Plasma Fentanyl Concentrations Research Articles

Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100 – 800 µg in healthy volunteers

Fentanyl pectin nasal spray (FPNS) is formulated as a solution utilizing PecSys®; pectin based enabling technology (Archimedes). On contact with the nasal mucosa the formulation will gel and modulate fentanyl absorption while limiting nasal drip or runoff. This single-dose volunteer study compared the pharmacokinetics of FPNS 100, 200, 400, and 800 µg doses and assessed bioavailability relative to oral transmucosal fentanyl (OTFC) 200 µg. Safety and dose proportionality were also examined. 16, opioid-naïve subjects were dosed on five separate visits under naltrexone block. FPNS doses were administered using a Pfeiffer device delivering 100 µl. Devices were filled with either 1.57 mg/ml (100 and 200 µg dosing) or 6.28 mg/ml fentanyl citrate (400 and 800 µg). Venous blood samples were collected up to 48 h after dosing and plasma fentanyl concentrations measured. Median tmax values for FPNS ranged from 15 to 21 min post-dose and were dose-independent. At 200 µg Cmax values were 2.3-fold higher for FPNS compared with OTFC. Mean relative bioavailability of FPNS to OTFC ranged from 103% to 163%. Dose proportionality for Cmax and AUC0-1 across the FPNS range was statistically confirmed. Drug absorption also increased in a close to dose-proportional manner for AUC0-inf. FPNS has a shorter tmax, higher Cmax and greater bioavailability than OTFC and is well tolerated. The dose proportionality of Cmax and AUC0-1 was demonstrated. It is concluded that the pharmacokinetic profile of FPNS suggests this product is suitable for clinical investigation in breakthrough pain in cancer patients.

Intranasal fentanyl spray for breakthrough cancer pain: An innovative approach to the unmet needs

The treatment of breakthrough pain (BTP) in cancer patients is often sub-optimal. Normal-release oral opioid formulations have a slow onset of action, such that the episode of pain has often spontaneously subsided by the time the opioid starts to work. Other oral formulations, such as oral transmucosal fentanyl citrate (OTFC), may be associated with administration problems in many cancer patients who have salivary gland dysfunction or mucositis. Thus, there is the need for a treatment that matches a typical BTP episode and that is easy to use. Intranasal fentanyl spray (INFS) has been developed as a new route of administration with a fast onset of action. INFS has been investigated in four key clinical studies involving cancer patients with BTP. Pharmacokinetic analysis has shown a dose response for maximal plasma concentrations ( C max) of fentanyl and a short venous time to maximum plasma concentration ( T max). A dose-ranging efficacy study demonstrated a significant improvement in pain intensity difference (PID) over placebo from as early as 10 min post-administration. A later titrated-dose efficacy study supported these findings. In a head-to-head comparative trial between INFS and OTFC, significantly more patients achieved a faster onset of ‘meaningful’ pain relief with INFS than with OTFC, with INFS producing a significantly greater PID as early as 5 min post-dosing. Furthermore, a significantly higher proportion of patients preferred INFS over OTFC. In all clinical studies, including a 10-month follow-up, INFS was well tolerated. INFS should be considered a significant advance for the management of BTP.

Evaluation of the Single‐ and Multiple‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film in Normal Healthy Volunteers

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations (mean C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) increased approximately 3-fold with the 3-dose regimen compared with the single-dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

Pharmacokinetics, analgesic effect, and tolerability of a single preprocedural dose of intranasal fentanyl in patients undergoing drain removal after breast reduction or augmentation surgery: A prospective, randomized, double-blind, placebo-controlled study

Background: Although acetaminophen is used to reduce pain after breast reduction or augmentation surgery, pain during the removal of the surgical drains is typically not specifically treated. Intranasally administered fentanyl may be suitable for pain control during removal of drains. The reported therapeutic window of fentanyl is between 0.2 and 1.2 ng/mL. Objective: The aim of this study was to evaluate the analgesic effect, tolerability, and pharmacokinetics of a single preprocedural dose of intranasal fentanyl administered before removal of surgical drains in patients who had undergone breast reduction or augmentation surgery. Methods: This was a randomized, double-blind, prospective study in healthy women (American Society of Anesthesiologists physical status I or II) between the ages of 18 and 65 years who were scheduled to undergo removal of surgical drains 1 to 4 days after breast reduction or augmentation surgery. A single dose of fentanyl nasal spray 0.05 mg/0.1 mL or placebo (preserved normal saline) 0.1 mL was administered 10 minutes before removal of drains. Because drain removal is generally carried out without specific analgesia, no rescue medication was provided. Pain intensity was measured on a visual analog scale (VAS) from 0 = no pain at all to 100 = worst pain possible. Pain intensity was evaluated immediately before administration of study medication (t = 0), at the time of drain removal (t = 10), and at 15, 20, 25, 40, and 70 minutes after administration of study medication. Safety measures included oxygen saturation, respiratory rate, heart rate, and blood pressure. Local and systemic adverse events were elicited by direct questioning throughout the study. Blood samples for pharmacokinetic analysis were collected at baseline and at 5, 10, 15, 30, 60, and 120 minutes after administration of study medication. The population pharmacokinetic parameters of fentanyl were calculated according to a 1-compartment open model with an iterative 2-stage Bayesian fitting procedure. Results: Thirty-six women were randomized to treatment, and 33 completed the study. Their mean (SD) age was 39.2 (13.0) years, and their mean weight was 68.9 (10.7) kg. Mean VAS scores at baseline were 14.8 (17.8) for the fentanyl group and 6.0 (9.7) for the placebo group ( P = NS); at the time of drain removal, the corresponding VAS scores were 31.0 (20.6) and 33.8 (25.7) ( P = NS). Analysis of a random-effects model with mean VAS scores as a function of time as the dependent variable indicated a significant difference in mean VAS scores between the fentanyl and placebo groups ( P = 0.006). The overall incidence of adverse events was 39.4% (13/33). Among the 17 patients in the fentanyl group, 8 reported ≥1 adverse event; among the 16 patients in the placebo group, 9 reported ≥1 adverse event. A mean estimated C max of 0.184 (0.069) ng/mL was reached at 13.76 (3.56) minutes after administration of intranasal fentanyl. The mean measured C max was 0.22 (0.088) ng/mL. Conclusions: In these women who had undergone breast reduction or augmentation surgery, a single preprocedural dose of intranasal fentanyl was significantly more effective than placebo in reducing pain intensity over the hour after removal of surgical drains. However, there was no significant difference in pain intensity between fentanyl at the time of drain removal and placebo. Intranasal fentanyl was generally well tolerated. At the dose used (0.05 mg), plasma fentanyl concentrations were below the reported therapeutic window.

Assessment of canine sensory function by using sine-wave electrical stimuli paradigm

The paradigm of sine-wave electrical stimuli has been used for sensory neurological assessment in humans. In the present study, we applied the paradigm to the dog for the quantitative assessment of sensory function. Sine-wave electrical current stimuli at frequencies of 2000, 250, and 5 Hz were delivered to bipolar electrodes attached to the skin surface of the hind paws. The stimulation intensity was gradually increased, and the minimum intensity required to elicit the lifting behavior in the stimulated paw was determined as current threshold (CT) for each of the three frequencies. Dogs consistently showed the lifting behavior at CTs without showing aversive behaviors such as vocalization and wriggling. The baseline CTs (mean ± SEM, n = 12) were 4430 ± 110 μA for CT2000, 2215 ± 173 μA for CT250, and 2305 ± 152 μA for CT5. The CTs immediately increased after bolus intravenous injection of fentanyl at 10 μg/kg, although the significant increase disappeared within 1 h. The time course for the CTs was parallel to that of plasma fentanyl concentration. In conclusion, the present study applied the paradigm of transcutaneous sine-wave electrical stimuli to the dog, and used the hind paw lifting as endpoint behavior. This paradigm is simple, non-invasive, useful in the assessment of sensory function, and can be adapted to investigate the pharmacokinetics/pharmacodynamics relation of drugs. Further studies are needed to give the conclusive interpretation of the endpoint behavior.

Dose Proportionality of Fentanyl Buccal Tablet in Doses Ranging from 600 to 1300μg in Healthy Adult Subjects

Background: Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving, and who are tolerant to, opioid therapy for underlying, persistent cancer pain. Breakthrough pain may be severe or excruciating, and some patients may require high doses of rapid-onset opioids to obtain adequate analgesia. Objective: The objective of this study was to assess the dose proportionality of FBT over a range of 600–1300 μg in healthy subjects. Methods: This was a randomized, open-label, four-period, crossover, single-centre study of FBT (Fentora®) conducted in healthy adult subjects who were not tolerant to opioids. The study included 120 men and women aged 18–45 years with a body mass index of 20–30 kg/m2 who had no clinically significant findings on medical and psychiatric histories, physical examination, ECG or standard clinical laboratory tests, and who had a negative urine screen for drugs and alcohol. Eligible subjects were randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 μg). Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was administered to block the opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentration was measured through 72 hours after placement of FBT. The main outcome measures, maximum plasma fentanyl concentration (Cmax) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞), were analysed to determine dose proportionality. Other pharmacokinetic parameters were also evaluated. Dose proportionality was concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the Cmax versus dose and AUC∞ versus dose curves were completely contained within the range of 0.711–1.289. The safety and tolerability of FBT were assessed throughout the study. Results: The slope for Cmax versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC∞ versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for Cmax and AUC∞ were within the predefined range of 0.711–1.289, dose proportionality was concluded over the 600–1300 μg range. The mean dose-normalized plasma fentanyl concentration reached 80% of Cmax within 25 minutes; plasma fentanyl concentration was maintained at this level for 3 hours after dose. No unexpected safety or tolerability concerns were noted in the naltrexone-blocked healthy subjects. Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and headache. No serious AEs were reported. Conclusion: The dose proportionality of FBT from 600–1300 μg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 μg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 μg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.

Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery: randomized controlled trial.

Controversy exists regarding the site of action of fentanyl after epidural injection. The objective of this investigation was to compare the efficacy of epidural and intravenous fentanyl for orthopedic surgery. A randomized double-blind study was performed in Hospital São Paulo. During the postoperative period, in the presence of pain, 29 patients were divided into two groups: group 1 (n = 14) received 100 microg of fentanyl epidurally and 2 ml of saline intravenously; group 2 (n = 15) received 5 ml of saline epidurally and 100 microg of fentanyl intravenously. The analgesic supplementation consisted of 40 mg of tenoxicam intravenously and, if necessary, 5 ml of 0.25% bupivacaine epidurally. Pain intensity was evaluated on a numerical scale and plasma concentrations of fentanyl were measured simultaneously. The percentage of patients who required supplementary analgesia with tenoxicam was lower in group 1 (71.4%) than in group 2 (100%): 95% confidence interval (CI) = 0.001-0.4360 (P = 0.001, Fisher's exact test; relative risk, RR = 0.07). Epidural bupivacaine supplementation was also lower in group 1 (14.3%) than in group 2 (53.3%): 95% CI = 0.06-1.05 (P = 0.03, Fisher's exact test; RR = 0.26). There was no difference in pain intensity on the numerical scale. Mean fentanyl plasma concentrations were similar in the two groups. Intravenous and epidural fentanyl appear to have similar efficacy for reducing pain according to the numerical scale, but supplementary analgesia was needed less frequently when epidural fentanyl was used. NCT00635986.

Effects of Intravenous Fentanyl Administration on End-Tidal Sevoflurane Concentrations in Thoroughbred Racehorses undergoing Orthopedic Surgery

To evaluate the effects of IV fentanyl administration on the end-tidal sevoflurane concentration (ET(SEVO)) in thoroughbred racehorses, the ET(SEVO) required for internal fixation of longitudinal fractures was compared between horses anesthetized with sevoflurane-fentanyl (Group SF; n=9) and those anesthetized with sevoflurane alone (Group S; n=9). The loading dose of fentanyl (5.0 µg/kg) was administered over 15 min followed by a maintenance dose of fentanyl (0.1 µg/kg/min) throughout the operation in Group SF. The mean ET(SEVO) during the operation in Group SF (2.6 ± 0.2%) was significantly lower than in Group S (3.0 ± 0.3%). The plasma fentanyl concentrations (6.12 ± 0.88 to 7.78 ± 1.12 ng/ml) in 7 out of 9 horses in Group SF were stable and did not change significantly throughout the operation. The mean dobutamine infusion rate required for maintaining a mean arterial blood pressure between 60 and 80 mmHg during the operation in Group SF (0.56 ± 0.30 µg/kg/min) was significantly lower than in Group S (0.90 ± 0.16 µg/kg/min). The qualities of the recoveries were clinically acceptable, and serious complications were not observed in either group. In conclusion, continuous IV fentanyl administration reduced the sevoflurane requirement by 13% in thoroughbred racehorses undergoing orthopedic surgery; however, fentanyl was considered to be less effective in horses compared with other species.

Influence of body fat in cancer patients on residual content of used fentanyl matrix patches

Purpose: The objective of this study was to investigate whether body fat rate (BFR) and triceps skinfold thickness (TSF) are associated with estimated fentanyl absorption in patients treated with the fentanyl transdermal matrix patch for moderate to severe cancer pain, by measuring the residual content of fentanyl in used matrix patches. Methods: Adult Japanese inpatients experiencing chronic cancer-related pain and receiving treatment for the first time with a transdermal fentanyl matrix patch (Durotep®MT patch) were included in the present study. During the initial application period, BFR was measured using a body fat scale, and TSF was measured by an experienced nurse with an adipometer. One patch was collected from each patient. The residual fentanyl content in used matrix patch was determined by high-performance liquid chromatography. The transdermal fentanyl delivery efficiency was estimated based on the fentanyl content of the used matrix patches. Results: Fifteen adult patients (5 males and 10 females) were included in this study. Nine patches with a release rate of 12.5μg/h and 6 patches with a release rate of 25μg/h were collected. The application site was the chest or upper arm. BFR and TSF both showed a significant positive correlation with delivery efficiency. Conclusion: In malnourished or low-body fat patients receiving DMP, pain intensity should be more carefully monitored, and fentanyl dose adjustment may be required. Additional parameters, such as nutritional status including body fat change, the degree of dry skin, and plasma fentanyl concentration, also require detailed evaluation. Palliat Care Res 2010; 5(2): 206-212

Pharmacokinetics of intranasal fentanyl spray in patients with cancer and breakthrough pain

This study reports the pharmacokinetics, tolerability, and safety of an intranasalfentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). A randomized, open-label, two-period, crossover trial. Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 microg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median T(max) values were 15, 12, and 15 minutes for the 50, 100, and 200 microg doses of INFS, respectively. Mean (SD) values for C(max) were 351 (+/- 226), 595 (+/- 400), and 1195 (+/- 700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. INFS at doses of 50, 100, and 200 microg showed a short T(max) and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP.

Obesity, obstructive sleep apnoea, and diabetes mellitus: anaesthetic implications

Obesity is an epidemic in much of the Western World. The extent of this problem, combined with the increasing preference for ambulatory surgical procedures, has produced a difficult situation for many anaesthesiologists. Even the simplest anaesthetic procedures can become very complicated and potentially difficult in this population. Although there are numerous complications associated with obesity, perhaps obstructive sleep apnoea (OSA) and diabetes mellitus are among the more significant. Patients with OSA are often not ideal candidates for certain day-case procedures, but many outpatient procedures can be performed on patients with OSA as long as attention is paid to anaesthetic technique. Diabetic patients are prone to numerous complications in the perioperative period, including cardiac problems, but with careful management, they are able to undergo day-case surgical procedures safely.

Effects of high plasma fentanyl concentrations on minimum alveolar concentration of isoflurane in horses

To verify the isoflurane anesthetic minimum alveolar concentration (MAC)-sparing effect of a previously administered target plasma fentanyl concentration of 16 ng/mL and characterize an anticipated further sparing in isoflurane MAC associated with higher target plasma fentanyl concentrations. 8 horses. Horses were assigned 2 of 3 target plasma fentanyl concentrations (16, 24, and 32 ng/mL), administered in ascending order. Following determination of baseline MAC, horses received a loading dose of fentanyl followed by a constant rate infusion; MAC determination was performed in triplicate at baseline and at each fentanyl concentration. Venous blood samples were collected throughout the study for determination of actual plasma fentanyl concentrations. Recovery from anesthesia was monitored, and behaviors were rated as excellent, good, fair, or poor. Mean + or - SD fentanyl plasma concentrations were 13.9 + or - 2.6 ng/mL, 20.1 + or - 3.6 ng/mL, and 24.1 + or - 2.4 ng/mL for target concentrations of 16, 24, and 32 ng/mL, respectively. The corresponding changes in the MAC of isoflurane were -3.28%, -6.23%, and +1.14%. None of the changes were significant. Recovery behavior was variable and included highly undesirable, potentially injurious excitatory behavior. Results of the study did not verify an isoflurane-sparing effect of fentanyl at a plasma target concentration of 16 ng/mL. Furthermore, a reduction in MAC was not detected at higher fentanyl concentrations. Overall, results did not support the routine use of fentanyl as an anesthetic adjuvant in adult horses.

Formulation Selection and Pharmacokinetic Comparison of Fentanyl Buccal Soluble Film with Oral Transmucosal Fentanyl Citrate

BioErodible MucoAdhesive (BEMA) is a new transmucosal drug delivery system designed to improve and ease the administration of drugs by this route. The first product that uses this novel delivery system contains fentanyl and is intended for the treatment of breakthrough pain in opioid-tolerant patients with cancer. The generic name is fentanyl buccal soluble film (FBSF). The objectives of this study were to compare the pharmacokinetic profile of FBSF formulations at three different pHs (pH 6, pH 7.25 and pH 8.5) and to understand the differences in the pharmacokinetics of fentanyl from FBSF compared with that of oral transmucosal fentanyl citrate (OTFC). This was a randomized, open-label, single-dose, four-period, Latin-square crossover study consisting of a 9-day inpatient treatment period. The study was conducted at a phase 1 clinical research unit in Austin, TX, USA. Twelve healthy subjects were enrolled, nine males and three females, between the ages of 21 and 44 years. Each subject received four 800 microg doses of fentanyl: single doses of the three FBSF formulations (pH 6, pH 7.25 and pH 8.5) and OTFC, with concurrent naltrexone. Plasma fentanyl concentrations were measured over a 48-hour period after each study dose. Pharmacokinetic parameters were calculated and compared. Peak plasma fentanyl concentrations (Cmax) and overall fentanyl systemic exposure (area under the plasma concentration-time curve from time zero extrapolated to infinity [AUCinfinity]) for each of the three FBSF formulations were greater than for OTFC. The pH 7.25 FBSF formulation provided the earliest time to reach Cmax (tmax), the highest Cmax value and the greatest AUC(infinity) value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03 ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUCinfinity 14.5 vs 10.3 ng . h/mL). All three FBSF formulations produced greater peak plasma concentrations and overall exposure to fentanyl than OTFC. In particular, the pH 7.25 FBSF formulation showed the most favourable pharmacokinetic profile of the three FBSF formulations. In comparison with OTFC, the pH 7.25 FBSF formulation produced the fastest and most efficient fentanyl delivery and was selected for further clinical development.

Effects of high plasma fentanyl concentrations on minimum alveolar concentration of isoflurane in horses

Effects of high plasma fentanyl concentrations on minimum alveolar concentration of isoflurane in horses

Pharmacokinetic and local tolerability profiles of three potential fentanyl nasal spray formulations developed for breakthrough cancer pain compared with oral transmucosal fentanyl citrate

e20554 Background: The nasal route offers the ability to enhance fentanyl delivery and better match the rapid onset and short duration (30–60 min) of breakthrough cancer pain compared with standard oral delivery. However, conventional nasal fentanyl solutions can be associated with variable, and sometimes supratherapeutic maximum plasma concentrations (Cmax). To optimise rapid absorption and delivery, three novel nasal spray formulations have been developed: fentanyl pectin nasal spray (FPNS), fentanyl chitosan nasal spray (FChNS), and fentanyl in chitosan-poloxamer 188 solute (FChP). Methods: This phase I, open-label, crossover study was conducted in 18 healthy adult volunteers to compare the pharmacokinetic profiles of the three new nasal fentanyl formulations with oral transmucosal fentanyl citrate (OTFC). Subjects were dosed on four occasions, separated by a &gt;3-day washout period, under naltrexone blockade, with the nasal sprays (each containing fentanyl citrate 100μg in 100μL) and OTFC 200μg according to a randomized sequence. Venous plasma fentanyl concentrations were measured before and up to 24 hours post-dose. Local nasal tolerability was assessed by a clinician and a reactogenicity questionnaire. Results: Compared with OTFC, mean AUCs∞ for all three nasal sprays were significantly higher (P&lt;0.05) and bioavailability significantly greater (FPNS 132%; FChNS 154%, FChP 122%). Median tmax (FPNS 19.8min; FChNS 10.2min, FChP 15.6min) were significantly (P&lt;0.001) reduced (OTFC 90min) and mean Cmax significantly increased with all nasal sprays compared with OTFC. Of the three nasal sprays, FPNS had the lowest nasal reactogenicity symptom incidence. Conclusions: Compared with OTFC, all three fentanyl nasal spray formulations demonstrated enhanced pharmacokinetic profiles appropriate for breakthrough cancer pain as evidenced by significantly increased systemic exposure and reduced times to peak plasma values. FPNS exhibited the most favourable tolerability profile. [Table: see text]

Transdermal fentanyl in cachectic cancer patients

Fentanyl is an opioid with high lipid solubility, suitable for intravenous, spinal, transmucosal and transdermal administration. The transdermal fentanyl patch has become widely used in the treatment of both malignant and non-malignant chronic pain. The absorption of fentanyl from the patch is governed by the surface area of the patch, by skin permeability and by local blood flow. The aim of this study is to find out whether absorption of fentanyl in cachectic patients with cancer-related pain is different from that of normal weight cancer patients. We recruited ten normal weight (mean body mass index (BMI) 23kg/m2) and ten cachectic (mean BMI 16kg/m2) cancer pain patients. A transdermal fentanyl patch with a dose approximately equianalgesic to the patients’ previous opioid dose was administered to the upper arm of the patient for 3days. Prior to patch application, the height, weight and BMI of the patient, as well as upper arm skin temperature, local sweating, thickness of skin fold and local blood flow were measured. Plasma fentanyl concentrations were analyzed from blood samples taken at baseline, 4, 24, 48 and 72h. Plasma fentanyl concentrations adjusted to dose were significantly lower at 48 and 72h in cachectic patients than normal weight patients. The cachectic patients had a significantly thinner upper arm skin fold, but no differences were found in local blood flow, sweating, or skin temperature. Absorption of transdermal fentanyl is impaired in cachectic patients compared with that of normal weight cancer pain patients.

Validated LC coupled to ESI-MS/MS analysis for fentanyl in human plasma and UV analysis in applied reservoir transdermal patches using a simple and rapid procedure

Fentanyl has been used for cancer pain in transdermal formulation. The aim of the present study was to establish an analytical method for fentanyl in human plasma and in an applied transdermal reservoir patch (Reservoir-TTS), as well as for therapeutic monitoring of fentanyl in cancer patients. Electro-spray ionization mass spectrometric (ESI-MS/MS) analysis followed solid phase extraction (SPE) from human plasma and drug reservoir extraction from an applied Reservoir-TTS. Each separation was completed within 9 min using an ODS column (particle size, 3 microm, 2.0 mm i.d. x 75 mm) with 25% acetonitrile containing 5 mm ammonium acetate at pH 3.5. In the ESI-MS/MS analysis, the calibration curve for fentanyl was linear over a concentration range of 0.05-7.2 ng/mL in human plasma. The extraction efficiency of fentanyl in the human plasma was more than 95%. The intra- and interassay precision and accuracy were within 7% and 97.3-101.2%, respectively. The lower LOQ for fentanyl was 0.05 ng/mL in the human plasma. The extraction of the 25 microg/h and 50 microg/h Reservoir-TTS gave reproducible recoveries of 88.3% and 90.9%, respectively. The plasma concentration of fentanyl showed large interindividual variation in 31 patients with cancer pain. The method described is simple, accurate, and reproducible, and should be helpful for the therapeutic monitoring of fentanyl in cancer patients.

Dose proportionality of fentanyl buccal tablet 600 to 1300 μg in healthy volunteers

Fentanyl buccal tablet (FBT), which provides rapid-onset analgesia, enhances fentanyl absorption across the buccal mucosa. In a pilot study, dose proportionality for FBT was established only up to 1000 μg. The current study was conducted to evaluate dose proportionality over an extended dose range (up to 1300 μg). Healthy volunteers received FBT as one 600 μg tablet, one 1000 μg tablet, one 1200 μg tablet, and one 800 μg plus 400 μg plus 100 μg tablet (1300 μg) in a randomized, crossover fashion with a ≥7-day washout between doses. As volunteers were not opioid-tolerant, naltrexone was administered to minimize opioid effects. Plasma fentanyl (from venous blood) was measured through 72 hours post dose. Peak plasma fentanyl concentration (Cmax) and area under the plasma concentration-vs-time curve (AUC0-∞) were evaluated, and dose proportionality was to be concluded if the 2-sided 90% confidence intervals (CIs) for the slopes of the Cmax vs dose and AUC0-∞ vs dose curves were completely within the limits of 0.711 to 1.289. Safety and tolerability were monitored throughout the study. 109 volunteers were enrolled (mean age 28 years, 51% male); 88 completed the study. The slopes (90% CI) for Cmax vs dose and AUC0-∞ vs dose were 0.8627 (0.7730, 0.9525) and 0.9330 (0.8738, 0.9922), respectively. CIs were contained completely within the prespecified limits, indicating that FBT was dose proportional from 600 to 1300 μg. 74 subjects (68%) experienced ≥1 adverse event (AE), either mild (n = 56 subjects) or moderate (n = 18 subjects) in severity. The most common AEs were nausea, dizziness and headache. Treatment-emergent AEs led to study withdrawal of 2 volunteers. In conclusion, FBT was dose proportional over the range 600 to 1300 μg, indicating that a predictable, linear increase in systemic exposure may be expected across this range when FBT is titrated to an effective dose. Fentanyl buccal tablet (FBT), which provides rapid-onset analgesia, enhances fentanyl absorption across the buccal mucosa. In a pilot study, dose proportionality for FBT was established only up to 1000 μg. The current study was conducted to evaluate dose proportionality over an extended dose range (up to 1300 μg). Healthy volunteers received FBT as one 600 μg tablet, one 1000 μg tablet, one 1200 μg tablet, and one 800 μg plus 400 μg plus 100 μg tablet (1300 μg) in a randomized, crossover fashion with a ≥7-day washout between doses. As volunteers were not opioid-tolerant, naltrexone was administered to minimize opioid effects. Plasma fentanyl (from venous blood) was measured through 72 hours post dose. Peak plasma fentanyl concentration (Cmax) and area under the plasma concentration-vs-time curve (AUC0-∞) were evaluated, and dose proportionality was to be concluded if the 2-sided 90% confidence intervals (CIs) for the slopes of the Cmax vs dose and AUC0-∞ vs dose curves were completely within the limits of 0.711 to 1.289. Safety and tolerability were monitored throughout the study. 109 volunteers were enrolled (mean age 28 years, 51% male); 88 completed the study. The slopes (90% CI) for Cmax vs dose and AUC0-∞ vs dose were 0.8627 (0.7730, 0.9525) and 0.9330 (0.8738, 0.9922), respectively. CIs were contained completely within the prespecified limits, indicating that FBT was dose proportional from 600 to 1300 μg. 74 subjects (68%) experienced ≥1 adverse event (AE), either mild (n = 56 subjects) or moderate (n = 18 subjects) in severity. The most common AEs were nausea, dizziness and headache. Treatment-emergent AEs led to study withdrawal of 2 volunteers. In conclusion, FBT was dose proportional over the range 600 to 1300 μg, indicating that a predictable, linear increase in systemic exposure may be expected across this range when FBT is titrated to an effective dose.

Distribution of fentanyl in the placental intervillous space and in the different maternal and fetal compartments in term pregnant women

Fentanyl is used in obstetrical practice to promote analgesia and anesthesia during labor and in cesarean delivery, with rapid and short-term effects. To determine fentanyl concentrations in maternal plasma, in the placental intervillous space, and in the umbilical artery and vein in term pregnant women. Ten healthy pregnant women underwent epidural anesthesia with fentanyl plus bupivacaine and lidocaine, and fentanyl concentrations were determined in the various maternal and fetal compartments, including the placental intervillous space, which has not been previously studied in the literature. The ratios of fentanyl concentrations in the various maternal and fetal compartments revealed an 86% rate of placental fentanyl transfer. The highest fentanyl concentrations were detected in the placental intervillous space, being 2.19 times higher than in maternal plasma, 2.8 times higher than in the umbilical vein and 3.6 times higher than in the umbilical artery, with no significant differences between the umbilical vein and artery, demonstrating that there was no drug uptake by fetal tissues nor metabolism of the drug by the fetus despite the high rates of placental transfer. The present study demonstrated that the placental intervillous space acted as a site of fentanyl deposit, a fact that may be explained by two hypotheses: (1) the blood collected from the placental intervillous space is arterial and, according to some investigators, the arterial plasma concentrations of the drugs administered to patients undergoing epidural anesthesia are higher than the venous concentrations, and (2) a possible role of P-glycoprotein (P-gp).

Comparison of effects and plasma concentrations of opioids between elderly and middle‐aged patients after cardiac surgery

In elderly patients, opioids may cause prominent postoperative sedation and respiratory depression. We evaluated the influence of age on the effects of opioids and plasma concentrations of fentanyl and oxycodone in cardiac surgery patients. Thirty (>or=75 years, gender M9/F21) and 20 (<or=60 years, gender M20/F0) patients scheduled to undergo cardiac surgery. A standard anesthesia with fentanyl as an opioid was used. Fentanyl plasma concentrations were measured at the end of surgery and 2 h later. After tracheal extubation, when the pain intensity was at least moderate, blood samples for fentanyl and oxycodone plasma concentration measurements were taken. Thereafter, oxycodone hydrochloride 0.05 mg/kg i.v. was administered. After 15 and 45 min, pain intensity, sedation and oxycodone plasma concentration were determined. This test protocol was repeated twice. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients (5.7+/-2.2 vs. 3.8+/-1.2 ng/ml, P=0.001). The plasma concentrations of oxycodone were comparable between the groups. The interval between the second and the third oxycodone dose was longer in the elderly patients (P=0.036). Pain intensity on the verbal rating scale was lower at the 45-min assessment point after all three oxycodone test doses (P=0.008) and sedation scores were significantly higher after the third dose in the elderly patients (P=0.035). In elderly patients, the plasma concentration of fentanyl was higher but plasma levels of oxycodone were at a similar level compared with middle-aged patients. However, the elderly patients had less pain and were more sedated after doses of oxycodone.