Serum Concentrations Of Fentanyl Research Articles

Oral and buccal abuse of transdermal opioids : an underdetected but potentially lethal practice

Objectives : Transdermal opioid patches (TOPs) are effective and well tolerated in patients with moderate to severe chronic pain syndromes. Their specific pharmacological properties, however, make them prone to abuse. The objective of this article is to describe the practice of oral and buccal abuse of TOPs and to discuss its clinical implications. Methods : We present the case of a patient admitted to the intensive care unit after oral abuse of transdermal opioid patches. Additionally, a narrative literature review on the topic is conducted, referring to Pubmed and Embase. Results : Oral or buccal TOP abuse is the most frequent method of TOP abuse, followed by intravenous injection, inhaling, and applying multiple patches. The main reasons for TOP abuse include drug addiction, suicidal behavior and self-medication. Oral ingestion is potentially lethal because of the high doses of fentanyl that are found in a single patch. Buccal abuse results in fast elevations of fentanyl serum concentrations, caused by transmucosal absorption of fentanyl, thus bypassing hepatic metabolism. During emergency management, naloxone should be administered in a continuous infusion, given the high risk of recurrence of symptoms. Evidence suggests that transdermal buprenorphine is safer in terms of abuse potential. This is explained by its ceiling effect for respiratory depression and its lower peak effects in supratherapeutic doses. Risk factors for abuse include history of substance use disorder, prior opioid overdose and mental illness. Patients with suspected opioid abuse should be referred to pain clinics, mental health specialists or drug addiction facilities. Conclusion : Oral or buccal abuse is the most reported non-dermal form of TOP abuse. When ingested or chewed, TOPs pose considerable health risks. It is critical to screen patients with chronic opioid therapy regularly for opioid use disorder. When confronted with patients at risk of abuse, close monitoring and referral to specialist care is advised.

Serum Concentration of Fentanyl During Conversion From Intravenous to Transdermal Administration to Patients With Chronic Cancer Pain

To the best of our knowledge, there have been no reports on the pharmacokinetics and pharmacodynamics during the conversion from continuous intravenous infusion (CII) to transdermal fentanyl administration. The primary objective of the present study was to clarify the pharmacokinetic characteristics during this conversion. A secondary objective was to identify an association between serum albumin and the absorption of fentanyl from the transdermal patch. A prospective study was conducted from February 2010 to August 2011 that enrolled 19 patients with chronic cancer pain. Patients were classified into 2 study groups according to body mass index and albumin level. All patients received the conversion from CII to transdermal fentanyl using a 2-step taper of CII over 6 hours. Comparisons of efficacy, toxicity, and serum fentanyl concentrations between study groups were analyzed at baseline, 3, 6, 9, 12, 15, 18, and 24 hours after initiation of the conversion. The dose-adjusted serum fentanyl concentrations for all patients were significantly decreased at 15 to 24 hours after conversion compared with baseline, although pain intensity and the number of rescue events remained stable during the conversion. The dose-adjusted serum fentanyl concentrations at 9 to 24 hours were significantly reduced in the low albumin group compared with the normal albumin group (P<0.05). Our study demonstrated that the dose-adjusted serum fentanyl concentrations remained relatively stable, and pain intensity and the number of rescue events remained stable during conversion. Hypoalbuminemia was strongly associated with poor absorption of transdermally administered fentanyl.

ChemInform Abstract: Solutions for the Clinical Problems of Analgesics for Cancer Pain Treatment in Japan

AbstractReview: 89 refs.

Solutions for the Clinical Problems of Analgesics for Cancer Pain Treatment in Japan

The pain experienced by cancer patients can be managed in 70-90% of cases by the World Health Organisation protocol for cancer pain. However, cancer pain treatment in Japan is not sufficiently effective. To use medicine safely and effectively, various problems must be solved. Therefore, in this study, appropriate usage of cancer pain treatment was examined. We were able to use acetaminophen suppositories (800 mg each) in cancer pain patients. It was suggested that high serum concentrations of oxycodone and hydrocotarnine might be observed in geriatric patients or in the state of decreased hepatic blood flow, making dose adjustment is necessary for such patients. We also clarified that the conversion ratio from oral oxycodone to intravenous ocycodone/hydrocotarnine was 0.71±0.12. In addition, we clarified the pharmacokinetics of controlled-release oxycodone in patients with cancer pain. Moreover, the findings of our study indicate that in the steady state, the serum concentrations of fentanyl are not maintained at a constant level for 3 days following the use of transdermal fentanyl. We established a method of appropriately passing a nasal duct for sustained release of fine granules of morphine sulfate. Resolution of the clinical problems associated with cancer pain treatments is anticipated to allow the proper use of cancer pain treatments in Japan.

Poster Abstracts from the AAAP 20th Annual Meeting and Symposium

Poster Abstracts from the AAAP 20th Annual Meeting and Symposium

Evaluation of an osmotic pump for fentanyl administration in cats as a model for nondomestic felids

To evaluate the reliability of an SC implanted osmotic pump (OP) for fentanyl administration in cats and to compare serum concentrations of fentanyl delivered via an OP and a transdermal patch (TP). Animals-8 spayed female cats. In a crossover design, cats received fentanyl at 25 microg/h via a TP or an OP. All cats were anesthetized for the pump or patch placement (0 hours) and again when it was removed (96 hours). Venous blood samples were collected for measurement of serum fentanyl concentrations at 0, 6, 12, 24, 36, 48, 72, and 96 hours and at 24 and 48 hours after device removal. After a 3-week washout period, the experiment was repeated with each cat receiving the other treatment. Mean serum fentanyl concentrations at 24, 36, 72, and 96 hours were greater when the OP was used than when the TP was used. Mean residence time and half-life were greater when the TP was used. Fentanyl concentration changed significantly faster in initial and elimination phases when the OP was used. Marked interindividual variation in serum fentanyl concentrations was evident with both administration methods. No adverse effects were evident with either method. Use of the OP to administer fentanyl to cats resulted in a shorter initial lag phase to a therapeutic serum concentration, higher bioavailability, and faster elimination after removal, compared with use of a TP. These advantages, in addition to the inability of cats to remove the OP, may make OPs useful for fentanyl administration in nondomestic felids.

Evaluation of the 2.5 mg Fentanyl Patch, Applied Using the Half-side Application Procedure in Patients with Cancer Pain

Occasionally, pain control with the fentanyl patch may lead to overdose at an initial dose of 2.5 mg, as well as during dose increase from 2.5 to 5.0 mg. Respiratory depression and other adverse drug reactions associated with fentanyl overdose have been observed in several of our patients. We developed a procedure for applying one-half of the fentanyl patch formulations and evaluated the new mode of application by examining the fentanyl concentration in 32 patients with cancer-related pain who had been using the fentanyl patch for pain control. While some patients were treated with the full-sized 2.5-, 5.0-, or 7.5-mg formulations, others were treated with the half-sized 2.5-mg formulation. The fentanyl patch was equally divided by drawing a line on the side on which the product name and dose were written. Tegaderm was applied to the patient's skin, and after detaching from the protective liner, half of the patch was applied to overlap Tegaderm along the line and the other half applied directly to the skin. Blood samples were collected 48-72 h after patch application. The mean serum concentration of fentanyl given in the half-sized 2.5-mg formulation was 0.286 ng/ml, which was approximately one-half of the concentration of the full-sized 2.5-mg formulation, 0.544 ng/ml. Therefore the 2.5-mg fentanyl patch, applied using the one-half procedure we developed, is clinically useful.

Transdermal Fentanyl in Childhood and Adolescence: A Comprehensive Literature Review

The recently introduced fentanyl transdermal therapeutic system (TTS) with a drug release rate of 12.5 microg/h matches the lower dosing requirements of cancer pain control in children. It is likely that fentanyl TTS will be used in pediatrics with increasing frequency. We compiled the published evidence on pediatric applications of this drug formulation to help physicians get the most benefit from its use. Within this systematic review, a total of 11 observational clinical or pharmacokinetic studies were identified. There are no pediatric randomized or controlled cohort studies. Pharmacokinetic studies poorly described time-concentration profiles after application. The time to reach steady-state serum drug concentrations seems to be longer, clearance (expressed as liters per kilogram per hour) higher, and elimination half-life shorter in children than in adults. There are no fundamental differences in effect or profile of adverse effects compared with adults. Fentanyl TTS may be associated with less constipation compared with morphine use. Frequently, pediatric patients need supplemental mechanical fixation of the fentanyl TTS by means of medical tape. Younger patients tend to have a higher fentanyl requirement when referenced to body weight. Both parents and medical professionals are satisfied with fentanyl TTS to a higher degree than with individual analgesic pretreatment regimens. Fentanyl TTS is a promising option for chronic pain control in children. An approximate conversion factor of 45 mg/day oral morphine to 12.5 microg/h fentanyl TTS is used for initial therapy dose estimation in children receiving long-term morphine therapy. This is conservatively low to avoid respiratory depression. Daily oral morphine equivalent dose should be at least 30 mg/d before fentanyl TTS therapy is started with 12.5 microg/h. Evidence for superiority of fentanyl TTS treatment above conventional opioid administration is both scarce and of low quality. The article gives a comprehensive overview of all pediatric data concerning the fentanyl TTS. Children may take longer to reach steady-state fentanyl serum concentrations than adults, and younger children may require higher doses referenced to body weight than older children or adults. Consequently, there is a need to provide sufficient medication in the phase of therapy initiation to prevent breakthrough pain. The 72-hour dosing schedule recommended by the manufacturers may not be applicable to children because of poor patch adhesiveness. The authors suggest to ensure firm fixation of the fentanyl TTS with additional medical tape if necessary and to change the fentanyl TTS after 48 hours. Transdermal fentanyl in children may exhibit fewer side effects when compared with other opioids, especially constipation. Randomized studies are urgently needed to definitively answer this question.

Relationship between Serum Fentanyl Concentration and Transdermal Fentanyl Dosage, and Intra-individual Variability in Fentanyl Concentration after Application of Fentanyl Patches in Patients with Cancer Pain

It has been reported that fentanyl is released from transdermal fentanyl at a constant rate,the concentration reaches a steady state within 24 hours,and a constant serum concentration of the drug can be maintained through repeated patch application at 72-hour intervals.However,we have encountered a number of patients who experienced pain on the third day after application of the patch,and who were not able to gain satisfactory pain relief even when the dosage was increased.In the current study,serum concentrations of fentanyl were determined to elucidate the relationship between fentanyl concentration and transdermal fentanyl dosage,and intra-individual variability in fentanyl serum concentration after fetanyl patch application in patients with cancer pain.Blood samples were collected from 38 patients at 24,48,and 72 hours since the second or later application of the fentanyl patch.A good correlation was obtained between the dose of transdermal fentanyl and the fentanyl serum concentrations(r=0.9565,0.8785 and 0.9351 at 19-30,45-55 and 65-79 hours,respectively,after patch application).When the intra-individual variabilities in serum concentrations were examined,significant differences were noted between 45-52 and 19-25 hours,between 65-72 and 19-25 hours,and between 65-72 and 45-52 hours after application of patches in a paired analysis of variance(P =0.0038,P <0.0001,and P =0.0029,respectively),showing that fentanyl serum concentrations declined between 24 and 72 hours after application of the patch.These findings indicate that in the steady state,fentanyl serum concentrations may not be maintained at a constant level for 3 days following application of transdermal fentanyl,and that the analgesic effect of the drug may be attenuated by 72 hours after applying the patch.

Comparative bioequivalence study between a novel matrix transdermal delivery system of fentanyl and a commercially available reservoir formulation

To determine the pharmacokinetics, safety and performance of a novel matrix formulation of fentanyl. Transdermal fentanyl was administered as the novel matrix and the Durogesic reservoir formulations (24 subjects, 100 microg h(-1)) in a randomized, fully replicate, four-way crossover study. Serum concentrations of fentanyl were assayed by LC/MS/MS. Pharmacokinetic parameters of fentanyl and performance (adherence and skin irritability) were evaluated. Test/reference ratio (90% confidence intervals) for AUC(0-t), AUC(inf) and C(max) were 105.5% (99.4, 112.0), 105.3% (99.3, 111.6) and 111.4% (100.4, 123.6), respectively. Adherence and skin irritability results of the two formulations were similar. The two formulations are expected to result in similar efficacy for the management of severe pain.

Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects

A novel transdermal formulation of fentanyl-containing dipropylene glycol droplets dispersed in a silicone matrix with a rate-controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72-hour applications of fentanyl (50 mug/h) as the novel matrix and the conventional reservoir formulations in a randomized, 2-way crossover study. Blood samples were collected, and serum concentrations of fentanyl were assayed using liquid chromatography with mass spectrometry detection. The mean area under the curve (AUCtau) and peak concentrations (C(max)) of the matrix formulation were 84 838 pg.h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUCtau and C(max) between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.

Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1080 pg versus Oral transmucosal fentanyl citrate 1600 pg and dose proportionality of FEBT 270 to 1300 μg: A single-dose, randomized, open-label, three-period study in healthy adult volunteers

Background: The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain. Objectives: The primary objective of this study was to compare the relative bioavailability of FEBT 1080 μg with that of oral transmucosal fentanyl citrate (OTFC®) 1600 μg, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1300 μg in healthy adult volunteers. Methods: This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1080 μg followed by single-dose OTFC 1600 μg, or vice versa; in period 3 (dose-proportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1300 μg. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 μg, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For tolerability analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed. Results: A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC 0−∞)) was statistically similar between FEBT 1080 μg and OTFC 1600 μg (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng h/mL). However, the mean (SD) C max with FEBT 1080 μg was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1600 μg ( P = NS), and the T max of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC 0−Tmax′; ie, AUC from time 0 to 1 hour the median T max of the reference dose of FEBT [810 μg]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] ng · h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC 0−∞ and AUC 0−Tmax′ over the range of FEBT 270 to 1300 μg. Increases in C max were less than dose proportional at FEBT doses >810 μg. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC. Conclusions: In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1300 μg, whereas doses above 810 μg showed a less-than-dose-proportional increase in C max. The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (C max and AUC 0−Tmax′) and significantly more rapidly (T max) with FEBT compared with OTFC.

Transdermal Fentanyl Combined with Nonsteroidal Anti‐Inflammatory Drugs for Analgesia in Horses

This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti‐inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 μg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2 1.1 ng/mL (mean ± SD) and a time to peak serum concentration of 26 ± 13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P &lt; .05), but lameness scores were not significantly different (P± .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.

Transdermal fentanyl therapy for pains in children withinfantile neuronal ceroid lipofuscinosis

We used infantile neuronal ceroid lipofuscinosis (INCL), in which deterioration of the central nervous system is extremely rapid, to study constant release of an opioid for pains of central origin in a metabolic disease. The effect of a transdermal fentanyl patch was studied in five children with INCL. In two of them, measurements of 17 fentanyl serum concentrations and also visual analogue pain scale were obtained during a 15-day study period. Low doses of transdermal fentanyl usually provided good pain relief for the first two days, but not for the third day, of the three-day patch change interval. Pain relief of this type seems mandatory for pains mostly of central origin.

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.

Transdermal fentanyl therapy: system design, pharmacokinetics and efficacy.

The transdermal route of drug delivery has been used for the effective administration of therapeutic agents for more than a decade. The most important consideration in selecting a drug for transdermal delivery is the potential for improving therapeutic efficacy. The development of a transdermal fentanyl system provided an opportunity to add fentanyl to the armamentarium of strong opioids available for the treatment of cancer pain. The transdermal route of administration has advantages over both the oral and parenteral routes. In addition, patient and caregiver factors allow improved acceptance of and compliance to strong opioids and therefore improved analgesic outcome. Four transdermal fentanyl systems are available, providing delivery rates ranging from 25-100 micrograms/h; higher rates can be achieved by multiple system application. The system releases fentanyl continuously for 3 days when applied to the skin. Concentrations of fentanyl in the blood are measurable within a few hours of system application. Fentanyl serum concentrations increase gradually, generally levelling off after 12-24 h and remaining relatively constant for the remainder of the 3-day period. Steady state serum concentrations are reached by the second application. Clinical trials have established the efficacy and safety of transdermal fentanyl for the treatment of cancer pain. Transdermal fentanyl is not licensed for the treatment of acute pain, e.g. postoperative pain, and should not be prescribed for this purpose.

Fentanyl inhibits the release of [3H]noradrenaline from SH-SY5Y human neuroblastoma cells

We have examined the effect of fentanyl on [3H]noradrenaline release in a human neuroblastoma cell preparation, SH-SY5Y. Fentanyl produced a significant, concentration-dependent inhibition of [3H]noradrenaline release with IC50 values of 5.5 x 10(-6) mol litre-1 and 15.5 x 10(-6) mol litre-1 for carbachol- and potassium-evoked release, respectively. The small difference in IC50 between the two evoking stimuli may be explained by the weak binding affinity of fentanyl to muscarinic receptors (Ki = 570 nmol litre-1). The minimum concentrations at which a significant effect was observed were 0.3 x 0.10(-6) mol litre-1 and 10.0 x 10(-6) mol litre-1 for carbachol- and potassium-evoked release, respectively; these values are considerably in excess of the serum concentration of fentanyl required to produce analgesia. Naloxone failed to antagonize the fentanyl inhibition and, furthermore, morphine and an enkephalin had no effect on evoked release, implying a non-opioid receptor mediated effect.

FENTANYL INHIBITS THE UPTAKE OF [3H]NORADRENALINE IN CULTURED NEURONAL CELLS

We have examined how fentanyl modulates [3H]noradrenaline uptake in two cultured neuronal cell preparations, the human neuroblastoma SH-SY5Y and the rat phaeochromocytoma PC12. Fentanyl produced a significant, dose-dependent inhibition of [3H]noradrenaline uptake at concentrations in excess of 0.1 mumol litre-1 (P < 0.05) and 0.3 mumol litre-1 (P < 0.05) for PC12 and SH-SY5Y cells, respectively. However, these values exceed the serum concentration of fentanyl required to produce analgesia. At the maximum concentration examined (100 mumol litre-1), fentanyl produced 85-95% inhibition of uptake. This effect was not antagonized by naloxone, implying a nonopioid mechanism of action. Imipramine 1 mumol litre-1 reduced [3H]noradrenaline uptake by 65-70% but morphine, in contrast to fentanyl, had no effect (P > 0.1).

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.

Radioreceptor assay of narcotic analgesics in serum.

A sensitive radioreceptor assay (RRA) to determine the serum concentrations of fentanyl, pentazocine and morphine was developed on the basis of the drug's competition with a labeled tracer ((3)H-naloxone) for the membrane bound opioid receptor in rat brain homogenates. The binding data were computer-fitted to a standard curve by means of nonlinear least square regression. Sensitivity of the assay applied directly to serum samples without extraction was limited to approximately 3, 5 and 25 ng/ml for fentanyl, morphine and pentazocine, respectively, because of endogenous plasma constituents that interfere with the opioid receptor binding. With the use of petrol-ether extraction the sensitivity was improved to 0.3 ng/ml fentanyl and 3 ng/ml pentazocine (0.3 ml serum samples). No RRA-active metabolites were detectable after HPLC separation of serum from a patient treated with fentanyl. The plasma concentration time course of fentanyl in a patient, measured by RRA, was similar to that obtained by a radioimmunoassay (RIA). The RRA represents a general procedure for the detection of clinically used opioid analgesics and their active metabolites.