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PubMed2004

Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain.

BACKGROUND: Patients with cancer often are rotated from other opioids to methadone to improve the balance between analgesia and side effects. To the authors' knowledge, no clear guidelines currently exist for the safe and effective rotation from transdermal fentanyl to methadone. METHODS: The authors evaluated a protocol for switching opioid from transdermal fentanyl to oral methadone in 17 patients with cancer. Reasons for switching were uncontrolled pain (41.1% of patients) and neurotoxic side effects (58.9% of patients). Methadone was initiated 8-24 hours after fentanyl withdrawal, depending on the patient's previous opioid doses (from < 100 microg per hour to > 300 microg per hour). The starting methadone dose was calculated according to a 2-step conversion between transdermal fentanyl:oral morphine (1:100 ratio) and oral morphine:oral methadone (5:1 ratio or 10:1 ratio). The correlation between previous fentanyl dose and the final methadone dose or the fentanyl:methadone dose ratio was assessed by means of Pearson and Spearman correlation coefficients (r), respectively. A Friedman test was used to compare pain intensity before and after the switch and the use of daily rescue doses. RESULTS: Opioid rotation was fully or partially effective in 80% and 20%, respectively, of patients with somatic pain. Neuropathic pain was not affected by opioid switching. Delirium and myoclonus were reverted in 80% and 100% of patients, respectively, after opioid switching. A positive linear correlation was obtained between the fentanyl and methadone doses (Pearson r, 0.851). Previous fentanyl doses were not correlated with the final fentanyl:methadone dose ratios (Spearman r, - 0.327). CONCLUSIONS: The protocol studied provided a safe approach for switching from transdermal fentanyl to oral methadone, improving the balance between analgesia and side effects in patients with cancer.

Administration, Cutaneous↗
PubMed1978

Pharmacokinetics of fentanyl as determined by radioimmunoassay.

The pharmacokinetics of fentanyl were determined in human surgical patients using radioimmunoassay. Fentanyl was measured in the serum, cerebrospinal fluid (CSF), and urine of patients receiving 0.1, 0.5, or 1.0 mg/m2 of fentanyl intravenously. The kinetics of the disappearance of fentanyl from the serum were very similar at the three administered doses. At all doses, levels fell rapidly in the first five minutes to approximately 20% of the peak value. Thereafter, serum levels fell more slowly with an observed half-life (t 1/2) of approximately 10 to 20 min. depending on dose. By 2 hr serum levels had stabilized at low values (1, 5, and 8 ng/ml) and continued to decrease very slowly thereafter, with an observed t 1/2 of 1 to 2 hr at the low dose (0.1 mg/m2) and greater than 4 hr at 0.5 and 1.0 mg/m2. The serum elimination curves were dissected and described mathematically in terms of a three-compartment model. Urinary excretion of fentanyl accounted for 15% to 20% of the administered dose. Urinary excretion was very low during the first 2 hr, suggesting that this route of elimination is not important in terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given the high dose (1 mg/m2) were low, and never exceeded 4 ng/ml. Peak levels of fentanyl in the CSF were not seen until at least 15 min after administration.

Adult↗
PubMed2001

Cardiovascular effects of fentanyl in conscious rats.

The polymicrobial sepsis induced by cecal ligation and puncture (CLP) in the rat is widely used in shock research. For ethical reasons, narcotic analgesics are often administered in this model, with the potential risk of confounding effects. In conscious non-septic rats, we investigated the cardiovascular effects of a continuous i.v. infusion of fentanyl (20 microg/kg per h) administered with fluid loading (10 ml/kg per h) for 24 h, a regimen commonly applied in rat CLP. Animals were randomly allocated to receive analgesia with fluid loading (Fentanyl group), or fluid loading alone (Control). All endpoints were assessed after 24 h of infusion. At that time, Control animals had mild respiratory alkalosis, which was essentially abolished by fentanyl. Analgesia mildly elevated the plasma norepinephrine levels [median (interquartile range): Control 232 pg/ml (0-292), Fentanyl 302 pg/ml (234-676), P=0.045] but was devoid of any effect on blood pressure, heart rate, cardiac output (mean +/-SD: Control 388+/-61 ml/kg per min, Fentanyl 382+/-62 ml/kg per min, P=0.87) and indices of left ventricular function derived from high-fidelity recordings of left ventricular pressure (dP/dtmax: Control 11782+/-2324 mmHg/s, Fentanyl 12107+/-2816 mmHg/s, P=0.77). In ex vivo experiments carried out immediately after animal sacrifice, no differences were noted between the Control and Fentanyl groups in the sensitivity of endothelium-intact aortic rings to norepinephrine-induced vasoconstriction (-logEC50: Control 8.78+/-0.28, Fentanyl 8.83+/-0.26, P=0.52) or acetylcholine-induced vasodilatation (-logEC50: Control 7.00+/-0.37, Fentanyl 7.06+/-0.26+/-0.53, P=0.75). In conclusion, the present data provide no contraindication, and even some support for the ethical use of a high dose i.v. infusion of fentanyl in cardiovascular studies of conscious catheterized rats undergoing CLP or other painful procedures.

Acetylcholine↗
PubMed1995

Direct effects of fentanyl on canine coronary artery rings.

The potent opioid fentanyl, is commonly used as a general anesthetic for coronary artery bypass surgery. Experiments were designed to determine the direct effects of fentanyl on unstimulated coronary artery tissue. Isolated, endothelium denuded canine epicardial rings were suspended in physiologic tissue baths. Changes in tension were measured as the concentration of fentanyl was increased. Fentanyl caused increases in ring tension at concentrations of 10(-6)M-10(-4)M, then caused a decrease in tension at 10(-3) M. Calcium channel blockade by 10(-7)M nifedipine abolished all increases in contractile responses to fentanyl and prevented the relaxation in tension produced by fentanyl. The fentanyl dose-response curve was unchanged by opioid receptor blockade with 10(-6)M naloxone and by alpha and beta adrenoceptor blockade produced by 10(-6)M prazosin and 10(-6)M propranolol. Muscarinic blockade with 10(-6)M atropine and cyclooxygenase inhibition by 10(-6)M indomethacin attenuated the constrictor response to fentanyl. The opioids alfentanil, sufentanil, morphine, and naloxone all produced a dose-response similar to fentanyl that varied only in amplitude. These findings indicate that increasing concentration of the anesthetic opioid fentanyl can cause biphasic changes in basal canine epicardial coronary artery ring tension. These responses are calcium dependent and may be characteristics of other opioid agonists and antagonists.

Adrenergic alpha-Antagonists↗
PubMed1991

Maternal and umbilical cord concentrations of fentanyl after epidural analgesia for cesarean section.

The maternal and umbilical concentrations of fentanyl were measured after epidural analgesia for cesarean section, using a highly sensitive radioimmunoassay method. Sixteen parturients were anesthetized with a single epidural injection of a mixture of 85 mg bupivacaine 0.5%, 60 mg etidocaine 1%, and 100 micrograms fentanyl with epinephrine 1:200,000. Apparent maternal individual maximum peak concentration (Cmax) of fentanyl was 0.38 +/- 0.16 ng/ml (mean +/- SD) (range 0.12-0.59 ng/ml) and the time to reach Cmax (Tmax) was 24 +/- 14 min (range 5-60 min). Infants were born 19 to 42 min after epidural administration of fentanyl (mean 27 min). Fentanyl concentrations in neonates was 0.13 +/- 0.04 ng/ml for the umbilical vein and 0.06 +/- 0.03 ng/ml for the artery. The fetus extraction ratio was 53 +/- 19% (range 20-83%). The large difference between arterial and venous concentrations of fentanyl may be due to a metabolization by the fetus and/or an uptake of the drug in the fetal tissues. Thus, even if fentanyl levels reaching the fetus after cesarean section under epidural anesthesia, using local anesthetics with 100 micrograms of fentanyl, are within safe range values, the likelihood of fentanyl uptake by fetal tissues calls for a cautious use of repeated fentanyl administration.

Analgesia, Epidural↗
PubMed1983

Characteristics of [3H]fentanyl binding to the opiate receptor.

The present study characterises the binding of the highly lipophilic opiate agonist [3H]fentanyl to homogenates of the rat central nervous system. At 25 degrees C, association of [3H]fentanyl with its binding site was rapid (t1/2 = 2.5 min). Dissociation from the binding site was biphasic (t1/2's = 4.0 and 100 min) suggesting the existence of high and low affinity binding sites. Scatchard plots of saturation isotherms were curvilinear, confirming the presence of high (KD = 0.46 nM) and low KD = 4.26 nM) affinity binding sites. Increasing temperature and the concentration of sodium ion decreased the [3H]fentanyl binding. Opiate agonists, antagonists and mixed agonist-antagonists were all potent (IC50's less than 20 nM) in displacing [3H]fentanyl and displacement by levorphanol and dextrorphan indicated that [3H]fentanyl binding was stereospecific. The mu and delta selective peptides, morphiceptin and [D-Ala2,D-Leu5]enkephalin, had IC50 values of 87 and 9.2 nM respectively. The regional distribution of [3H]fentanyl binding was in the rank order striatum approximately equal to midbrain greater than hypothalamus greater than cortex greater than hippocampus greater than brainstem greater than spinal cord greater than cerebellum. Comparison of [3H]fentanyl, [3H]naloxone and [3H-D-Ala2,D-Leu5]enkephalin binding in the hypothalamus-thalamus (mu-enriched) compared with the frontal cortex-striatum (delta-enriched) indicated that the pattern of [3H]fentanyl labelling was similar to that obtained with [3H]naloxone, but differed from that obtained with [3H-D-Ala2,D-Leu5]enkephalin. These characteristics suggest that [3H]fentanyl binds to the mu-opiate receptor. These findings are discussed in relation to the high lipid solubility of fentanyl as compared with morphine.

Animals↗
PubMed1993

Effect of stress on oral fentanyl consumption in rats in an operant self-administration paradigm.

The effect of intermittent footshock stress (0.8 mA; 0.2 s on; 40 s off on the average; for 10 min/day) on oral fentanyl (50 or 75 micrograms/ml) self-administration (SA) in operant chambers was examined in male rats. In Experiment 1, after 1 month of initiation of the fentanyl SA by partial water deprivation, animals were tested for lever-pressing for fentanyl (75 micrograms/ml) under fixed-ratio-4 (FR-4) and progressive-ratio (PR) schedules of reinforcement for 30 min/day in operant chambers. Exposure to footshock stress increased fentanyl SA under the FR-4 and PR schedules compared with a nonstress condition. When water was substituted for the drug, the operant behavior persisted before extinction. In Experiment 2, different rats were tested for lever-pressing for fentanyl (50 micrograms/ml) under FR-6 and PR schedules. This experiment further assessed the role of taste in the stress-induced fentanyl SA and examined the effect of increasing the schedule requirements (i.e., FR-3, 6, and 12) on lever-pressing for fentanyl. Exposure to footshock stress increased lever-pressing for oral fentanyl SA under the FR schedules of reinforcement. When a quinine solution (30 micrograms/ml), matched for bitter taste with the fentanyl solution, was substituted for the drug solution, an extinction of the drug-reinforced behavior occurred, indicating that the stress-induced oral fentanyl SA is not related to stress-induced changes in taste sensitivity. In both experiments, no significant stress effects were observed for water consumption in home cage and lever-pressing on the nonoperative lever.

Animals↗
PubMed1995

Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management.

Eleven patients with cancer pain in a palliative care and chronic pain service required cessation of morphine due to unacceptable opioid side effects. In this retrospective study fentanyl was evaluated as a second-line subcutaneously infused opioid. Starting doses ranged from 100 to 1000 micrograms/24 h, and the duration of fentanyl infusion was 3-70 days. The clinically derived mean relative potency of fentanyl to morphine infusions was 68:1 (SD +/- 23; range: 15-100), and we now recommend cautious dose conversion at an approximate equivalence of 150-200 micrograms fentanyl for 10 mg morphine in non-opioid naive chronic cancer pain patients. All patients demonstrated an improvement in the adverse effect(s) for which the change in opioid was undertaken. Adequate pain relief was achieved in all but 1 patient with mixed nociceptive and neuropathic pelvic pain for whom an epidural infusion of a local anaesthetic/opioid mixture was required. Fentanyl was changed to the more potent synthetic opioid sufentanil in 2 patients for whom the fentanyl dose necessitated too large a volume for the portable syringe driver in use. The clinically derived sufentanil to fentanyl relative potencies were 24:1 and 16:1, respectively. This achieved good analgesia and maintained the favourable side-effect profile seen with fentanyl. Subcutaneous infusion appears to be a safe and viable route of fentanyl delivery, and provided effective analgesia with a low incidence of adverse effects in this small selected group of patients who were intolerant of subcutaneous morphine. We suggest a trial of subcutaneous fentanyl for selected patients who have intractable adverse effects on morphine, and it is now the second-line infusable opioid in our service. Further prospective evaluation of the role of these two synthetic mu opioid agonists in palliative care practice is warranted, as part of an evolving picture of variation in opioid side-effect profile seen with different drugs within the class.

Adult↗
PubMed1992

Transdermal fentanyl: clinical pharmacology.

The transdermal therapeutic system (TTS) fentanyl has been designed for rate-controlled drug delivery. It provides a convenient regimen for the use of a drug previously limited by a short duration of action and a noninvasive parenteral route for a drug that is unsuitable for oral administration. TTS fentanyl has been developed to provide continuous controlled systemic delivery of fentanyl base for 72 hr. It is a rectangular, transparent unit composed of a protective peel strip and four functional layers. The amount of fentanyl released from each system (25 micrograms/hr per 10 cm2) is proportional to the surface area. So far, four patch sizes are available (10-40 cm2). When the system is applied, a fentanyl depot concentrates in the upper skin layers. Fentanyl plasma concentrations are not measurable until 2 hr after application, and it takes 8-16 hr latency until full clinical fentanyl effects are observed. Steady-state serum concentrations are obtained after several sequential 72-hr applications, and these are maintained for as long as a system is applied. Following removal, serum fentanyl concentrations decline gradually and fall about 50% in approximately 16 hr. This prolonged apparent elimination half-life occurs because fentanyl continues to be absorbed from the skin. Transdermal fentanyl transport is essentially the same between the chest, abdomen, and thigh. The skin-permeability constant is about 0.0125 mL/hr/cm2, much lower than the regional blood supply to a chest-skin area. Because of potential permeability variations among individuals, a special rate-controlling membrane in the system provides additional control of drug release.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

In vitro variability in fentanyl absorption by different membrane oxygenators.

The membrane oxygenator has replaced the bubble oxygenator in a wide variety of clinical settings. The membrane oxygenators now manufactured can be grouped into three categories based on composition and design: (1) silicone with a true membrane structure; (2) polypropylene with a microporous sheet; and (3) polypropylene with a microtubular structure. The capacity for fentanyl uptake by membrane oxygenators from these three categories was studied in vitro. Representative membrane samples were incubated in solutions containing tritiated fentanyl in Normosol-R (Abbott, North Chicago, IL) with pH adjusted to 7.4 at 37 degrees C. Fentanyl analysis was performed using liquid scintillation and radioimmunoassay techniques. The uptake of fentanyl at various concentrations (340 to 10 ng/mL) was studied. The SciMed (type 1; SciMed, Minneapolis, MN) membrane showed the greatest capacity for fentanyl uptake at all concentrations. The SciMed oxygenator was capable of binding 130 ng fentanyl/cm2 membrane. When presented with a smaller concentration (less than or equal to 20 ng/mL) of fentanyl, the membrane was able to extract all available fentanyl from solution. All of the microporous polypropylene oxygenators (types 2 and 3) absorbed significantly less fentanyl than did the SciMed brand. When exposed to 10 or 20 ng/mL, the Shiley and Omnis brands (type 2) absorbed 0.1 and 0.4 ng/cm2, respectively. Using the higher fentanyl concentrations (greater than or equal to 200 ng/mL) uptake by the Omnis membrane was 11 ng/cm2 compared with only 2 ng/cm2 by the Shiley. The Bentley BCM 7 and Terumo Capiox II 08 microtubular microporous membranes (type 3) did not show absorption of fentanyl using isolated or intact membrane models.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed2006

Patterns of dosage changes with transdermal buprenorphine and transdermal fentanyl for the treatment of noncancer and cancer pain: a retrospective data analysis in Germany.

BACKGROUND: Previous studies have suggested that buprenorphine may have a low association with tolerance development compared with other strong opioids. In a previous study by our group, mean cohort and intraindividual dosage increases over an entire course of treatment and on a per-day basis were significantly lower with transdermal (TD) buprenorphine than with TD fentanyl. However, no information concerning the relationship between qualitative and quantitative dose changes is available. OBJECTIVE: The aim of this study was to compare TD buprenorphine and TD fentanyl with respect to dosage increases, dosage stability, and the nature of dosage changes. METHODS: This retrospective analysis used data from the IMS Disease Analyzer-Mediplus database, which contains patient-related data documented by 400 medical practices in Germany. Data from patients with noncancer or cancer pain treated with TD buprenorphine or TD fentanyl for at least 3 months between May 2002 and April 2005 were analyzed. Daily dosages were directly determined from the prescribed patch strength, taking into account the possibility of multiple patches applied simultaneously. To determine dosage stability, patients were classified based on the type of dosage change (stable, increase, alternating, or decrease) of the prescribed dosages. From the prescribed daily dosages, mean percentage increases were calculated on a per-patient basis for the entire treatment period and per day, and these were assessed in relation to the type of dosage change. RESULTS: In total, 631 patients with noncancer pain and 605 patients with cancer pain were included in the analysis (782 women, 454 men; mean age, 76.3 years [range, 29-100 years]). Treatment indications included osteoarthritis, low back pain, osteoporosis (noncancer groups), and neoplasm (cancer groups). Patients had similar analgesic premedication requirements based on steps 1 to 3 of the World Health Organization analgesic ladder. Comedication requirements for breakthrough pain were also similar between the TD buprenorphine and TD fentanyl groups. The mean percentage increases per day were 0.10% (TD buprenorphine) and 0.25% (TD fentanyl) in the noncancer groups and 0.19% (TD buprenorphine) and 0.47% (TD fentanyl) in the cancer groups (both, P < 0.05). A significantly larger proportion of patients receiving TD buprenorphine had stable dosages over the entire treatment period compared with patients receiving TD fentanyl (noncancer groups: 56.9% vs 41.6%; cancer groups: 50.0% vs 26.2% [both, P < 0.05]). Compared with TD buprenorphine, the proportion of patients with alternating dosage changes was significantly greater in patients receiving TD fentanyl (noncancer groups: 22.7% vs 13.1%; cancer groups: 30.6% vs 11.8% [both, P < 0.05]). CONCLUSIONS: In this retrospective data analysis, compared with TD buprenorphine, the increase in mean daily dosage was significantly greater in patients treated with TD fentanyl. Also, compared with TD buprenorphine, alternating dosage changes were seen in a significantly greater proportion of patients receiving TD fentanyl. On the other hand, a significantly greater proportion of patients treated with TD buprenorphine had stable dosages over their entire treatment periods.

Administration, Cutaneous↗
PubMed1998

Long-term alterations in opiate antinociception resulting from infant fentanyl tolerance and dependence.

Postnatal day-14 (P14) infant rats remained naive or were implanted with osmotic minipumps infusing saline or fentanyl (50 microg kg(-1) h(-1)). Fentanyl was administered 72 h later for measurement of antinociception in the tail-flick test. The potency of fentanyl was 3.0-fold lower in fentanyl-infused compared to saline-infused P17 rats. Fentanyl-infused P17 rats injected with naloxone underwent withdrawal characterized by increases in spontaneous activity, wall climbing, diarrhea, abdominal stretching, forepaw treading/tremors, wet-dog shakes, jumping, ptosis, rhinorrhea and hypothermia. Other naive, saline-infused and fentanyl-infused P17 rats not challenged with fentanyl or naloxone were housed until maturing into P42 juveniles. Fentanyl's potency was equal among each treatment group. However, morphine's potency was reduced in juveniles tolerant to fentanyl as infants. Morphine was also less potent in P90 adults tolerant to fentanyl as infants. Thus, chronic opiate exposure during infancy may affect the developing central nervous system, and desensitize animals and humans to opiate analgesia throughout life.

Analgesics, Opioid↗
PubMed1998

Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats.

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.

Analgesics, Opioid↗
PubMed1999

Isoflurane, nitrous oxide, and fentanyl pharmacodynamic interactions in surgical patients as measured by effects on median power frequency.

STUDY OBJECTIVE: To identify and quantify the simultaneous interactions of isoflurane, nitrous oxide (N2O), and fentanyl during surgical procedures. The slowing of the EEG to a median power frequency of 2 Hz to 3 Hz was chosen as the measure of pharmacodynamic drug effect. DESIGN: Prospective, randomized, open label. SETTING: Operating room of a university hospital. PATIENTS: 65 ASA physical status I and II patients undergoing gynecological laparatomies. INTERVENTIONS: 25 patients received no fentanyl. 20 patients received a loading dose of 100 micrograms fentanyl and a continuous infusion of 70 micrograms.h-1 fentanyl. Calculated effect compartment concentrations were 0.7 ng.ml-1 between the first and second hours after induction of anesthesia. Another 20 patients received a loading dose of 200 micrograms fentanyl and a continuous infusion of 150 micrograms.h-1 fentanyl; the respective effect compartment concentrations were 1.5 ng.ml-1. N2O was randomly administered in concentrations of 0, 20, 40, and 60 vol%; in the group that did not receive fentanyl, we additionally investigated 75 vol% N2O. Each patient received two different N2O concentrations, with each combination of N2O and fentanyl finally applied to ten patients. Isoflurane vaporizer settings were chosen so that the median power frequency was held between 2 Hz and 3 Hz. The type and degree of interaction among the three anesthetic drugs was analyzed based on a generalized isobole approach. MEASUREMENTS AND MAIN RESULTS: The interaction of isoflurane, N2O, and fentanyl is compatible with additivity. A model with regard to the relative potencies and age dependency is given by: [formula: see text] with C0,iso = 1.30 vol%, C0,N2O = 177 vol%, C0,fen = 10.6 ng.ml-1, and a = -0.0031 yr-1. where conc. = end-tidal or effect compartment concentrations. CONCLUSION: The potency of N2O and fentanyl to substitute isoflurane in maintaining a median power frequency of 2 Hz to 3 Hz during surgery is less than anticipated from minimum alveolar concentration studies.

Adult↗
PubMed2003

The in vitro effects of remifentanil and fentanyl on isolated human right atria and saphenous veins.

OBJECTIVE: To determine the myocardial and vascular effects of remifentanil and fentanyl in human atria and saphenous veins. DESIGN: In vitro, prospective with repeated measures. SETTING: University research laboratory. INTERVENTIONS: The direct effects of remifentanil and fentanyl on the electrical stimulation-induced contraction of nonfailing human atrium and saphenous veins contracted with 5-hydroxytryptamine were studied. MEASUREMENTS AND MAIN RESULTS: In human atrial trabeculae, cumulative (10(-9)-10(-5) mol/L) added remifentanil had no effect on contractile force, compared with untreated muscles (p > 0.05). The force of contraction was significantly less than control values with concentrations of fentanyl ranging from 10(-8) to 10(-5) mol/L (p < 0.05). At the highest concentration (10(-5) mol/L), the inhibition by fentanyl of the electrical stimulation-induced contraction was 40.6% +/- 6.32%. In human saphenous vein strips preconstricted with 5-hydroxytryptamine, remifentanil (10(-8)-10(-5) mol/L) and fentanyl (10(-8)-10(-5) mol/L) produced "concentration-dependent" relaxation when compared with the control contraction value (p < 0.05). The IC(50) was similar with remifentanil and fentanyl and the E(max) of fentanyl was significantly higher than remifentanil (p < 0.05). The venodilatory effects of remifentanil and fentanyl were similar on veins with or without endothelium (p > 0.05). CONCLUSIONS: Remifentanil has no direct effect on the contraction of myocardium. Fentanyl inhibits the electrical stimulation-induced contraction in human right atrial muscles in vitro. Remifentanil and fentanyl produce "concentration-dependent" relaxation in human saphenous vein strips independent from the endothelium.

Adult↗
PubMed1997

Comparison of isoflurane and midazolam as hypnotic supplementation to moderately high-dose fentanyl during coronary artery bypass grafting: effects on systemic hemodynamics and early postoperative recovery profile.

OBJECTIVE: The aim of this study was to compare isoflurane and midazolam as hypnotic adjuncts to moderately high-dose fentanyl during coronary artery bypass grafting (CABG) with regard to perioperative hemodynamics and early postoperative recovery profile. DESIGN: Prospective open randomized clinical trial. SETTING: Single university-affiliated medical center. PARTICIPANTS: Thirty patients scheduled for elective primary CABG were randomly divided into two groups receiving either isoflurane or midazolam as adjuncts to 50 micrograms/kg of fentanyl. INTERVENTION: Anesthesia was induced with intravenous fentanyl, 10 micrograms/kg, and midazolam, 0.1 mg/kg, and maintained with either isoflurane, 0.6% or midazolam, 0.1 mg/kg/hour, in intravenous infusion. Before the sternotomy, all patients received 30 micrograms/kg of fentanyl. Midazolam and isoflurane were stopped at the start of cardiopulmonary bypass (CPB). At rewarming, all patients received fentanyl, 5 to 10 micrograms/kg, and either isoflurane, 0.6%, or midazolam, at a reduced rate of 0.05 mg/kg/h. Changes in systolic blood pressure of more than 20% from baseline were first treated with vasoactive drugs. Hypertension was corrected with ketanserin, 10 to 20 mg; hypotension with ephedrine, 5 mg. For a mean blood pressure of less than 50 mmHg during CPB phenylephrine, 0.25 to 0.5 mg, was administered. When hypotension persisted despite a vasopressor, the administration of midazolam or isoflurane was stopped. Postoperatively, the patients were mechanically ventilated overnight and sedated with intermittent doses of fentanyl, 0.15 mg, and midazolam, 5 mg. MEASUREMENTS AND MAIN RESULTS: Routine five-lead electrocardiogram (ECG) and invasive hemodynamic monitoring using a pulmonary artery catheter were performed. The mean dose of fentanyl was 3.9 mg in the midazolam group versus 3.6 mg in the isoflurane group. There were no significant perioperative differences between groups in cardiac output, filling, or pulmonary artery pressures. Systolic blood pressure from the initial incision to CPB was lower in the isoflurane group compared with the midazolam group. During this interval, ketanserin was required in nine patients from the midazolam group at a mean dose of 26 mg, compared with only one patient in the isoflurane group. During and after CPB, there was no difference in ketanserin and in vasopressive/inotropic agent requirements. Temporary cessation of midazolam was required in four patients, for a mean of 34 minutes; whereas isoflurane was stopped in 10 patients for 36 minutes, mostly in the post-CPB period. Time to awakening and to extubation in the midazolam group (217 minutes and 19.5 hours) and the isoflurane group (193 minutes and 18.2 hours) were comparable. Between intensive care unit (ICU) admission and extubation, the patients in the midazolam group received 0.89 mg of fentanyl and 36.5 mg of midazolam compared with 0.98 mg of fentanyl and 36.2 mg of midazolam in the isoflurane group. There was a tendency for a higher postoperative pulmonary shunt and more severely impaired oxygenation in the isoflurane group. CONCLUSION: Midazolam supplementation to fentanyl required more frequent antihypertensive escape during the pre-CPB period than isoflurane. However, more frequent cessation of isoflurane caused by hypotension was needed in the post-CPB period. No difference in awakening and ICU discharge was found.

Aged↗
PubMed2000

The effect of paracetamol (acetaminophen) on fentanyl metabolism in vitro.

BACKGROUND: Fentanyl is a synthetic opioid widely used in anesthesia and analgesia. In experimental animals and in humans it has been shown that most fentanyl biotransformation occurs in the liver, where this opioid is converted primarily to its N-dealkylated derivative, norfentanyl. Recent studies have shown that fentanyl is metabolized to norfentanyl via cytochrome P-450 3A4 (CYP3A4). CYP3A4 is responsible for the metabolism of numerous other therapeutic agents, including those administered concurrently with fentanyl (e.g., nifedipine, lidocaine, erythromycin and cyclosporine). Paracetamol is also metabolized by the CYP3A family, with a Km that is nearly equal to therapeutic blood concentrations. Since paracetamol is widely used, its potential interaction with fentanyl metabolism would be of great interest. METHODS: In the present study, rat and human liver microsomes were used to assess the ability of paracetamol to inhibit fentanyl metabolism. RESULTS: In both sets of microsomes, paracetamol produced a concentration-dependent inhibition of fentanyl oxidation to norfentanyl. Kinetic analysis of the data showed that 0.5-5 mM paracetamol inhibited fentanyl metabolism in a noncompetitive fashion. A Dixon plot revealed that the Ki for paracetamol inhibition of fentanyl metabolism is approximately 3.2 mM and 2.8 mM for human and rat liver microsomes, respectively. CONCLUSIONS: Since these concentrations of paracetamol are approximately one order of magnitude greater than therapeutic concentrations, it would appear that potentially important and possibly harmful fentanyl-paracetamol drug interactions do not occur with therapeutic concentrations of paracetamol.

Acetaminophen↗
PubMed2000

Effect of fentanyl on baroreflex control of circumflex coronary conductance.

1. Fentanyl, a synthetic mciro-opioid receptor agonist, is the preferred induction and maintenance anaesthetic agent in cardiac surgery. 2. Its actions on myocardial blood flow are poorly understood. There are reports of intra-operative myocardial ischaemia. Its reported actions on cardiorespiratory control vary widely, but do involve hypertension, bradycardia and peripheral vasoconstriction. 3. Accordingly, the postulate that fentanyl would cause coronary vasoconstriction and myocardial disadvantage was examined in awake dogs with a continuous wave Doppler flow probe mounted on the circumflex coronary artery. 4. Continuous intravenous infusion of fentanyl citrate (550 ng/kg per min) raised plasma concentrations of fentanyl to 3.37 ng/mL in a linear fashion at 20 min. There was a fall in core temperature of 0.7 degrees C and, although no apparent depression of ventilation or fall in arterial or coronary sinus PO2, there was a rise in PCO2 and H+ concentration. Some dogs salivated and panted transiently. Thus, fentanyl may reset temperature regulation in low doses but, at higher doses, is associated with metabolic acidosis. 5. In sinus rhythm, the arterial pressure of the dogs fell slightly, then rose to 115% of resting control. Circumflex flow and conductance rose early, then conductance steadily declined to 83%. Heart rate fell, then rose before returning to pre-infusion levels. The early circumflex coronary vasodilator effects, but not the later vasoconstrictor effects, were reduced in dogs with paced hearts. 6. In dogs with paced hearts, a dose-effect study using 138, 275, 550 and 1100 ng/kg per min fentanyl suggested that, at low plasma concentrations of 1-2 ng/mL, vasodilatation does occur in both coronary and systemic circulations; however, at higher doses, intense coronary and systemic vasoconstriction supervenes. 7. The dose-response effect of fentanyl on arterial baroreflex control of circumflex conductance was examined during the immediate 8 s circumflex vasodilator response to a step rise in aortic pressure caused by inflation of an intra-aortic balloon. At low plasma concentrations of fentanyl, baroreflex control of circumflex conductance appears to be enhanced but, with increasing plasma concentrations of fentanyl, appears to be depressed. 8. Therefore, the effects of fentanyl are dose dependent. At low plasma concentrations, left ventricular blood flow and its baroreflex control is enhanced but, at higher concentrations, it is depressed.

Analgesics, Opioid↗