Absorption Of Fentanyl Research Articles

(732): Patients’ experience with fentanyl effervescent buccal tablets: Interim analysis of a long-term, multicenter, open-label study in cancer-related breakthrough pain

Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. The results reported here represent the 3-month interim analysis of an ongoing safety study of FEBT in the treatment of cancer-related breakthrough pain (BTP). The study enrolled patients who were receiving stable doses of around-the-clock opioids for baseline pain and supplemental opioids for BTP. As of July 29, 2005, 129 participants (aged 24 to 95 years) constituted the safety population of the open-label phase, having consumed at least 1 dose of FEBT (100-800 μg).

(804): Open-label study of fentanyl effervescent buccal tablets in patients with noncancer pain and breakthrough pain: Patient preference assessment

Many patients with chronic pain experience breakthrough pain (BTP); no currently available pharmacologic agent is optimal for managing BTP. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This is an ongoing 2-year, multicenter study of FEBT in opioid-tolerant patients with chronic pain and BTP; its primary objective is to assess the safety and tolerability of FEBT. This abstract reports interim results for a secondary objective: assessment of patient preference for FEBT versus their previous supplemental opioids after 1 month of use. Eligible patients (18-80 years old) with low back pain, diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, trauma, osteoarthritis, or chronic headache experienced 1-4 episodes/day of BTP and were receiving around-the-clock and supplemental opioids. After titration, patients managed episodes of BTP with 100-800 μg of FEBT. Of 98 enrolled patients, 94 (61% women) consumed at least 1 dose of FEBT; 86 completed titration, and 85 continue with open-label therapy. Previous supplemental opioids included oxycodone (23%), hydrocodone-acetaminophen (22%), and oxycodone-acetaminophen (14%). Effective doses of FEBT were 100 μg for 1%, 200 μg for 15%, 400 μg for 16%, 600 μg for 16%, and 800 μg for 44% of patients; 9% found no effective dose. Patients used FEBT for a mean of 58.2 BTP episodes total or 2.5 per day. After 1 month of open-label therapy with FEBT, 73% of patients preferred FEBT to their previous supplemental opioids, 75% believed FEBT provided a more rapid onset of analgesia than their previous supplemental opioids, 66% found FEBT easier to use than their previous supplemental opioids, and 64% found FEBT more convenient than their previous supplemental opioids. Current results suggest that a majority of patients with chronic pain and BTP prefer FEBT over their previous supplemental opioids. Many patients with chronic pain experience breakthrough pain (BTP); no currently available pharmacologic agent is optimal for managing BTP. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This is an ongoing 2-year, multicenter study of FEBT in opioid-tolerant patients with chronic pain and BTP; its primary objective is to assess the safety and tolerability of FEBT. This abstract reports interim results for a secondary objective: assessment of patient preference for FEBT versus their previous supplemental opioids after 1 month of use. Eligible patients (18-80 years old) with low back pain, diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, trauma, osteoarthritis, or chronic headache experienced 1-4 episodes/day of BTP and were receiving around-the-clock and supplemental opioids. After titration, patients managed episodes of BTP with 100-800 μg of FEBT. Of 98 enrolled patients, 94 (61% women) consumed at least 1 dose of FEBT; 86 completed titration, and 85 continue with open-label therapy. Previous supplemental opioids included oxycodone (23%), hydrocodone-acetaminophen (22%), and oxycodone-acetaminophen (14%). Effective doses of FEBT were 100 μg for 1%, 200 μg for 15%, 400 μg for 16%, 600 μg for 16%, and 800 μg for 44% of patients; 9% found no effective dose. Patients used FEBT for a mean of 58.2 BTP episodes total or 2.5 per day. After 1 month of open-label therapy with FEBT, 73% of patients preferred FEBT to their previous supplemental opioids, 75% believed FEBT provided a more rapid onset of analgesia than their previous supplemental opioids, 66% found FEBT easier to use than their previous supplemental opioids, and 64% found FEBT more convenient than their previous supplemental opioids. Current results suggest that a majority of patients with chronic pain and BTP prefer FEBT over their previous supplemental opioids.

Fentanyl Effervescent Buccal Tablets

Noninvasive opioid delivery systems that provide rapid pain relief offer advantages for outpatients with high-intensity, rapid-onset pain. fentanyl effervescent buccal tablets (FEBT) employ a novel delivery system that uses an effervescence reaction to enhance the rate and efficiency of oral transmucosal fentanyl absorption. Enhanced absorption of fentanyl is considered to be caused primarily by dynamic shifts in pH within the microenvironment lying between a dissolving tablet and the buccal mucosa. The initial drop in pH is a result of the dissolution of citric acid, which combines with bicarbonate to form carbonic acid. Carbonic acid dissociates into carbon dioxide and water. As carbon dioxide dissipates, the pH increases. The initial drop in pH favors the dissolution of fentanyl citrate, the ionized form of fentanyl, whereas the subsequent increase in pH favors the formation of nonionized fentanyl. Nonionized fentanyl prefers to associate with the more lipophilic molecules in the buccal mucosa rather than stay in solution surrounded by water molecules. The dynamic changes in pH that occur on the surface of FEBT as they dissolve can be measured in vitro. Pharmacokinetic studies in healthy volunteers have demonstrated more rapid and more complete fentanyl absorption with effervescent buccal delivery compared with noneffervescent buccal delivery. Controlled clinical studies in patients with high-intensity, rapid-onset pain are the next step in defining the clinical utility of this enhanced buccal absorption of fentanyl.

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.

Inter- and intra-individual variability in transdermal fentanyl absorption in cancer pain patients

A transdermal therapeutic system (TTS) is recommended for use in chronic cancer pain, particularly in the advanced stages. The aim of this trial was to study intra- and interindividual variabilities in fentanyl transdermal absorption and investigate physiological and clinical parameters that can influence the absorption in patients treated using a TTS for moderate to severe cancer pain. The study group consisted of 108 patients (71 men and 37 women; mean age, 61.3 years) with chronic cancer pain. A total of 507 patches were analysed. The TTSs used to administer fentanyl were removed after a 72-h period. The amount of fentanyl remaining in the patches was determined using a high-performance liquid chromatography method with ultraviolet detection. Depending on the analgesic requirements of the patient, the dose of fentanyl administered by TTS ranged from 25 to 500 microg/h. The study period was 6 months. Large interindividual variability in the amount of remaining fentanyl in the patches occurred. For 58.1% of patches, absorption was 60 to 84%; for 33.2% of them, it was lower; and for 8.8%, it was higher than this range. The intra-individual variability ranged from 2.8 to 75.1%. The bioavailability of fentanyl was statistically different according to patient age. Patients >75 years of age absorbed 50% of the fentanyl during the selected 72-h period, whereas patients <65 years absorbed 66%. Moreover, there is a significant difference in the percentage of absorbed fentanyl according to the type of cancer. The absorption was higher in patients with breast or digestive cancer than in those with lung cancer. Hyperhidrosis, hypertrichosis and the localization of patches on the skin did not influence bioavailability. For the entire group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

Postoperative pain management with a patient-controlled transdermal delivery system for fentanyl

The efficacy and safety of fentanyl hydrochloride patient-controlled trans-dermal system (PCTS) for management of acute postoperative pain are discussed. Fentanyl hydrochloride PCTS is a self-contained, needle-free, credit-card-sized fentanyl-delivery system that is worn on the patient's arm or chest. The system uses iontophoretic technology to actively deliver preprogrammed doses of fentanyl into the systemic circulation when activated by the patient on demand. PCTS is as safe and effective as i.v. morphine patient-controlled analgesia and superior to placebo for managing acute postoperative pain. Fentanyl absorption from PCTS is clinically insignificant when the device is not activated. This contrasts with the transdermal fentanyl patch, which delivers fentanyl continuously for 72 hours via passive absorption and is indicated only for use in the management of chronic pain. Fentanyl hydrochloride PCTS is a self-contained iontophoretic fentanyl-delivery system that provides patients control over pain management and consistent management of pain without analgesic peaks and troughs.

使用済みフェンタニルパッチ内のフェンタニル残存量の測定および残存率に影響を及ぼす要因―個人差および貼付部位―

Though a change from oral morphine dosage forms to transdermal fentanyl patches achieved good pain relief in 70% of cancer patients, the remaining 30 % still showed poor pain control or fentanyl vitiation. In some cases when pain control was poor, effective pain-relief was only sustained for 3 days. This suggests that the absorption of fentanyl was being hampered in such cases.In view of these findings, we investigated the relationship between the amount of fentanyl released and plasma fentanyl concentrations. To estimate amounts of fentanyl delivered into the skin, we measured the amount of fentanyl remaining in fentanyl patches after 3 days of continuous use. Amounts of fentanyl remaining in the patches ranged from 41-58%, which was close to the design residual amount of 40%. However, the amount of fentanyl release varied between patches applied to patients at home and those applied to hospitalized patients, and the fentanyl was more steadily released from patches applied to the sides of the body or back than those applied to the chest. The fentanyl release also varied with the caregivers who were applying them.Thus, it is essential to apply patches according to the instructions to ensure steady release. In this study, we observed that plasma fentanyl concentrations rapidly decreased for some patients 3 days after patch application so in such cases, patches should be changed every 2 days.

Pharmacokinetics and Dose Proportionality of Fentanyl Effervescent Buccal Tablets in Healthy Volunteers

Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This study was undertaken to characterise the pharmacokinetics and assess the dose proportionality of FEBT in healthy volunteers within the potential therapeutic dose range. Twenty-five healthy adults (mean age 33 years) completed a single-dose, randomised, open-label, four-dose, four-period, crossover study of FEBT. They were administered FEBT 200, 500, 810 or 1080microg. The subjects in this study were not opioid tolerant; therefore, naltrexone was administered to block any opioid receptor-mediated effects of fentanyl. Venous blood samples for measurement of serum fentanyl concentrations were obtained over 36 hours following dosing. Adverse events were recorded throughout the study. The pharmacokinetics of FEBT were characterised by an absorption phase with a median time to reach maximum serum concentration (tmax) of 0.75-0.99 hours that was consistent irrespective of dose. Mean serum fentanyl concentrations exhibited a biexponential decline from peak after FEBT 200 and 500microg doses and a triexponential decline after FEBT 810 and 1080microg doses. The maximum serum concentration (Cmax) of fentanyl was proportional up to and including the 810microg dose. The increase in Cmax was 20% less than proportional at the 1080microg dose. Systemic exposure to fentanyl, as measured by the area under the serum concentration-time curve from time zero to infinity (AUCinfinity), increased proportionally with increasing doses of FEBT (200-1080microg). No serious adverse events were reported during the study. The pharmacokinetics of FEBT were characterised by a high early fentanyl concentration as a result of absorption across the buccal mucosa of the oral cavity, which results in bypassing first-pass metabolism. This high early tmax contributed to enhanced early systemic fentanyl exposure. Maximum concentration and AUCinfinity of FEBT increased in a dose-proportional manner from 200 to 810microg. This study provides preliminary pharmacokinetic data for FEBT across the potential therapeutic dose range.

Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Skin samples from 5 Greyhounds. Skin samples from the dogs' thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32 degrees C). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Mean+/-SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01+/-0.05 microg/cm2 of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.

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.

Role of P‐Glycoprotein in the intestinal absorption of morphine, fentanyl and methadone

Clinical Pharmacology &amp; Therapeutics (2003) 73, P58–P58; doi:

Transdermal fentanyl: little absorption in two patients with systemic sclerosis?

Two patients suffering from systemic sclerosis (SSc) were treated with the 25 micro/hr transdermal fentanyl patch for pain from either deltoid muscle tendinitis of the left arm or from ischemia of the left-hand thumb. When the medication was changed to either oral morphine or oral methadone, the effects did not correspond to the drug conversion table. These findings suggest that patients with SSc and other systemic skin diseases may be at risk for limited absorption of transdermal fentanyl. In contrast, no restriction of the absorption of transdermal testosterone was observed.

Adrenaline markedly improves thoracic epidural analgesia produced by a low‐dose infusion of bupivacaine, fentanyl and adrenaline after major surgery: A randomised, double‐blind, cross‐over study with and without adrenaline

Basic pharmacological research indicates that there are synergistic antinociceptive effects at the spinal cord level between adrenaline, fentanyl and bupivacaine. Our clinical experience with such a mixture in a thoracic epidural infusion after major surgery confirms this. The objectives of the present study were to evaluate the effects on postoperative pain intensity, pain relief and side effects when removing adrenaline from this triple epidural mixture. A prospective, randomised, double-blind, cross-over study was carried out in 24 patients after major thoracic or abdominal surgery. Patients with only mild pain when coughing during a titrated thoracic epidural infusion of about 10 ml.h-1 of bupivacaine 1 mg.ml-1, fentanyl 2 micrograms.ml-1, and adrenaline 2 micrograms.ml-1 were included. On the 1st and 2nd postoperative days each patient was given a double-blind epidural infusion, at the same rate, with or without adrenaline. The effect was observed for 4 h or until pain when coughing became unacceptable in spite of a rescue analgesic procedure. Rescue analgesia consisted of up to two epidural bolus injections per hour and i.v. morphine if necessary. All patients received rectal paracetamol 1 g, every 8 h. Fentanyl serum concentrations were measured with a radioimmunoassay technique at the start and end of each study period. Main outcome measures were extent of sensory blockade and pain intensity at rest and when coughing, evaluated by a visual analogue scale, a verbal categorical rating scale, the Prince Henry Hospital pain score, and an overall quality of pain relief score. The number of hypaesthetic dermatomal segments decreased (P < 0.001) and pain intensity at rest and when coughing increased (P < 0.001) when adrenaline was omitted from the triple epidural mixture. This change started within the first hour after removing adrenaline. After 3 h pain intensity when coughing had increased to unacceptable levels in spite of rescue analgesia (epidural bolus injections and i.v. morphine). Within 15-20 min after restarting the triple epidural mixture with adrenaline, pain intensity was again reduced to mild pain when coughing. Serum concentration of fentanyl doubled from 0.22 to 0.45 ng.ml-1 (P < 0.01), and there was more sedation during the period without adrenaline. Adrenaline increases sensory block and improves the pain-relieving effect of a mixture of bupivacaine and fentanyl infused epidurally at a thoracic level after major thoracic or abdominal surgery. Serum fentanyl concentrations doubled and sedation increased when adrenaline was removed from the epidural infusion, indicating more rapid vascular absorption and systemic effects of fentanyl.

Fentanyl remaining in a transdermal system following three days of continuous use.

To determine whether there was a sufficient amount of fentanyl remaining in a patch that had been used continuously for 3 days to warrant establishment of disposal policies to prevent diversion of fentanyl. Nine patches were applied and removed by hospice nurses after 3 days of continuous use on hospice patients with cancer. Patches were analyzed for the remaining fentanyl contents using the Coat-A-Count Fentanyl radioimmunoassay. Five 2.5-mg patches and four 10.0-mg patches were opened, solubilized with methanol, diluted with water, and analyzed in duplicate. An unused 2.5-mg patch also was analyzed as a control and showed a 94% recovery of fentanyl. A methanol blank was negative for fentanyl. The study determined the amount of fentanyl in milligrams remaining in a used patch. Using pharmacokinetics principles, this quantity was compared with a potential lethal dose of fentanyl. Analysis showed 0.7-1.22 mg remaining in the 2.5-mg patches and 4.46-8.44 mg remaining in the 10.0-mg patches. These numbers represent 28-84.4% of the original contents. Using the pharmacokinetic values of the volume of distribution of 4L/kg and a potential lethal blood concentration of 3.7 micrograms/L, one can calculate the potential lethal dose for a 70-kg person to be 1036 micrograms. This is well within the amount remaining in the patch. This study also demonstrated that a wide patient variability exists in the absorption of fentanyl from the patch. There is a sufficient amount of fentanyl available for abuse and misuse after 3 days of therapeutic use. Adequate disposal policies currently are not established and need to be implemented.

Biopharmaceutics of a New Transdermal Fentanyl Device

Compared with conventional routes of delivering potent analgesics to postoperative patients, transdermal administration of fentanyl offers the advantages of simplicity and noninvasive delivery. The only available form of transdermal fentanyl, the Duragesic system, has been implicated in preventable patient deaths when used for postoperative analgesia and is contraindicated in the management of postoperative pain. We examined the biopharmaceutics of a new transdermal fentanyl device developed by Cygnus and intended for use as a postoperative analgesic to see whether the new formulation offers pharmacokinetic advantages that might permit safe use in postoperative patients. We studied 15 consenting male adult surgical patients. Patients received 650 or 750 micrograms intravenous fentanyl as part of the induction of anesthesia. Plasma fentanyl concentrations were measured over the following 24-h period. On the first postoperative day, 24 h after the intravenous dose of fentanyl, a transdermal fentanyl device was placed on the upper torso of the patient for 24 h and then removed. Plasma fentanyl concentrations were measured for 72 h after application of the transdermal fentanyl device. From the concentration versus time profile for the 24 h after intravenous fentanyl administration we determined each patient's clearance and unit disposition function by moment analysis and constrained numeric deconvolution, respectively. From the concentration versus time profile for the 72 h after application of the transdermal device we determined the amount of fentanyl absorbed and the rate of absorption, again by moment analysis and constrained numeric deconvolution. The residual fentanyl in the transdermal fentanyl device was measured, permitting calculation of the absolute bioavailability of transdermally administered fentanyl. Of the 14 subjects who received transdermal fentanyl, 3 had clinically significant fentanyl toxicity, mandating early removal of the device. The range during the plateau from 12 to 24 h in subjects still wearing the device was 0.34-6.75 ng/ml, a 20-fold range in concentration. In subjects wearing the device for 24 h, the terminal half-life of fentanyl after removal of the device was 16 h. The bioavailability of transdermally administered fentanyl was 63 +/- 35% coefficient of variation. The rate of fentanyl absorption from 12-24 h ranged from 10 to 230 micrograms/h in subjects still wearing the device. In two subjects, the rate within the first 6 h briefly exceeded 300 micrograms/h. Both of these subjects demonstrated fentanyl toxicity, requiring early removal of the device. The Cygnus transdermal fentanyl device shows great variability in the rate of fentanyl absorption, resulting in highly variable plasma fentanyl concentrations. Some persons may rapidly absorb fentanyl from the device in the first few hours after application, leading to fentanyl toxicity. The variability in effect of the Cygnus transdermal fentanyl device is appreciably greater than that reported for the currently available Duragesic transdermal fentanyl device, which is contraindicated for postoperative analgesia.

Buccal Absorption of Fentanyl Is pH-Dependent in Dogs

Analgesia and sedation have been achieved noninvasively by fentanyl administration through the oral and nasal mucosa. In theory, the transmucosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrounding pH. The authors tested this hypothesis in dogs. Under general anesthesia, each of six mongrel dogs was given fentanyl on repeated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accomplished by placement of a pH-buffered solution of fentanyl into a specially constructed cell, which was clamped to the dog's buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. Femoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasma concentration verses time profile. Terminal elimination half-life, bioavailability, and permeability coefficients were calculated using standard pharmacokinetic techniques. The variables peak plasma concentration, bioavailability, and permeability coefficient increased three- to fivefold as the pH of the fentanyl buccal solution increased and more fentanyl molecules became unionized. There was no difference in terminal elimination half-life after intravenous fentanyl (244 +/- 68 min) or buccal fentanyl administration (pH 7.7, 205 +/- 89 min; pH 7.2, 205 +/- 65 min; pH 6.6, 196 +/- 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa. The buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. Most likely, this is because of an increase in the fraction of unionized fentanyl.

Transdermal Fentanyl for Cancer Pain Repeated Dose Pharmacokinetics

The transdermal therapeutic system (fentanyl), or TTS(fentanyl), continuously delivers fentanyl for up to 72 h. The transdermal therapeutic system (fentanyl)-100 delivers approximately 100 micrograms/h. The repeated dose pharmacokinetics of this drug using the recommended dosing interval have not been evaluated previously and were determined in the present study. Blood samples were obtained from ten opioid-tolerant cancer patients who received five applications of TTS(fentanyl) at 72-h intervals. A sample of venous blood was taken before each dose; multiple samples were taken during and after the fifth application. A gas chromatographic/mass spectrometry method was used to assay fentanyl (limit of detection 0.2 ng/ml). For the fifth dose, the mean (SD) maximum concentration was 2.6 (1.3) ng/ml and the mean (SD) area under the serum fentanyl concentration-time curve (0-72 h) was 116.9 (59.9). Following removal of the system, the mean (SD) apparent half-life was 21.9 (8.9) h. There were no differences among the serum fentanyl concentrations measured before the second through fifth doses. Fentanyl absorption was 47% complete at 24 h, 88% complete at 48 h, and 94% complete at 72 h. The mean (SD) dose delivered during the 72-h period was 4.3 (1.1) mg. A first-dose trough concentration predicted from fifth-dose kinetics and the actual first-dose trough concentration were very similar. Adverse effects ascribed to the transdermal system were minimal. These results suggest that steady-state serum concentrations are approached by the second dose of TTS(fentanyl) and that the kinetics are stable with repeated dosing. The apparent half-life following system removal is relatively long, indicating ongoing absorption from a subcutaneous depot.

Absorption and Bioavailability of Oral Transmucosal Fentanyl Citrate

Oral transmucosal fentanyl citrate (OTFC) is a novel, noninvasive dosage form of fentanyl used to provide children and adults with sedation, anxiolysis, and analgesia. In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 micrograms/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 h for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl, clearance (mean +/- standard deviation) was 0.67 +/- 0.15 l/min; volume of distribution at steady state was 287 +/- 79 l; and the terminal elimination half-life was 425 +/- 102 min. Peak plasma concentrations of fentanyl were higher (3.0 +/- 1.0 vs. 1.6 +/- 0.6 ng/ml, P = 0.01) and occurred sooner (22 +/- 2.5 vs. 101 +/- 48.8 min, P = 0.003) after OTFC than after oral solution administration. Plasma concentrations of fentanyl after OTFC decreased rapidly, to less than 1.0 ng/ml within 75-135 min after the beginning of administration. Peak absorption rate was greater (11.1 +/- 4.3 vs. 3.6 +/- 2.1 micrograms/min, P = 0.004) and occurred much sooner after OTFC than after oral solution administration (19 +/- 2.6 vs. 87.5 +/- 38.1 min, P = 0.001). Systemic bioavailability was greater after OTFC administration than after the oral solution (0.52 +/- 0.1 vs. 0.32 +/- 0.1, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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°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/cm 2 membrane. When presented with a smaller concentration (≤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/cm 2, respectively. Using the higher fentanyl concentrations (≤200 ng/mL) uptake by the Omnis membrane was 11 ng/cm 2 compared with only 2 ng/cm 2 by the Shiley. The Bentley BCM 7 and Terumo Capiox 1108 microtubular microporous membranes (type 3) did not show absorption of fentanyl using isolated or intact membrane models. It is concluded that oxygenators of different design and/or composition have different capacities for fentanyl uptake.