Death in Sauna Associated With a Transdermal Fentanyl Patch.

We present a case of an accidental fatal fentanyl overdose caused by increased uptake of the drug from a transdermal patch while experiencing the heat of a sauna.The transdermal patch administers fentanyl at a relatively constant rate through the skin. However, in the subcutaneous tissue, blood circulation greatly influences the rate of this drug's systemic intake. In the present case, an elderly woman with multiple health conditions was prescribed fentanyl patches but was unaware of the risks associated with external heat sources when one wears the patch. She was found dead in the sauna with a postmortem femoral blood concentration of fentanyl that was elevated (15 µg/L). The cause of death was determined to be fatal poisoning by fentanyl with the contributing factor of external heat from the sauna.Risks associated with transdermal administration of a potent opioid-like fentanyl are widely described in the scientific literature and described in the manufacturer's summary of product characteristics. Physicians and pharmacists should take particular care to ensure that patients understand these risks.

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.

The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg-1 bolus followed by continuous infusion of 0.05 mg·kg-1 ·h-1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg-1 bolus followed by a 0.2 mg·kg-1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL-1 after infusion and 0.4 and 1.1 ng·mL-1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.

Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB.

Tramadol is used for the treatment of pain, and it is generally believed to activate the µ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 µg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

[The adaptive mechanisms of cardio- and angioprotective action of reflexotherapy].

The adaptive mechanisms of action of reflexotherapy are analysed. It was shown in physiological and biochemical experiments on the whole organism, the isolated hearts and strips of resistive arteries of animals that stimulation of acupuncture points by different physical factors increased the activity of opioid, antioxidative, and other stress-limiting systems, reduced secretion of corticosteron during stress, stimulated biosynthesis of stress proteins, induced cyto- and cardioprotective effects, prevented or limited functional and structural hyperadrenal damages. Clinical investigations demonstrated significant hypothensive, anti-ishemic and anti-arrhythmic effects of reflexotherapy, improved resistance of healthy subjects and patients with cardiovascular diseases to physical and emotional loadings.

Randomized 5-treatment crossover study to assess the effects of external heat on serum fentanyl concentrations during treatment with transdermal fentanyl systems.

This randomized, open-label, 5-treatment, 5-sequence crossover study was designed to evaluate the effects of a heating pad on serum fentanyl concentrations with reservoir and matrix transdermal fentanyl systems. Subjects were randomized to 1 of 5 treatment sequences, receiving 5 fentanyl treatments (1 per period) for 36 hours: 25 µg/h reservoir without heat, 25 µg/h reservoir with heat, 25 µg/h matrix without heat, 25 µg/h matrix with heat, and a 50 µg/h reservoir without heat. The 25 µg/h systems with heat had a heating pad applied from 0 to 10 and 26 to 36 hours post application. Washout periods between treatments were 5 to 14 days. Naltrexone was given to block the opioid effects of fentanyl. Study results indicate that external heat had a similar effect on both matrix and reservoir systems, with heat applied during the first 10 hours of treatment increasing fentanyl exposure by approximately 61% to 81% at 10 hours (observed serum concentration at 10 hours) and overall exposure (area under the curve from 0 to 10 hours) by approximately 120% to 184%, but had minimal effect from 26 to 36 hours. The increased exposure observed with heat in both 25 µg/h systems, between 0 and 10 hours, was higher than that obtained with the 50 µg/h reservoir system applied without heat.

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.

In vitro and in vivo evaluation of the metabolism and pharmacokinetics of sebacoyl dinalbuphine.

A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t(1/2) of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.

The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions.

From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta-9-tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC-morphine combination (THC-morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC-morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo-controlled, double-blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side-effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC-morphine. A slight additive analgesic effect could be observed for THC-morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC-morphine. Psychotropic and somatic side-effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.

Methadone maintenance treatment and St. John's Wort - a case report.

St. John's wort, a popular over-the-counter drug for treatment of depression, might reduce concentrations of drugs such as cyclosporin and indinavir and lead to drug resistance and treatment failure. No studies as yet have examined its influence on methadone plasma levels. The trough methadone plasma levels were measured in four patients (2 males, median age: 31 years; range 19 - 40 years) in methadone maintenance treatment just before the introduction of St. John's wort (900 mg/d) and after a median period of 31-day treatment (range 14 - 47). The study was proposed to addict patients about to start an antidepressant therapy. Introduction of St. John's wort resulted in a strong reduction of (R,S)-methadone concentration-to-dose ratios in the four median patients included, with a median decrease to 47 % of the original concentration (range: 19 % - 60 % of the original concentration). Two patients reported symptoms that suggested a withdrawal syndrome. Thus, prescription of St. John's wort might decrease methadone blood levels and induce withdrawal symptoms which, if not correctly identified and handled (by changing the antidepressant or by increasing the methadone dose), might cause unnecessary discomfort to the patient, lead to resumption of illicit drug uses, or be a risk factor for discontinuation of the methadone or antidepressant treatment.

Gas chromatographic method using nitrogen-phosphorus detection for the measurement of tramadol and its O-desmethyl metabolite in plasma and brain tissue of mice and rats.

A method that allows the measurement of plasma and brain levels of the centrally-acting analgesic tramadol and its major metabolite (O-desmethyl tramadol) in mice and rats was developed using gas chromatography equipped with nitrogen-phosphorus detection (GC-NPD). Plasma samples were extracted with methyl tert.-butyl ether (MTBE) and were injected directly into the GC system. Brain tissue homogenates were precipitated with methanol, the resulting supernatant was dried then acidified with hydrochloric acid. The aqueous solution was washed with MTBE twice, alkalinized, and extracted with MTBE. The MTBE layer was dried, reconstituted and injected into the GC system. The GC assay used a DB-1 capillary column with an oven temperature ramp (135 to 179 degrees C at 4 degrees C/min). Dextromethorphan was used as the internal standard. The calibration curves for tramadol and O-desmethyl tramadol in plasma and brain tissue were linear in the range of 10 to 10000 ng/ml (plasma) and ng/g (brain). Assay accuracy and precision of back calculated standards were within +/- 15%.

Quantitative analysis of fentanyl in rat plasma by gas chromatography with nitrogen-phosphorus detection.

A sensitive assay method was developed to determine fentanyl, an opiate agonist, in rat plasma by gas chromatography with nitrogen-phosphorus detection. For the pretreatment of plasma samples, sodium hydroxide was added to denature protein and n-butyl chloride was used to extract fentanyl. The calibration curve was linear within the concentration range 0.5 to 50 ng/ml (r=0.9997). The limit of detection was 0.1 ng/ml, and 0.5 ng/ml could be quantified with acceptable precision. Furthermore, fentanyl could be determined in only 200 microl of rat plasma. The method has been successfully applied to an intramuscular pharmacokinetic study at a dose of 10 microg/kg. Therefore, the current method is a valuable analytical tool for investigating the pharmacokinetics of fentanyl at low clinical doses.

[RP-HPLC method for determination of protopine in plasma and pharmacokinetics in rats].

AIM: To develop a reversed phase high performance liquid chromatographic method (RP-HPLC) for determination of protopine (Pro) in rat plasma and to investigate the pharmacokinetics of Pro in rats. METHODS: The column was packed with 5 microns C18. The mobile phase (pH 5.6) was a mixture of methanol-water-10% acetic acid (80:20:2). After twice extracted with ether under basic condition, and reextracted with 0.02 mol.L-1 sulfuric acid, protopine in the plasma samples was isolated well. The content of protopine in the plasma sample was measured by UV detector at 285 nm. RESULTS: The lowest limit of detection was 50 ng.mL-1. The intraday and interday precisions were 1.5%-3.0% and 2.1%-6.2%, respectively. The mean recovery was 80.6%-97.6%. A good linear relationship between the peak height and the concentration of protopine in rat plasma was observed. The pharmacokinetics of protopine had been investigated in rats after intravenous administration 10 mg.kg-1. The concentration-time curve of protopine in rat was confirmed to two-compartment open model. The T1/2 alpha, T1/2 beta, Ke, CL, Vd were 0.05 h, 1.85 h, 1.52 h, 6.41 L.h-1 and 17.27 L, respectively. CONCLUSION: This method is suitable for studies on pharmacokinetics of protopine.

Morphine-induced analgesia in rats withdrawn from concurrent nimodipine and morphine treatment.

The effect of repeated administration of dihydropyridine calcium channel antagonist, nimodipine, given concurrently with morphine on the development of tolerance to the antinociceptive actions of morphine in rats was studied. In acute experiments nimodipine (1 mg/kg i.p.) enhanced the antinociceptive effect of morphine (2.5 mg/kg s.c.) in the hot-plate and tail immersion tests. Daily administration of morphine either for 10 days (increasing the daily dose from 20 to 35 mg/kg) or for 24 days (increasing the daily dose from 20 to 70 mg/kg) induced tolerance to the antinociceptive effect of a challenge dose of morphine (10 mg/kg) administered 24 h after the withdrawal from chronic morphine. Concurrent administration of nimodipine (1 mg/kg per day) with morphine for 10 or 24 days augmented the reduction of the antinociceptive effect of morphine. Neither acute nor repeated administration of nimodipine with morphine altered the concentrations of morphine or its metabolite morphine 6-glucuronide in the brain tissue or in the plasma. The observed further reduction in the nociceptive response in morphine tolerant animals pre-treated with nimodipine is, most probably, due to the adaptive changes in the central dihydropyridine calcium channels induced by the withdrawal from repeated nimodipine treatment.

Effect of current density on pharmacokinetics following continuous or intermittent input from a fentanyl electrotransport system.

The pharmacokinetics of fentanyl were determined in two open-label crossover studies following 24-h periods of delivery by an electrotransport transdermal system (E-TRANS [fentanyl] system) in young healthy male volunteers. A direct current was applied continuously in study 1 (at 50, 100, and 200 microA; surface area = 5 cm2; n = 8), but in study 2 it was limited to the first 20 min of each hour (at 150, 200, and 250 microA; surface area = 2 cm2; n = 12). The opioid effects of fentanyl were blocked with naltrexone administered every 12 h. With increasing electrical current, the increase in serum fentanyl concentration, amount absorbed, and AUC values were proportional in study 2 but not in study 1. It is hypothesized that the lack of proportionality in study 1 is due to lower current density (microA/cm2) in this study. It appears that for fentanyl, the current density should be about 75 microA/cm2 or greater for a linear relation between current and amount absorbed as seen in study 2. Compared with intravenously infused fentanyl, the serum concentrations resulting from E-TRANS (fentanyl) system application revealed a slightly dampened rate of increase (stratum-corneum barrier effect) and decrease in serum concentrations, and a similar intersubject variability in fentanyl AUC values. Fentanyl pharmacokinetics with either E-TRANS (fentanyl) or intravenous infusion were time-invariant over a 24-h application period, with similar mean half-life values (about 15-18 h). E-TRANS (fentanyl) administration (either continuous or intermittent input) was safe and well tolerated. Adverse effects were mild to moderate; they consisted mainly of local erythema and pruritus (which resolved in most patients within 24 h after system removal) and occasional opioid effects.

Postoperative epidural opioid analgesia: what are the choices?

The administration of hydrophilic opioids via a continuous infusion results in selective spinal analgesia with a low incidence of side effects. Lipophilic opioids may also be associated with spinal effects. However, the doses required to produce postoperative analgesia also produce plasma concentrations within the MEAC. Thus, in clinical practice it may not be possible to limit epidural doses of lipophilic opioids to those associated with spinal analgesia. Regardless of the mechanism of action, epidural administration of lipophilic opioids may offer no clinical advantages over the IV route. Notwithstanding, epidural administration of small doses of lipophilic opioids in combination with local anesthetics may offer significant clinical advantages over systemic administration of opioids alone. Dose-ranging studies will be necessary to determine the ideal concentrations of opioids and local anesthetics, as well as the ratios of the two drugs to obtain optimal analgesia with minimal incidence of side effects.

Intratracheal administration of fentanyl: pharmacokinetics and local tissue effects.

OBJECTIVE: To study the pharmacokinetics and local tissue effects resulting from the intratracheal administration of preservative-free fentanyl. DESIGN: Prospective, randomized, blinded and controlled animal study. SETTING: University research laboratory. SUBJECTS: Eighteen adult male New Zealand rabbits. INTERVENTIONS: Preservative-free fentanyl citrate or normal saline was administered by the intratracheal (i.t.) and intravenous (i.v.) routes to randomized groups of rabbits. The animals were killed at 24, 48 and 72 h following administration. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of fentanyl were measured before administration and at 2, 5, 10, 30, 60 and 120 min following administration by a specific radioimmunoassay. A detailed histological examination of the lung and tracheal tissue was performed to identify local side effects. There were no significant differences in the plasma fentanyl concentrations resulting from the i.v. or i.t. route of administration. In both groups, the concentrations of fentanyl were within the therapeutic range (i.t. 2.37 ng/ml, i.v. 2.53 ng/ml) by 2 min after injection and reached a maximum concentration within 5 min. The bioavailability of i.t. fentanyl was 71%. Microscopic examination of the respiratory system did not show significant differences between the two random groups overall. However, in the sub-group of animals killed at 24 h, more animals in the i.t. group showed signs of inflammation in the lung parenchyma. CONCLUSIONS: There is rapid absorption of fentanyl following i.t. administration. Pharmacokinetic parameters for fentanyl were not significantly altered by the route of administration. Although there were no signs that i.t. administration of preservative-free fentanyl produces lung injury, a transient and mild inflammatory response was detected at 24 h after administration.