Delivery Of Fentanyl Research Articles

Transdermal delivery of fentanyl by electroporation. I. Influence of electrical factors.

Electroporation, a method of reversibly permeabilizing lipid bilayers by the application of an electric pulse, has been shown to induce increased transdermal passage of molecules. The aim of the present report was to study in vitro with hairless rat skin the potential of electroporation for transdermal delivery of fentanyl. The application of electric pulses can strongly promote transdermal delivery of fentanyl compared to passive diffusion through untreated skin. We also point out that the choice of the waveform of the electric pulses is important: at the same applied energy, a few exponentially-decaying (ED) pulses increased fentanyl permeation more than a few square-wave pulses and to the same extent as the repeated application of higher voltage-shorter duration ED pulses. A factorial design showed that the voltage, duration, and number of ED pulses allowed control of the quantity of drug transported through the skin. Skin electroporation could be a good way to improve the transdermal diffusion of fentanyl.

Transdermal delivery of fentanyl by electroporation. II. Mechanisms involved in drug transport.

The aim of the present report was to systematically analyze the mechanisms involved in fentanyl transdermal transport by skin electroporation. The study was performed in vitro with full-thickness hairless rat skin, skin electroporation being carried out with five exponentially-decaying pulses of 100 V applied voltage and around 600 ms pulse duration. Transport during and after pulsing are both important in transdermal delivery of fentanyl by skin electroporation. Rapid transport occurred during pulsing due to electrophoresis and diffusion through highly permeabilized skin. No electroosmosis was observed. The slow post-pulse passive transport was explained by lasting changes in skin permeability. Measurements of fentanyl quantities in the skin demonstrated that pulses rapidly loaded the viable part of the skin with fentanyl and hence rapidly overcame skin barrier. The different contributions of the transport mechanisms appear to depend on the physicochemical parameters of the transported molecule as well as the solution, suggesting that mechanistic analysis and careful consideration of formulation variables are essential for the development and optimization of drug delivery by skin electroporation.

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 μg/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 μg 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.

Acute Toxic Delirium

Acute Toxic Delirium

Postoperative Pain Control with a New Transdermal Fentanyl Delivery System

A new transdermal delivery system for fentanyl is available in two strengths: 70-80 and 90-100 micrograms.kg-1.h-1 (40- and 60-cm2 patches, respectively). Their short onset and 24-h drug delivery make them attractive for postoperative pain control. Both doses of the new transdermal fentanyl patches were evaluated for the relief of postoperative pain in 143 patients after gynecologic exploratory laparotomy. The study was conducted at four centers using a prospective, randomized, placebo-controlled, double-blind format. Patients were randomly assigned to one of three study groups: group 1 patients received two placebo patches: group 2 patients received a 40-cm2 fentanyl patch and a 60-cm2 placebo patch; and group 3 patients received a 60-cm2 fentanyl patch and a 40-cm2 placebo patch. Patient-controlled morphine use and pain, sedation, and comfort scores were assessed postoperatively every 4 h for 36 h after patch placement. Patients' assessment of their analgesia was significantly (P < or = 0.05) better in group 2 at 16 and 24 h and in group 3 at 8, 12, 16, 20, and 24 h postoperatively, compared with the patients in group 1. Patients in groups 2 and 3 required less supplemental morphine to maintain satisfactory analgesia than did the patients in group 1. Patients in groups 2 and 3 had greater incidences of pruritus, erythema, and respiratory depression than did those receiving placebo. Concern exists regarding the side effects of this this new transdermal fentanyl patch. Therefore, this new patch will need further research before it can be recommended as an adjunct in controlling postoperative pain.

Pharmacokinetics of inhaled liposome-encapsulated fentanyl.

Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers. After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution. The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively. The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.

The Iontophoresis of Fentanyl Citrate in Humans

Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge-dose relation in the delivery of fentanyl by iontophoresis. Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA.min), iontophoresis 1.0 mA for 2 h (120 mA.min), and iontophoresis 2.0 mA for 2 h (240 mA.min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay. No fentanyl was detected after passive (0.0-mA) fentanyl delivery. The following results were obtained for the 1.0- and 2.0-mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 119 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng.ml-1.min (P = 0.003); and mean elimination half-lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid-related effects occurred frequently in the 1.0- and 2.0-mA administration groups. Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge-dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.

Postoperative analgesia with transdermal fentanyl following lower abdominal surgery

In a randomised, placebo-controlled, double-blind study involving 81 patients undergoing total abdominal hysterectomy, the postoperative analgesia provided by transdermal fentanyl given at 25, 50, or 75 micrograms.h-1 for 72 h was compared with a placebo group. The efficacy of the Transdermal Therapeutic System was related to the rate of fentanyl delivery, higher rates being associated with significantly lower visual analogue pain scores (24, 20, 17 and 13, for placebo, 25, 50 and 75 micrograms.h-1 respectively) and reduced patient controlled analgesia morphine requirements (44, 38, 33 and 31 mg respectively). Patients' overall sedation scores were not increased by transdermal fentanyl, but respiratory rates decreased with higher transdermal fentanyl dosage.

Analgésie contrôlée par le patient : étude de la demande en fentanyl chez le brûlé à la phase aiguë

This study assessed over the first post-burn week the patients' demands for opiates delivered with a PCA device, changes in opioid delivery along the day, especially during painful events and the incidence of side effects. Twenty-two patients (8 women, 14 men), mean age 33 years (± 12 SD), mean BSA 21 % (± 13 SD), mean deep dermal burn 12 % (± 11 SD) were included. Fentanyl was delivered by i.v. route using a PCA device during the first 6 days post burn. Bolus dose was fixed at 1 μg · kg −1, lock-out time at 30 min and the 4 h limit dose at 7 μg · kg −1. The following data were collected every day : satisfied and non-satisfied demands, total daily dose, demands during and after dressing change period (4 h), during afternoon (10 h) and overnight periods (10 h). Heart rate (HR), respiratory rate (RR), blood pressure (BP), Pa co 2 and Sp o 2 were also monitored. The mean total daily demands were similar from D1 to D6 (28 ± 7). Around 7 demands/day were not satisfied. The mean total daily satisfied demands were also the same : 21 ± 5. Individual demands were over a wide range (minimum : 15, maximum : 41 demands/day for total demands and 13 and 34 respectively for the satisfied ones). Mean fentanyl delivery was 1,7 ± 0,1 μg · kg −1 · h −1 during dressing period, 0,9 ± 0,3 μg · kg −1 · h −1 during afternoon period (10 h) and 0,5 ± 0,2 during overnight period (10 h). No-satisfied demands were around 4 boluses during dressing change period, 2 boluses during afternoon period, and one bolus during overnight period. Neither HR nor BP were modified for more than 20 % of control values ; RR never decreased under 12 c · min −1 and Pa co 2 remained unchanged. This study showed that the provision of analgesia in burn injury requires large doses of opioids. Individual demands are scattered over a wide range. The need for analgesics remains unchanged for several days. A PCA device is an efficient and safe tool for administration of opioids. Analgesia is appropriate, except during the dressing period.

System functionality and physicochemical model of fentanyl transdermal system

Fentanyl is an opioid traditionally administered by infusion or injection and more recently in a rate-controlled transdermal dosage form. This system is a four-layer laminate on a protective liner. A backing layer seals and protects the drug reservoir, the source for continuous delivery of fentanyl. A membrane controls the release rate of fentanyl from the system. An adhesive layer attaches the system to skin and releases an initial loading dose of fentanyl. The rate of fentanyl delivery through skin is determined by the system and the skin at the application site. The release rate from the system is approximated by Fick's first law of diffusion and is controlled by the rate-controlling membrane. A complete simulation model that combines both in vitro release data and the pharmacokinetic model has been developed and used to show the influence of various physiologic and system variables on serum fentanyl concentrations.

Transdermal fentanyl: Clinical trial at the University of Colorado Health Sciences Center

Transdermal fentanyl is a new fentanyl delivery system recently approved by the FDA for use in patients with chronic pain. In an open-label clinical trial, 5 patients with cancer pain were switched to transdermal fentanyl patches. Patients were evaluated with visual analogue scales (VAS) for pain, mood, and pain relief. A Functional Laving Index—Cancer and a symptom questionnaire were filled out 2 wk and 4 wk after initiation of transdermal fentanyl patches. After 2 wk of treatment all patients had VAS improvements in pain control. Patients experienced a decrease in constipation, improved appetite, and improved mood. One patient had drowsiness, which limited dose. The improvements in pain control allowed these patients to perform tasks that they had previously not felt well enough to do.

Transdermal Fentanyl Delivery System vs Morphine IM

Transdermal Fentanyl Delivery System vs Morphine IM

Transdermal fentanyl for pain control in patients with cancer

Five cancer patients experienced satisfactory pain relief for periods of 3–156 days using continuous transdermal delivery of the narcotic fentanyl. The patients, aged 16–68 years, had all been experiencing pain and were either unable to take oral analgesic medications or these agents were ineffective in controlling pain. Doses were adjusted to individual patient needs and varied from 75 μg/h to 350 μ/h ( median = 225 μg/ h). Plasma fentanyl levels reflected the administered dose and remained constant throughout the treatment. Transdermal delivery of narcotics provides a new option for the cancer patient unable to achieve satisfactory analgesia with oral medications.

POSTOPERATIVE ANALGESIA WITH FENTANYL: PHARMACOKINETICS AND PHARMACODYNAMICS OF CONSTANT-RATE I.V. AND TRANSDERMAL DELIVERY

We have investigated the use of constant-rate delivery of fentanyl by i.v. and transdermal routes for the treatment of pain after major surgery. Forty-five males, ASA I-III, received in a double-blinded fashion either placebo (n = 6) or fentanyl (n = 39) i.v. at one of four dose rates (25, 50, 100 or 125 micrograms h-1). Stable serum concentrations of fentanyl were produced by the end of surgery and were maintained for a total of 24 h. Calculated clearance of fentanyl was 1.05 +/- 0.38 litre min-1 and was not related to weight or age. Both the 100- and 125-micrograms h-1 dose rates produced significant analgesic efficacy as assessed by postoperative morphine requirements. Mean serum concentrations of fentanyl in these groups were 1.42 +/- 0.14 (SD) and 1.90 +/- 0.30 ng ml-1, respectively. One of 10 patients receiving fentanyl 100 micrograms h-1 and three of nine patients receiving 125 micrograms h-1 had evidence of respiratory depression. Eight additional patients were treated with a transdermal drug delivery system containing fentanyl (TTS-fentanyl). Steady-state serum concentrations in this group were 2.15 +/- 0.92 (SD) ng ml-1. Post-operative morphine requirements were minimal (less than 0.5 mg h-1) and PaCO2 remained acceptable in all patients. Serum concentrations of fentanyl increased slowly (15 h to plateau) and decreased slowly (apparent half-life, 21 h). We conclude that delivery of analgesic doses of fentanyl is feasible by the transdermal route.

PLASMA FENTANYL CONCENTRATIONS DURING TRANSDERMAL DELIVERY OF FENTANYL TO SURGICAL PATIENTS

Plasma fentanyl concentrations were measured during and after transdermal fentanyl delivery in groups of patients undergoing general surgery. At 8 and 12 h, concentrations did not differ from those observed in a matched group of patients receiving fentanyl by i.v. infusion. At 24 h, concentrations were significantly lower in one of the transdermal groups. Plasma fentanyl clearance did not differ significantly between the groups. Plasma fentanyl concentrations decreased slowly after removal of the transdermal system.