Pharmacokinetics Of Fentanyl Research Articles

Pharmacokinetics of Levobupivacaine, Fentanyl, and Clonidine After Administration in Thoracic Paravertebral Analgesia

There is little knowledge of the pharmacokinetics of local anesthetics and adjunctive analgesics after paravertebral blockade. We evaluated the pharmacokinetics of low-dose levobupivacaine, fentanyl, and clonidine after paravertebral analgesia for breast surgery. Thirty-eight patients receiving paravertebral analgesia for breast surgery received a 19-mL paravertebral bolus of levobupivacaine 0.25% combined with a 1-mL volume of saline (group L, 13 patients), fentanyl 50 microg (group LF, 13 patients), or clonidine 150 microg (group LC, 12 patients) followed 1 hour later by infusion of levobupivacaine 0.1% (L), levobupivacaine 0.05% with fentany l 4 microg/mL (LF), or levobupivacaine 0.05% with clonidine 3 microg/mL (LC), respectively. Plasma concentrations of study drugs were determined at intervals up to 24 hours after bolus injection. There was rapid absorption of levobupivacaine after bolus with mean (standard deviation) maximum plasma concentration (Cpmax) of 0.51(0.24) microg/mL in a median time to maximum concentration tCpmax of 15 minutes. Mean Cpmax fentanyl and clonidine after bolus were 0.62 (0.37) and 0.79 (0.23) ng/mL, in a median tCpmax of 15 and 22.5 minutes, respectively. Mean Cpmax levobupivacaine after infusion was 0.47 (0.41) microg/mL in a median tCpmax of 24 hours. There was progressive accumulation of fentanyl and clonidine at 24 hours with a mean Cpmax of 0.72 (0.33) and 1.74 (0.70) ng/mL, respectively. After paravertebral bolus and infusion administration, Cpmax levobupivacaine was within the safe range. Cpmax fentanyl and clonidine were less than the effective levels after IV administration, suggesting that their analgesic effect may be partly attributed to a peripheral mechanism of action.

Influence of general anaesthesia on the pharmacokinetics of intravenous fentanyl and its primary metabolite in horses

In order to evaluate its potential as an adjunct to inhalant anaesthesia in horses, the pharmacokinetics of fentanyl must first be determined. To describe the pharmacokinetics of fentanyl and its metabolite, N-[1-(2-phenethyl-4-piperidinyl)maloanilinic acid (PMA), after i.v. administration of a single dose to horses that were awake in Treatment 1 and anaesthetised with isoflurane in Treatment 2. A balanced crossover design was used (n = 4/group). During Treatment 1, horses received a single dose of fentanyl (4 microg/kg bwt, i.v.) and during Treatment 2, they were anaesthetised with isoflurane and maintained at 1.2 x minimum alveolar anaesthetic concentration. After a 30 min equilibration period, a single dose of fentanyl (4 microg/kg bwt, i.v.) was administered to each horse. Plasma fentanyl and PMA concentrations were measured at various time points using liquid chromatography-mass spectrometry. Anaesthesia with isoflurane significantly decreased mean fentanyl clearance (P < 0.05). The fentanyl elimination half-life, in awake and anaesthetised horses, was 1 h and volume of distribution at steady state was 0.37 and 0.26 l/kg bwt, respectively. Anaesthesia with isoflurane also significantly decreased PMA apparent clearance and volume of distribution. The elimination half-life of PMA was 2 and 1.5 h in awake and anaesthetised horses, respectively. Pharmacokinetics of fentanyl and PMA in horses were substantially altered in horses anaesthetised with isoflurane. These pharmacokinetic parameters provide information necessary for determination of suitable fentanyl loading and infusion doses in awake and isoflurane-anaesthetised horses.

Pharmacokinetics of fentanyl delivered transdermally in healthy adult horses – variability among horses and its clinical implications

The safety and pharmacokinetics of fentanyl, delivered transdermally at a dosage of 60-67 microg/kg, were investigated in six healthy adult horses. Three transdermal fentanyl patches (Duragesic), each containing 10 mg of fentanyl citrate, were applied to the mid-dorsal thorax of each horse and left in place for 72 h. Plasma fentanyl concentrations were periodically measured throughout this period and for 12 h after patch removal. After an initial delay of approximately 2 h, the plasma fentanyl concentration rose rapidly in a fairly linear fashion, reaching a peak at around 12 h; thereafter, it gradually declined in a roughly linear manner over the next 72 h. There was much individual variation, however. The initial delay ranged from 0 to 5.1 h (mean, 1.91+/-2.0 h), Tcmax ranged from 8.5 to 14.5 h (mean, 11.4+/-2.7 h) and Cmax ranged from 0.67 to 5.12 ng/mL (mean, 2.77+/-1.92 ng/mL). In two horses, the plasma fentanyl concentration failed to reach even 1 ng/mL, whereas in the other four horses it was >1 ng/mL for at least 40 h and for at least 72 h in two of these horses. No adverse effects attributable to fentanyl were observed in any of the horses, indicating that this dosage is safe in systemically healthy adult horses. However, it failed to achieve plasma fentanyl concentrations generally considered to be analgesic (>or=1 ng/mL) in about one-third of horses.

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

ObjectiveTo determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 μg kg−1) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 μg kg−1 hour−1 lasting 1, 3 or 4 hours in dogs. AnimalsFourteen healthy adult beagles (seven males and seven females). Experimental designRandomized cross-over design. Materials and methodsDogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 μg kg−1). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 μg kg−1 hour−1) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography–mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). ResultsPlasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration–time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2α was 4.5 minutes), a relatively long elimination half time (t1/2β was 45.7 minutes), a large volume of distribution (approximately 5 L kg−1) and high total body clearance (77.9 mL minute−1 kg−1). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. Conclusions and Clinical relevanceWhile this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.

Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk

Lactating women undergoing operations requiring general anesthesia are advised to pump and discard their milk for 24 hours after the procedure. Data on anesthetic drug transfer into breast milk are limited. This study determined the pharmacokinetics of midazolam, propofol, and fentanyl transfer into milk to provide caregivers with data regarding the safety of breast milk after administration of these drugs. Five lactating women participated in this study after providing institutionally approved written informed consent. Patients underwent premedication with midazolam before induction of anesthesia with propofol and fentanyl. Anesthesia was maintained with a potent volatile anesthetic. Milk and blood were collected before drug administration. Milk was collected 5, 7, 9, 11, and 24 hours after drug administration. Venous blood was collected at intervals up to 7 hours. Plasma and milk midazolam, propofol, and fentanyl concentrations were measured by HPLC with tandem mass spectrometric or fluorescence detection. The pharmacokinetics of drug transfer into milk was modeled with plasma pharmacokinetics. Plasma midazolam, propofol, and fentanyl pharmacokinetics were consistent with reports of others. In 24 hours of milk collection, averages of 0.005% (range, 0.002%-0.013%) of the maternal midazolam dose, 0.027% (0.004%-0.082%) of the propofol dose, and 0.033% (0.006%-0.073%) of the fentanyl dose were collected in milk, representing averages of 0.009%, 0.025%, and 0.039% of the respective elimination clearances. The amount of midazolam, propofol, and fentanyl excreted into milk within 24 hours of induction of anesthesia provides insufficient justification for interrupting breast-feeding.

The effect of acutely induced hepatic failure on remifentanil and fentanyl blood levels in a pig model

Opioids and especially fentanyl are widely used during the intensive care unit management of intracranial pressure in fulminant hepatic failure patients as well as during and after liver transplantation. The newer synthetic opioid remifentanil is also increasingly being used in critical care patients. Due to a lack of data relating to the influence of acute hepatic failure on remifentanil and fentanyl pharmacokinetics, this study was designed in order to determine the impact of this condition on the blood levels of these opioids using a pig model. Twenty pigs were randomly assigned to one of two groups: A group with surgically induced acute hepatic failure by hepatic devascularization (acute hepatic failure, n=10) and a control group (SHAM, n=10), subjected to a SHAM operation. Postoperatively, five animals in each group were administered remifentanil (1 microg kg-1 min-1) or fentanyl (0.2 microg kg-1 min-1) by continuous intravenous infusion. Blood samples for determination of drug concentrations were withdrawn at 0 h and 0.5, 1, 5, 7, 9 h after initiation of dosing. Significantly higher blood concentrations were found in animals with acute hepatic failure compared to SHAM-operated animals receiving remifentanil at 5 h (P=0.003), 7 h (P=0.007) and 9 h (P=0.004) and fentanyl at 7 h (P<0.0005) and 9 h (P=0.05). The small number and the great variability in drug concentrations did not allow a detailed kinetic analysis to be performed. Approximate clearance values were found to be greater for the SHAM compared with the acute hepatic failure animals for both fentanyl and remifentanil. Hepatic devascularization in our porcine acute hepatic failure model, appears to have significantly altered the disposition of fentanyl and unexpectedly remifentanil. These changes were thought to be brought about by severe disruption of blood flow and biotransformation in the liver, as well as by haemodynamic changes in the acute hepatic failure animals.

Comparison of Equivalent Doses of Fentanyl Buccal Tablets and Arteriovenous Differences in Fentanyl Pharmacokinetics

The fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa. To evaluate the bioequivalence of microg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers. Twenty-seven healthy adults, aged 19-45 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100 microg tablets simultaneously or one FBT 400 microg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400 microg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout. Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100 microg tablets simultaneously compared with one FBT 400 microg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study. Despite small differences in C(max) and AUC(infinity) (on average 12% and 13%, respectively), FBT administered as four 100 microg tablets simultaneously compared with one 400 microg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum concentrations observed with four 100 microg tablets. A substantially higher C(max) was reached earlier in the arterial than in the venous circulation.

Characterisation of the Pharmacokinetics of the Fentanyl HCl Patient-Controlled Transdermal System (PCTS)

The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, noninvasive analgesic delivery system for acute pain management. We carried out three studies with the following objectives: study I to evaluate the relationship between fentanyl absorption and the magnitude of current applied to the system; study II to determine dose-proportionality for the fentanyl HCl PCTS (25 and 40 microg); and study III to describe the effects of single- and multiple-day administration on the pharmacokinetics of fentanyl delivered by the PCTS. All studies were open-label, crossover studies with washout periods between treatments. In study I, randomised participants (n = 36) received three of a potential five fentanyl HCl PCTS prototypes, each of which used a different current magnitude, and each of which was evaluated for 24 hours. In study II, participants (n = 40) received fentanyl (25 microg) from the PCTS for 23.33 hours, followed by fentanyl (40 microg) from the PCTS for 23.33 hours. Intravenous (IV) fentanyl (80 microg/h) was administered intermittently over 24 hours as a reference treatment in Studies I and II. In study III, participants (n = 28) received fentanyl (40 microg) from the PCTS for 20 hours, followed by fentanyl (40 microg) from the PCTS for 68 hours. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)), were determined for each treatment. The amount of fentanyl absorbed from the PCTS was linearly dependent on the magnitude of current applied to the system, with a current of 170 microA resulting in the absorption of 39.5 microg of fentanyl at hour 23. Mixed-effect ANOVA indicated no significant difference (p > 0.1) in the dose-normalised pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. No significant difference existed between the corrected AUC(0-5) of the fentanyl HCl PCTS during the single- and multiple-day treatment periods (0.40 and 0.54 microg x h/L, respectively; p = 0.133). The system was well tolerated, with headache and mild application site erythema being the most common treatment-related adverse events. A linear relationship exists between the amount of current applied to the fentanyl HCl PCTS and the amount of fentanyl absorbed. There is dose-proportionality in the pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. Multiple-day administration does not affect the pharmacokinetics of the fentanyl HCl PCTS 40 microg. The system was well tolerated, even after repeated application.

The Effect of Dosing Frequency on the Pharmacokinetics of a Fentanyl HCl Patient-Controlled Transdermal System (PCTS)

The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS. All three studies were single-centre, open-label, randomised, crossover studies. The fentanyl HCl PCTS was applied to the upper outer arm of all participants. In the first study, participants (n = 30) received three fentanyl HCl PCTS 25 microg treatments: two sequential doses hourly for 23.33 hours, six sequential doses every 3 hours for 22 hours, and 72 doses continuously over 12 hours. Participants (n = 31) in the second study received three fentanyl HCl PCTS 40 microg treatments: two sequential doses hourly over 23.33 hours, six sequential doses every 3 hours over approximately 10 hours, and 80 doses continuously over 13.33 hours. In the third study, participants (n = 28) received four fentanyl HCl PCTS 40 microg treatments: 6, 18, 36 and 80 doses over 1, 3, 6 and 13.33 hours, respectively. Naltrexone was used to block the opioid effects of fentanyl. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)) were determined. In the first study, the dose-normalised AUC (AUCn) values for the 2- and 6-dose sequence treatments were not significantly different (p = 0.937), suggesting that the frequency of dosing has little effect on the amount of fentanyl absorbed; however, the AUCn for the 72-dose treatment was significantly lower than that of the other treatments (p = 0.001), which were of longer duration. The results of the second study paralleled those from the first, suggesting that the bioavailability of fentanyl delivered by the PCTS increases as a function of time and is likely to be independent of dosing frequency. Results from the third study suggested that approximately 40% of the nominal 40 microg fentanyl dose is absorbed during the first hour of treatment, with the full nominal dose absorbed after approximately 10 hours. The fentanyl HCl PCTS was well tolerated. The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.

Effects of Application Site and Subject Demographics on the Pharmacokinetics of Fentanyl HCl Patient-Controlled Transdermal System (PCTS)

The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, needle-free system currently in development for acute pain management in a medically supervised setting. The objectives of these studies were to evaluate skin application sites for the fentanyl HCl PCTS and to evaluate the effect of patient demographics on its pharmacokinetics. The first study was a randomised, open-label, single-centre, 3-treatment, crossover study in which the fentanyl HCl PCTS was applied to the upper outer arm, lower inner arm or chest of healthy volunteers. Fentanyl 25 microg was then delivered via this system twice during the first 20 minutes of every hour for 24 hours. The pharmacokinetics of fentanyl were determined and analysed for each application site using ANOVA. The second study was a nonrandomised, nonblind, multicentre, sequential treatment study. Healthy volunteers received fentanyl HCl 40 microg via the PCTS three times during the first 30 minutes of each hour for 3 hours. After a 5- to 10-day washout period, fentanyl HCl 120 microg was administered intravenously during the first 30 minutes of each hour for 3 hours as a reference treatment. Pharmacokinetic parameters were determined for the fentanyl HCl PCTS, and results were analysed using ANOVA. Safety and tolerability were evaluated in both studies. Application of the system to the upper outer arm or chest resulted in similar maximum serum concentrations (Cmax; 1.193 and 1.176 microg/L, respectively) and areas under the serum concentration-time curve (AUC24-25; 1.033 and 1.015 microg h/L). However, both Cmax and AUC24-25 were less when the system was applied to the lower inner arm (0.859 microg/L and 0.757 microg x h/L). Subject age, bodyweight, sex and ethnicity had no significant effect on pharmacokinetic parameters. No serious adverse events were reported in either study during or after administration of the fentanyl HCl PCTS. Fentanyl HCl is comparably absorbed from the PCTS when it is applied to the upper outer arm or chest. The pharmacokinetics of fentanyl HCl delivered by the PCTS are unaffected by sex, age, race or weight.

Inter- and Intraindividual Variabilities in Pharmacokinetics of Fentanyl After Repeated 72-Hour Transdermal Applications in Cancer Pain Patients

Perception of pain by the patient is frequently one of the early signs preceding a diagnosis of cancer and, later, a sinister sign of disease progression. Among opioid drugs, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The objective of this study was to investigate the intra- and interindividual variabilities in pharmacokinetics after fentanyl drug delivery by the transdermal fentanyl patch delivery system in patients with cancer pain. As a first step, a liquid chromatography-mass spectrometry method was developed for the determination of the analgesic fentanyl in human plasma. This method was validated over the concentration range 0.15-100 ng/mL. The study group consisted of 29 inpatients (18 men and 11 women; age range 29-80 years). The initial transdermal fentanyl delivery rate was chosen depending on the patient's analgesic requirements. For 20 patients, the initial TTS fentanyl delivery rate was 25 or 50 microg/h. For 6 patients, the initial delivery rate was 75-150 microg/h. Two patients received up to 300 microg/h fentanyl delivery rate, and 3 patients received up to 350 microg/h fentanyl delivery rate. Fifteen of the 29 patients received rescue doses of subcutaneous or oral morphine, and 26 patients received paracetamol with codeine (30 mg per os). Blood samples were collected at the following intervals: 2-5, 22-26, or 45-47 hours following fentanyl patch application. The severity of pain experienced by the patient was assessed thrice daily using a visual analogue scale. The study period was 46 days. Large patient-to-patient variations in pharmacokinetic parameters occurred, although intraindividual variability was limited. A mean bioavailability of 78% was estimated; the total clearance averaged 41 L/h. From 25 to 100 mug/h fentanyl delivery rate, the pharmacokinetics was linear. At the 2 highest doses, an increase of total clearance was observed (>60 L/h). For the whole group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

Steady-state pharmacokinetics of fentanyl after administration of a novel non-occlusive transdermal system

8199 Background: Transdermal fentanyl patches are widely used to treat chronic pain. However, drawbacks include the variability in fentanyl delivery over the 3 day dosing period and the patches cau...

Pharmacokinetics, safety and tolerability of a novel 100 ?g/h transdermal fentanyl patch co-administered with 100 mg oral naltrexone in healthy males

Background/Aims Recommended initial dose of fentanyl (FEN) in opioid-naive patients is 25μg/h with upward titration. The aim was to assess the pharmacokinetics (PK), safety and tolerability of a FEN patch given with naltrexone (NAL), an opioid receptor antagonist. Methods In a randomized crossover study, healthy male subjects (n=24) received a single 72h application of two formulations of FEN (100μg/h) given with oral NAL (100mg) in a clinical setting. Blood samples were collected and serum FEN was assayed using a LC/MS/MS method. Results Mean (CV%) for AUC and Cmax were 142.7ng·h/mL (25.0) and 2.35ng/mL (34.8), respectively. PK parameters of FEN were similar for the reference product with and without NAL. Even though a high dose of FEN was administered, oral NAL prevented the occurrence of opioid adverse events (AEs). Of the 281 AEs, 139 were drug-related with 100 specific to the patch application site. Most AEs were mild and none were severe. Conclusions Co-administration of oral NAL did not affect the PK of FEN and prevented the occurrence of opioid AEs. Results from this study confirm that a 100μg/h dose of FEN was well tolerated and safe when given with NAL in healthy males. Clinical Pharmacology & Therapeutics (2005) 77, P76–P76; doi: 10.1016/j.clpt.2004.12.181

Lung Injury Induced by Major Burns does not Affect Fentanyl Clearance

Background: Major burns can alter the pharmacokinetics of opiate analgesics, which are commonly used perioperatively. Fentanyl undergoes a significant amount of pulmonary pharmacokinetic transition. This study was conducted to compare the pharmacokinetics of fentanyl in major burns, with and without lung injury, during the subacute hyperdynamic phase of recovery. Methods: Twelve adults, with total body surface area (TBSA) 51.0 11.8% burns, aged 34.9 9.6 years, with a lung injury related to the burn, were studied at 15.4 9.4 days after the injury. Another 8 patients, aged 39.8 10.5 years, with TBSA 46.3 19.4%, at 19.3 10.9 days, without lung injury, served as controls. Fentanyl 200 was given intravenously over 10 seconds. Blood samples (n = 20) were collected at predetermined intervals. A two-compartment model was used for pharmacokinetic analyses of the fentanyl concentrations, as determined by LC/MS. The cardiac index (CI) was also measured using an esophageal Doppler monitor. Results: There were no differences in the patient characteristics between the two groups. Those with burns had a significantly higher cardiac index (4.1 2.4 L/min/), clearance (Cl), central (V1) and total volume of distribution (Vd), but there were no differences between those with and without lung injury (30.2 14.3 vs. 30.1 5.8 ml/min/kg, 0.8 0.3 vs. 0.6 0.2 L/kg, 5.8 1.7 vs. 5.2 2.1 L/kg, respectively). Prolonged distribution () and elimination half-lives () were noted in those with burns, but there were no differences between the two groups (3.2 1.3 vs. 3.3 1.3 minutes, 2.6 1.4 vs. 2.0 0.7 hours, respectively). Conclusions: The increased Cl of fentanyl in those with burns is primarily dependent upon the resultant increased hepatic blood flow. The pulmonary kinetics is a saturable process, which is not affected by a single bolus of fentanyl. The lung injury induced by major burns would have no influence on the elimination kinetics of fentanyl.

Are Preemptive Analgesic Effects of Ketamine Linked to Inadequate Perioperative Analgesia?

To the Editor: We read with interest the article by Kwok et al. (1). The authors demonstrated that small dose of the N-methyl-d-aspartic acid (NMDA) receptor antagonist ketamine provides preemptive analgesia in patients undergoing gynecologic laparoscopic surgery. There are conflicting results in the literature concerning preemptive effect of ketamine. Studies have documented a preemptive effect (2–5) and others have not (6–10). The efficacy of ketamine is linked to activation of NMDA receptors of the dorsal horn of the spinal cord. In case of adequate perioperative analgesia, NMDA receptors activation is likely to be suppressed and ketamine administration useless. In the studies that have documented a preemptive effect of ketamine (2–5), the perioperative opioid analgesia is questionable and likely to have induced intraoperative activation of NMDA receptors. In the study of Kwok et al. (1) patients were administered an average total dose of 2 μg/kg of fentanyl. Surgery lasted more than 60 min. Given the pharmacokinetics of fentanyl, we can wonder whether intraoperative analgesia was adequate, even in these minimally invasive surgery procedures. Inadequate analgesia might have, therefore, led to NMDA receptor activation and subsequent positive action of ketamine. The real challenge, however, in the clinical setting might not be to use the least amount of analgesic drug but to minimize long-term complications and occurrence of chronic pain syndromes. The study of Kwok et al. would have gained in interest if they had more focused on the long-term follow-up of the patients, using clinical assessment of allodynia and hyperalgesia. Alain C. Van Elstraete, MD Thierry Lebrun, MD Ignace Sandefo, MD Bruno Polin, MD Department of Anesthesiology Centre Mèdico-Chirurgical Saint Paul Clairiëre, Fort de France, Martinique [email protected]

This Month in Anesthesiology

This Month in Anesthesiology

Cardiopulmonary Bypass Has Minimal Effects on the Pharmacokinetics of Fentanyl in Adults

Although fentanyl has been widely used in cardiac anesthesia, no complete pharmacokinetic model that has assessed the effect of cardiopulmonary bypass (CPB) and that has adequate predictive accuracy has been defined. The aims of this investigation were to determine whether CPB had a clinically significant impact on fentanyl pharmacokinetics and to determine the simplest model that accurately predicts fentanyl concentrations during cardiac surgery using CPB. Population pharmacokinetic modeling was applied to concentration-versus-time data from 61 patients undergoing coronary artery bypass grafting using CPB. Predictive ability of models was assessed by calculating bias (prediction error), accuracy (absolute prediction error), and measured:predicted concentration ratios versus time. The predictive ability of a simple three-compartment model with no covariates was initially compared to models with premedication (lorazepam vs. clonidine), sex, or weight as covariates. This simple model was then compared to 18 CPB-adjusted models that allowed for step changes in pharmacokinetic parameters at the start and/or end of CPB. The predictive ability of the final model was assessed prospectively in a second group of 29 patients. None of the covariate (premedication, sex, weight) models nor any of the CPB-adjusted models significantly improved prediction error or absolute prediction error, compared to the simple three-compartment model. Thus, the simple three-compartment model was selected as the final model. Prospective assessment of this model yielded a median prediction error of +3.8%, with a median absolute prediction error of 15.8%. The model parameters were as follows: V1, 14.4 l; V2, 36.4 l; V3, 169 l; Cl1, 0.82 l. min-1; Cl2, 2.31 l x min-1; Cl3, 1.35 l x min-1. Compared to other factors that cause pharmacokinetic variability, the effect of CPB on fentanyl kinetics is clinically insignificant. A simple three-compartment model accurately predicts fentanyl concentrations throughout surgery using CPB.

The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat

Preliminary reports have demonstrated that the application of local heat to the transdermal fentanyl patch significantly increased systemic delivery of fentanyl. The objective of this study was to further evaluate the pharmacokinetic effect of local heat administration on fentanyl drug delivery through the transdermal fentanyl patch delivery system in volunteers. In addition, the study was intended to document the effect of heat on steady-state transdermal fentanyl delivery. This was an open, 3-period, crossover study that evaluated the pharmacokinetics and safety of 25 μg/h transdermal fentanyl administered with and without local heat. During Sessions A and B, subjects received transdermal fentanyl for a 30-hour period. During Session A, heat was applied for 1 hour at the 24-hour time point during the 30-hour period. During Session B, heat was applied for the first 4 hours and then again for 1 hour at the 24-hour time point during the 30-hour period. The order of Sessions A and B was randomized, and a minimum of 2 weeks separated the sessions. Five of the 10 subjects returned to participate in Session C. During Session C, subjects received transdermal fentanyl 25 μg/h for 18 hours. Heat was applied during the first 4 hours of administration and then again for 15-minute periods at the 12- and 16-hour time points. Arterial blood samples for determination of serum fentanyl concentration were collected. Maximum concentration (C max), time to maximum concentration (t max), and area under the curve (AUC) were determined for each treatment period. Sedation, vital signs, oxygen saturation, and adverse events were recorded. During a period of 36 hours, there were no significant differences in C max, AUC, or T max between transdermal fentanyl delivery with no heat and heat. However, significant differences were seen during the first 4 hours, with C max and AUC values almost 3 times higher for the heated administrations than for the administrations without heat. With heat, the mean C max was 0.63 ng/mL compared with a C max of 0.24 ng/mL without heat ( P = .007). With early heat, the mean AUC was 1.22 ng/mL · h compared with 0.42 ng/mL · h without heat ( P = .003). There was no statistically significant difference between the median times to achieve peak values (T max) during the first 4 hours. The addition of heat at 24 hours resulted in rapid increases in serum fentanyl concentrations for both groups and higher serum fentanyl concentrations for the administration that did not receive heat previously. Applying heat for 15 minutes at the 12-hour and 16-hour time points produced a rapid but short duration increase in serum fentanyl concentrations. The results suggest controlled heat might be used to significantly shorten the time needed to reach clinically important fentanyl concentrations. Controlled heat might be useful to produce rapid increases in serum concentrations for the rapid treatment of breakthrough pain.

Pharmacokinetics of fentanyl following intravenous and transdermal administration in horses.

Although fentanyl has been reported to cause CNS excitation in horses, a transdermal therapeutic system (TTS) containing this mu agonist has recently been used empirically in equine medicine to treat moderate to severe pain. A better understanding of the disposition of fentanyl following transdermal administration would facilitate the clinical use of TTS fentanyl to obtain analgesia in horses. To determine the pharmacokinetics of fentanyl following i.v. and TTS patch administration in healthy, mature horses and to evaluate the tolerance of horses to TTS fentanyl administration. The pharmacokinetics of fentanyl in serum were assessed following a single i.v. dose, a single TTS dose, and multiple TTS doses in 6 healthy horses. Physical examinations, haematology and serum biochemistry analyses during transdermal fentanyl application were then performed to determine tolerance of continuous fentanyl administration. Fentanyl was very rapidly and completely absorbed following a single TTS dose. Mean serum fentanyl concentrations consistent with analgesia in other species were reached by 1 h and maintained until 32 h after patch application. Similar steady state serum concentrations were obtained when multiple doses of TTS fentanyl were administered every 48 or 72 h over 8 or 9 days, with less fluctuation in serum concentrations during the 48 h dosing interval. Three horses exhibited brief (< 12 h) episodes of increased body temperature; however, transdermal fentanyl administrations were not associated with other significant changes in haematology and biochemistry panels or physical examination findings. Although the pharmacodynamics of fentanyl have not been investigated fully in horses, transdermally-administered fentanyl exhibited a favourable pharmacokinetic profile without clinically relevant side effects and may be a useful analgesic in equine patients.

Pharmacokinetics of Nasal Fentanyl

Objective: To investigate the pharmacokinetics of intranasal fentanyl in adult post‐operative female patients.Method: Patients received both intravenous and intranasal fentanyl (approximately 50 µg) in a randomised cross‐over study.Results: Pharmacokinetic data sets from 19 patients showed intranasal fentanyl produced plasma levels within the therapeutic range within two minutes, with median bioavailability values of 55 % (pH 6 formulation) and 71% (pH 8 formulation) . Mean peak serum concentrations were 0.33 ng/mL (pH 6) and 0.37 ng/mL (pH 8) respectively, compared with 2.33 ng/mL after intravenous fentanyl.Conclusion: We conclude that the absorption of intranasal fentanyl is rapid, the bioavailability more than half that of intravenous administration and that the formulations studied are suitable for more extensive clinical evaluation.