally injected fentanyl. Epidural fentanyl increases temporal summation threshold and could therefore contribute to prevention and treatment of central hypersensitivity states. I.M. injection of hypertonic saline is a sensitive technique for detecting the analgesic action of epidural opioids.

Adult↗
PubMed2007

Autonomic effects of epidural and intravenous fentanyl.

BACKGROUND: We tested the hypothesis that there is greater suppression of autonomic reflexes during general anaesthesia when fentanyl is administered epidurally than when it is given intravenously. METHODS: Ten volunteers were anaesthetized with desflurane. Noxious stimuli of variable intensity were then delivered by tetanic electrical stimuli. Heart rate, arterial pressure, and pupillary dilation in response to these stimuli defined nociception. Seven of these volunteers participated twice using a crossover design: they received i.v. fentanyl on one study day and epidurally on the other. Autonomic responses to alternative tetanic stimuli at L4 and C5 dermatomes were measured every 5 min for 3 h after fentanyl administration. RESULTS: After a brief redistribution period, plasma fentanyl concentrations were virtually identical on both days. After stimulation of the L4 dermatome only, block of pupillary reflex dilation was greater by 47 (22)% after epidural fentanyl compared with i.v. fentanyl. Time to maximal depression of reflex dilation after L4 stimulation was 41 (13) min. Arterial pressure and heart rate decreased after fentanyl by either route but there were no differences observed between L4 and C5 stimulations. CONCLUSION: We conclude that during general anaesthesia, epidural fentanyl enhances antinociception by a spinal mechanism which can be detected by pupillary dilation but not by changes in arterial pressure or heart rate.

Adult↗
PubMed1995

Fentanyl prolongs lidocaine spinal anesthesia without prolonging recovery.

Lidocaine spinal anesthesia is a popular anesthetic for short procedures due to its brief duration. The addition of fentanyl may improve the quality and duration of lidocaine spinal anesthesia. Eight volunteers received plain lidocaine 5% in dextrose (50 mg) both with and without 20 micrograms of fentanyl in a randomized, double-blind, cross-over fashion. Sensory analgesia was assessed with pinprick, cold, touch, transcutaneous electrical stimulation equivalent to surgical incision, and duration of tolerance of pneumatic thigh tourniquet. Motor block was assessed with isometric force dynamometry. Regression of pinprick, touch, and cold was prolonged with fentanyl. Duration of tolerance of electrical stimulation at the umbilicus, hip, knee, and ankle was increased with fentanyl (181% increase from plain lidocaine on average; P < 0.01). Duration of tolerance of tourniquet-induced pain was increased by an average of 48% with addition of fentanyl (P = 0.02). Neither motor block nor time to void was prolonged with fentanyl. Pruritus occurred in all subjects receiving fentanyl but was treated easily and were well tolerated. We recommend the addition of 20 micrograms of fentanyl to lidocaine spinal anesthesia as a means to improve duration of sensory anesthesia without prolonging recovery of motor function or time to micturition.

Adult↗
PubMed1995

Activity changes in rat raphe magnus neurons at different concentrations of fentanyl in vitro.

The nucleus raphe magnus (NRM) is an important descending pain inhibitory system. We postulated that the analgesic action of supraspinally administered opiates results from increased descending inhibitory control of the NRM. We tested whether fentanyl activates NRM neurons in the rat slice preparation using extra-cellular recording. Eighty-seven percent of NRM neurons (total number = 68) tested were spontaneously active with firing frequencies of 0.2-4 spikes/s in artificial cerebrospinal fluid. Application of fentanyl (0.25, 0.5, and 1 mumol/L) increased firing frequencies in 12 of 59 (20%) spontaneously active neurons. In 6 of 9 (67%) silent neurons, fentanyl induced firing activities. Naloxone (1-2 mumol/L) antagonized the increased or induced activities by fentanyl in three neurons. In 13 of 59 (22%) spontaneously active neurons, fentanyl decreased the firing frequencies. Although fentanyl was associated with increased activity in a total of 18 NRM neurons, fentanyl at a higher concentration significantly increased the number of inhibited neurons. The results indicate that fentanyl partly activates the descending inhibitory system originating from the NRM; however, at higher concentrations, it appears also to inhibit this same system.

Action Potentials↗
PubMed1996

Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation.

Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-dealkylation in the liver. We have previously shown that cytochrome P-450 3A4 (CYP3A4) contributes significantly to human liver microsomal alfentanil oxidation. Since identification of specific drug-metabolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P-450 enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with 0.25 microM 3H-fentanyl or 3H-sufentanil. Rates of N-dealkylated metabolite formation significantly correlated with nifedipine oxidation activity (a marker of CYP3A4 activity) for fentanyl and sufentanil (r = 0.93 and 0.87, n = 18, respectively), but not with the oxidation activity for ethoxyresorufin (CYP1A2), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2E1). Gestodene and troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhibitors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentanyl and sufentanil. Recombinant CYP3A4 expressed in Escherichia coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYP1A2, 2C10, and 2E1 enzymes did not. We conclude that CYP3A4 is responsible for fentanyl and sufentanil N-dealkylation in vitro.

Analgesics, Opioid↗
PubMed1997

Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography.

Recent positron emission tomography (PET) studies have demonstrated areas of pain processing in the human brain. Given the inhibitory effects of opioids on neuronal activity, we predicted that fentanyl's analgesic effects would be associated with suppression of pain-evoked responses in these distinct brain areas. To test this, PET was used to measure cerebral blood flow responses, as reflections of regional neuronal activity, to painful and nonpainful thermal stimuli both in the absence and presence of fentanyl in humans. During each PET scan in nine healthy volunteers a tonic heat source was placed against the subject's left forearm, delivering a preset temperature of either 40 degrees C (nonpainful) or 47-48 degrees C (painful). Subjects underwent eight blood flow studies, each consisting of 50 mCi [15O]water injection and a PET scan. The first four studies were performed during placebo administration in the stimulus sequence: nonpainful, painful, painful, nonpainful. This sequence was then repeated during intravenous (i.v.) administration of fentanyl 1.5 micrograms/kg [corrected]. Significant differences in regional cerebral blood flow (rCBF) between the placebo and the fentanyl conditions during nonpainful and painful stimuli were identified using statistical parametric mapping. It was found that pain increased rCBF in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, and contralateral supplementary motor area. Fentanyl increased rCBF in the anterior cingulate and contralateral motor cortices, and decreased rCBF in the thalamus (bilaterally) and posterior cingulate during both stimuli. During combined pain stimulation and fentanyl administration, fentanyl significantly augmented pain-related rCBF increases in the supplementary motor area and prefrontal cortex. This activation pattern was associated with decreased pain perception, as measured on a visual analog scale. In contrast to our hypothesis, these data indicate that fentanyl analgesia involves augmentation of pain-evoked cerebral responses in certain areas, as well as both activation and inhibition in other brain regions unresponsive to pain stimulation alone.

Adult↗
PubMed1998

Postoperative analgesic effects of three demand-dose sizes of fentanyl administered by patient-controlled analgesia.

UNLABELLED: Many studies have demonstrated the postoperative analgesic efficacy of fentanyl delivered i.v. by patient-controlled analgesia (PCA) devices at demand doses ranging from 10 to 50 microg, but none has sought to define the optimal fentanyl PCA dose. In this randomized, double-blind, multicenter study, we compared the safety and efficacy of three administered demand-dose sizes of fentanyl (20, 40, and 60 microg) in 150 patients after major surgery. Efficacy was dose-dependent; positive response rates (i.e., a global assessment score of "very good" or "excellent" and the absence of severe opioid adverse effects) were 42%, 52%, and 68% for the 20, 40, and 60 microg demand-dose groups, respectively, and were significantly higher in the 60 microg demand-dose group. The number of doses administered and missed attempts were significantly smaller in the 40 and 60 microg demand-dose groups compared with the 20 microg demand-dose group. This suggests that the 20 microg demand dose provided inadequate pain relief. Adverse respiratory events were more frequent and mean respiratory rates were significantly slower with the 60 microg demand dose, compared with the 20 or 40 microg demand doses. These results indicate that, of these three doses, the 40 microg demand dose was optimal for fentanyl PCA management of moderate to severe pain after major surgery. IMPLICATIONS: The postoperative analgesic efficacy of fentanyl delivered i.v. by patient-controlled analgesia devices has been demonstrated for demand doses ranging from 10 to 50 microg, but the optimal fentanyl dose remains unknown. In this randomized, double-blind study, we compared three demand dose sizes of fentanyl (20, 40, and 60 microg) and found that the 40 microg demand dose was the most appropriate for fentanyl patient-controlled analgesia management of postoperative pain.

Adult↗
PubMed1999

A comparison of levobupivacaine 0.125%, fentanyl 4 microg/mL, or their combination for patient-controlled epidural analgesia after major orthopedic surgery.

UNLABELLED: Levobupivacaine, the isolated S(-) isomer of bupivacaine, is less cardiotoxic than racemic bupivacaine in animal studies. We studied the effectiveness of patient-controlled epidural analgesia (PCEA) with either levobupivacaine 0.125% or fentanyl 4 microg/mL alone, or a combination of levobupivacaine and fentanyl in 65 patients after total joint arthroplasty in a prospective, random, double-blinded fashion. Intraoperatively, all patients received 20 mL of 0.75% levobupivacaine. Study medication was infused at an initial rate of 4 mL/h, with additional medication available on patient demand (2 mL/10 min). The combination of levobupivacaine and fentanyl produced better analgesia (longer time to first PCEA request; P = 0.007 combination versus fentanyl and P = 0.006 combination versus levobupivacaine) than either drug alone. Patients in the levobupivacaine groups had appreciable sensory blockade to pinprick with minimal motor impairment. Resting and dynamic visual analog scale pain scores were lower in the combination group than in the plain fentanyl group at 6 (P = 0.022 and 0.036) and 12 h (P = 0.002 and 0.001). The 24-h overall patient- and investigator-rated visual analog scale pain scores were also lower in the combination group (resting P = 0.007, dynamic P = 0.005). There was no significant difference among the groups in the incidence of postoperative nausea (26.2%), pruritus (9.2%), hypotension (23.1%), or sedation (0%). We conclude that the analgesic effects of levobupivacaine 0.125% and fentanyl (4 microg/mL) are additive and beneficial for the management of orthopedic surgical pain by the PCEA method. Patients in this study began demand-dosing later, reported lower pain scores, and had no greater risk of adverse events than those who were given either levobupivacaine or fentanyl alone. IMPLICATIONS: We demonstrated a significant additive effect of the combination of levobupivacaine (0.125%) and fentanyl (4 microg/mL), compared with either drug alone, when using patient-controlled epidural analgesia in patients after total joint arthroplasty.

Adolescent↗
PubMed2000

Fentanyl improves analgesia but prolongs the onset of axillary brachial plexus block by peripheral mechanism.

UNLABELLED: We evaluated the effects of fentanyl added to lidocaine for axillary brachial plexus block in 66 adult patients scheduled for elective hand and forearm surgery. In this double-blinded study, all patients received 40 mL of 1.5% lidocaine with 1:200,000 epinephrine, injected into the brachial plexus sheath using the axillary perivascular technique, and they were randomized into three groups. Group 1 was given lidocaine containing 2 mL of normal saline plus 2 mL of normal saline IV. Patients in Group 2 received lidocaine containing 100 microg fentanyl plus 2 mL of normal saline IV. Group 3 patients received lidocaine containing 2 mL of normal saline plus 100 microg fentanyl IV. Sensory and motor blockade were evaluated by using a pinprick technique and by measuring the gripping force, respectively. The success rate of sensory blockade for radial and musculocutaneous nerves and the duration of the sensory blockade significantly increased in Group 2 (323 +/- 96 min) as compared with Group 1 (250 +/- 79 min). However, onset time of analgesia was prolonged in every nerve distribution by adding fentanyl to brachial plexus block. IV fentanyl had no effect on the success rate, onset, or duration of blockade. We conclude that the addition of fentanyl to lidocaine causes an improved success rate of sensory blockade but a delayed onset of analgesia, although this may be accounted for by the decreased pH caused by the fentanyl. IMPLICATIONS: It is still unclear whether the addition of a peripheral opioid is useful for nerve blockade in humans. Peripheral application of fentanyl to lidocaine for axillary brachial plexus blockade in this study provided an improved success rate of sensory blockade and prolonged duration.

Analgesics, Opioid↗
PubMed2001

A comparison of fentanyl, sufentanil, and remifentanil for fast-track cardiac anesthesia.

UNLABELLED: Cardiac surgery is estimated to cost $27 billion annually in the United States. In an attempt to decrease the costs of cardiac surgery, fast-track programs have become popular. The purpose of this study was to compare the effects of three different opioid techniques for cardiac surgery on postoperative pain, time to extubation, time to intensive care unit discharge, time to hospital discharge, and cost. Ninety adult patients undergoing cardiac surgery were randomized to a fentanyl-based, sufentanil-based, or remifentanil-based anesthetic. Postoperative pain was measured at 30 min after extubation and at 6:30 AM on the first postoperative day. Pain scores at both times were similar in all three groups (P > 0.05). Median ventilator times of 167, 285, and 234 min (P > 0.05), intensive care unit stays of 18.8, 19.8, and 21.5 h (P > 0.05), and hospital stays of 5, 5, and 5 days (P > 0.05) for the Fentanyl, Sufentanil, and Remifentanil groups did not differ. Three patients needed to be tracheally reintubated: two in the Sufentanil group and one in the Fentanyl group. Median anesthetic costs were largest in the Remifentanil group ($140.54 [$113.54-$179.29]) and smallest in the Fentanyl group ($43.33 [$39.36-$56.48]) (P < or = 0.01), but hospital costs were similar in the three groups: $7841 (Fentanyl), $5943 (Sufentanil), and $6286 (Remifentanil) (P > 0.05). We conclude that the more expensive but shorter-acting opioids, sufentanil and remifentanil, produced equally rapid extubation, similar stays, and similar costs to fentanyl, indicating that any of these opioids can be recommended for fast-track cardiac surgery. IMPLICATIONS: To conserve resources for cardiac surgery, fentanyl-, sufentanil-, and remifentanil-based anesthetics were compared for duration of mechanical ventilation, intensive care unit length of stay, hospital length of stay, and cost. The shorter-acting anesthetics, sufentanil and remifentanil, produced equally rapid extubation, similar stays, and similar costs to fentanyl; thus, any of these opioids can be recommended for fast-track cardiac surgery.

Adjuvants, Anesthesia↗
PubMed2002

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance.

UNLABELLED: Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. IMPLICATIONS: Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.

Analgesics, Opioid↗
PubMed1977

Alpha-adrenergic blocking action of fentanyl on the isolated aorta of the rabbit.

The contractile response of helically-cut strips of rabbit ascending aorta to transmural electrical stimulation was attenuated in a dose-dependent manner by treatment for 20 min with fentanyl, 10(-6) to 10(-5) M. Fentanyl also shifted the dose-response curve of the contractile response of aorta to norepinephrine to the right. The response to transmural stimulation was more resistant to fentanyl than was the response to an equipotent dose of norepinephrine. The inhibitory effect of fentanyl was neither prevented nor reversed by naloxone, but was partially reversed by repeated washing of the preparations. The contractile responses to histamine and serotonin were not significantly altered by fentanyl. Treatment with fentanyl as well as phentolamine protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Morphine to 10(-3) M failed to influence the dose-response curve of norepinephrine significantly. It may be concluded that fentanyl reversibly blocks alpha-adrenergic receptors in a competitive manner in vascular smooth muscle, and the potency of fentanyl is approximately 1/30 that of phentolamine.

Adrenergic alpha-Antagonists↗
PubMed1981

Hemodynamic changes during fentanyl--oxygen anesthesia for aortocoronary bypass operation.

Fentanyl in doses of 50-60 microgram/kg has been reported to produce anesthesia with remarkable hemodynamic stability in patients with coronary artery disease (CAD). Because the authors had observed hypertension and tachycardia in response to noxious stimulation during aortocoronary bypass (ACB) operations in patients so anesthetized, they studied the hemodynamic changes and anesthetic conditions produced by fentanyl/O2/relaxant anesthesia in patients undergoing elective ACB. Twelve patients with left ventricular (LV) ejection fractions greater than 0.4 were maintained on propranolol until 10 hours before operation and were premedicated with fentanyl, diazepam, and scopolamine. Cannulae were inserted before the study commenced for measurement of intravascular pressures, arterial blood gases, and thermodilution cardiac output. The patients breathed 100 per cent oxygen throughout the study. Controlled ventilation aided by succinylcholine to reduce truncal rigidity maintained PaCO2 at 30-45 torr. Measurements were made after each of the following: breathing oxygen (control), 10 microgram/kg fentanyl, 50 microgram/kg fentanyl, and 0.1 mg/kg pancuronium, tracheal intubation, skin incision, and sternotomy. Fentanyl alone produced no significant hemodynamic changes. Fentanyl and pancuronium in combination produced increased heart rate and reduced stroke volume. Significant and progressively greater increases in mean arterial pressure and systemic vascular resistance followed intubation, skin incision, and sternotomy. Chest rigidity occurred in every patient at a lower fentanyl dose than did unresponsiveness. While fentanyl, 62.4 +/- 2.9 microgram/kg (SE), produced minor hemodynamic changes, it failed to block hemodynamic responses to noxious stimulation. Such changes resulted in increased cardiac work, and could have affected myocardial oxygen balance unfavorably. In eight of the 12 patients, following the last set of measurements, supplementary anesthetic agents were required to maintain hemodynamic stability during the surgical procedure. The authors suggest that this fentanyl/O2/relaxant technique should be modified for patients with severe CAD and reasonably good LV function.

Blood Pressure↗