Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the µ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept.

BACKGROUND AND OBJECTIVES: Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations. METHODS: Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time. RESULTS: We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time. CONCLUSIONS: One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption.

A Novel Faster-Acting, Dry Powder-Based, Naloxone Intranasal Formulation for Opioid Overdose.

OBJECTIVE: To examine the pharmacokinetics and safety of FMXIN001, a new intranasal powder-based naloxone formulation, in comparison to Narcan® nasal liquid spray. METHODS: FMXIN001, was developed by blending drug microspheres with larger lactose monohydrate particles, that serve as diluent and carrier, as well as a disaggregating agent. Scanning electron microscopy and X-ray were used to characterize the formulation and in vitro deposition was investigated using a nasal cast. We compared the pharmacokinetics and safety of FMXIN001 versus Narcan® in two clinical trials: a pilot study with 14 healthy adults and a pivotal trial in 42 healthy adults (NCT04713709). The studies were open-label, single-dose, randomized, two-period, two-treatment, two-sequence crossover studies to assess the pharmacokinetics and safety of FMXIN001 versus Narcan® nasal spray. RESULTS: FMXIN001 comprises naloxone microspheres (5-30 µM) and lactose particles (40-240 µM). Upon in vitro testing, naloxone deposits mainly to the middle turbinates region and the upper part of the nasal cavity of a nasal cast. In human subjects, FMXIN001 produced significantly higher exposure at the initial time points of 4, 10, and 30 min, post-administration, compared to Narcan®. Both treatments were safe and well tolerated. FMXIN001, powder-based spray, results in similar overall exposure to Narcan®, but with more rapid absorption in the first 30 min. CONCLUSIONS: FMXIN001 is expected to have a shorter onset of action for a more effective therapeutic intervention to manage opioid overdose. Rapid administration of naloxone in cases of opioid overdose is imperative, given the alarming increase in mortality rates.

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers.

PURPOSE: Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. METHODS: We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). RESULTS: Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8-8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30-90 min and were 2-3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. CONCLUSION: Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.

Engineering Quick- and Long-acting Naloxone Delivery Systems for Treating Opioid Overdose.

PURPOSE: Opioids have been the main factor for drug overdose deaths in the United States. Current naloxone delivery systems are effective in mitigating the opioid effects only for hours. Naloxone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared as quick- and long-acting naloxone delivery systems to extend the naloxone effect as an opioid antidote. METHODS: The naloxone-PLGA microparticles were made using an emulsification solvent extraction approach with different formulation and processing parameters. Two PLGA polymers with the lactide:glycolide (L:G) ratios of 50:50 and 75:25 were used, and the drug loading was varied from 21% to 51%. Two different microparticles of different sizes with the average diameters of 23 µm and 50 µm were produced using two homogenization-sieving conditions. All the microparticles were critically characterized, and three of them were evaluated with ß-arrestin recruitment assays. RESULTS: The naloxone encapsulation efficiency (EE) was in the range of 70-85%. The EE was enhanced when the theoretical naloxone loading was increased from 30% to 60%, the L:G ratio was changed from 50:50 to 75:25, and the average size of the particles was reduced from 50 µm to 23 µm. The in vitro naloxone release duration ranged from 4 to 35 days. Reducing the average size of the microparticles from 50 µm to 23 µm helped eliminate the lag phase and obtain the steady-state drug release profile. The cellular pharmacodynamics of three selected formulations were evaluated by applying DAMGO, a synthetic opioid peptide agonist to a µ-opioid receptor, to recruit ß-arrestin 2. CONCLUSIONS: Naloxone released from the three selected formulations could inhibit DAMGO-induced ß-arrestin 2 recruitment. This indicates that the proposed naloxone delivery system is adequate for opioid reversal during the naloxone release duration.

Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine.

Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs cleared majorly via glucuronidation (lorazepam, oxazepam, naloxone, and zidovudine). In vitro to in vivo scaling of intrinsic clearance generated with co-cultured human hepatocytes was applied for hepatic metabolism and extra-hepatic clearance was extrapolated based on relative expression of UGT isoforms in the liver, kidney, and intestine. Non-metabolic clearance and the contributions of individual UGT isoforms to glucuronidation were based on in vitro and in vivo studies taken from the literature and simulations were verified and evaluated with a broad set of clinical pharmacokinetic data. Model evaluation showed systemic clearance predictions within 1.5-fold for all drugs and all simulated parameters were within 2-fold of observed. However, during the verification step, top-down model fitting was necessary to adjust for under-prediction of zidovudine VSS and renal clearance and over estimation of intestinal first pass for lorazepam, oxazepam, and zidovudine. The impact of UGT2B15 polymorphisms on the pharmacokinetics of oxazepam and lorazepam was simulated and glucuronide metabolites were also simulated for all four drugs. To increase confidence in predicting extra-hepatic clearance, improvement of enzyme phenotyping for UGT substrates and more quantitative tissue expression levels of UGT enzymes are both needed. Prediction of glucuronide disposition is also challenging when active transport processes play a major role.

An open-label, randomized, single-dose, two-period, two-treatment crossover bioavailability study comparing 5 mg/0.5 mL of intramuscular naloxone hydrochloride to 2 mg/0.4 mL intramuscular naloxone hydrochloride autoinjector in healthy subjects.

Naloxone is an opioid antagonist used for the acute treatment of opioid overdoses. There has been a dramatic increase of deaths due to synthetic opioids such as fentanyl, some requiring multiple doses of naloxone for reversal of opioid tox-icity. Fentanyl appears to differ from other opiates as having a very rapid onset and transport in and out of the central nervous system (CNS). Fentanyl is therefore widely distributed in the CNS. Furthermore, a high range of systemic levels of fentanyl have been observed in overdose victims. Taken together, we believe it is very likely that higher doses of naloxone are needed to combat this new era of overdoses. We examined the bioavailability of an investigational 5 mg intramuscular naloxone in a prefilled syringe (PFS) compared to 2 mg intramuscular naloxone in an autoinjector (AI) at the current approved dose in a crossover design which included 14 healthy subjects. Overall, both doses were well tol-erated with no adverse events noted during the trial. The pharmacokinetic results showed that a higher dose of intra-muscular naloxone hydrochloride increases Cmax, AUC, and t1/2; however, Tmax was similar for both treatments. Statistical analysis indicated that there were statistical differences between the test and reference treatments for Cmax, AUCs, and t1/2 with ratios of test to reference for Cmax of 337.1 percent (CI: 263.3 percent, 431.5 percent), AUC0-t of 277.5 percent (CI: 260.4 percent, 295.7 percent), AUC0-inf of 273.4 percent (CI: 255.6 percent, 292.4 percent), and t1/2 of 110.5 percent (CI: 95.5, 127.9). These results are consistent with the study rationale that indicated higher doses of intramuscular naloxone hy-drochloride would result in higher Cmax and AUCs. These PK characteristics may be desirable for reversing opioid toxicity caused by the higher, more potent synthetic opioids.

Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl.

INTRODUCTION: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS). METHODS: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test. RESULTS: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4-1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4-1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4-1.6). CONCLUSION: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed.

Determination of buprenorphine, naloxone and phase I and phase II metabolites in rat whole blood by LC-MS/MS.

Buprenorphine and buprenorphine/naloxone combination are maintenance treatments used worldwide. However, since their marketing, despite ceiling respiratory effects, poisonings and fatalities have been attributed to buprenorphine misuse and overdose. Therefore, to better understand the mechanisms of buprenorphine-related toxicity in vivo, experimental investigations have been conducted, mainly in the rat. We developed a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method with electrospray ionization for the simultaneous quantification of buprenorphine, naloxone and their metabolites (norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide and naloxone glucuronide) in rat whole blood. Compounds were extracted from whole blood by protein precipitation and chromatographically separated using gradient elution of aqueous ammonium formate and methanol in a Raptor Biphenyl core-shell column (100 mm x 3,0 mm x 2,7 µm). Following electrospray ionization, quantification was carried out in the multiple reaction monitoring (MRM) mode by the tandem mass spectrometer API 3200 system. The LC-MS/MS method was validated according to the currently accepted criteria for bioanalytical method validation. The method required small sample volumes (50 µL) and was sensitive with limits of quantification of 6.9, 6.2, 3.6, 3.3, 1.3 and 57.7 ng/mL for buprenorphine, norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide, naloxone and naloxone glucuronide respectively. The upper limit of quantification was 4000 ng/ml for all the studied compounds. Trueness (88-115 %), repeatability and intermediate precision (both <15%) were in accordance with the international recommendations. The procedure was successfully used to quantify these compounds in the whole blood sample from one rat 24 h after the intravenous administration of buprenorphine/naloxone (30.0/7.5 mg/kg).

Naloxone nasal spray - bioavailability and absorption pattern in a phase 1 study. / Naloksonnesespray ­ biotilgjengelighet og opptaksmønster i en fase 1-studie.

BACKGROUND: Bystander administration with naloxone nasal spray can prevent deaths from opioid overdose. To achieve optimal nasal absorption of naloxone, the spray must be administered at low volume with high concentration of the drug. The study aimed to investigate the bioavailability and absorption pattern for a new naloxone nasal spray. MATERIAL AND METHOD: In an open, randomised, two-way crossover study undertaken in five healthy men, naloxone 2 mg (20 mg/ml) in nasal spray was compared with 1 mg intravenously administered naloxone. A total of 15 blood samples were taken over a period of six hours after administration. The drug concentration was determined using liquid chromatography tandem-mass spectrometry. Pharmacokinetic variables were calculated using non-compartmental analysis. RESULTS: Bioavailability for intranasal naloxone was 47 % (minimum-maximum values 24-66 %). Maximum concentration (Cmax) was 4.2 (1.5-7.1) ng/ml, and this was achieved (Tmax ) after 16 (5-25) minutes. INTERPRETATION: The nasal spray resulted in a rapid systemic absorption with higher serum concentrations than intravenous naloxone 10-240 minutes after intake. The pilot study indicated that the highly concentrated nasal spray may provide a therapeutic dose of naloxone with a single spray actuation. The findings led to further commercial development of the medication.

Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes.

The primary goal of this work was to develop a computational tool to enable personalized prediction of pharmacological disposition and associated responses for opioids and antidotes. Here we present a computational framework for physiologically-based pharmacokinetic (PBPK) modeling of an opioid (morphine) and an antidote (naloxone). At present, the model is solely personalized according to an individual's mass. These PK models are integrated with a minimal pharmacodynamic model of respiratory depression induction (associated with opioid administration) and reversal (associated with antidote administration). The model was developed and validated on human data for IV administration of morphine and naloxone. The model can be further extended to consider different routes of administration, as well as to study different combinations of opioid receptor agonists and antagonists. This work provides the framework for a tool that could be used in model-based management of pain, pharmacological treatment of opioid addiction, appropriate use of antidotes for opioid overdose and evaluation of abuse deterrent formulations.

Pharmacokinetics and pharmacodynamics of intranasal and intravenous naloxone hydrochloride administration in healthy dogs.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of naloxone hydrochloride in dogs following intranasal (IN) and IV administration. ANIMALS: 6 healthy adult mixed-breed dogs. PROCEDURES: In a blinded crossover design involving 2 experimental periods separated by a washout period (minimum of 7 days), dogs were randomly assigned to receive naloxone IN (4 mg via a commercially available fixed-dose naloxone atomizer; mean ± SD dose, 0.17 ± 0.02 mg/kg) or IV (0.04 mg/kg) in the first period and then the opposite treatment in the second period. Plasma naloxone concentrations, dog behavior, heart rate, and respiratory rate were evaluated for 24 hours/period. RESULTS: Naloxone administered IN was well absorbed after a short lag time (mean ± SD, 2.3 ± 1.4 minutes). Mean maximum plasma concentration following IN and IV administration was 9.3 ± 2.5 ng/mL and 18.8 ± 3.9 ng/mL, respectively. Mean time to maximum concentration following IN administration was 22.5 ± 8.2 minutes. Mean terminal half-life after IN and IV administration was 47.4 ± 6.7 minutes and 37.0 ± 6.7 minutes, respectively. Mean bioavailability of naloxone administered IN was 32 ± 13%. There were no notable changes in dog behavior, heart rate, or respiratory rate following naloxone administration by either route. CONCLUSIONS AND CLINICAL RELEVANCE: Use of a naloxone atomizer for IN naloxone administration in dogs may represent an effective alternative to IV administration in emergency situations involving opioid exposure. Future studies are needed to evaluate the efficacy of IN naloxone administration in dogs with opioid intoxication, including a determination of effective doses.

Pharmacokinetics of Sublingual Buprenorphine Tablets Following Single and Multiple Doses in Chinese Participants With and Without Opioid Use Disorder.

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).

Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs.

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α2-adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.

Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects.

Naloxone (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one HCl), a µ-opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate subsequent doses. The addition of naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one], another µ-receptor antagonist, which has a reported half-life of 3 1/2 hours, may extend the available time to receive medical treatment. In a phase 1 pharmacokinetic study, healthy adults were administered naloxone and naltrexone intranasally, separately and in combination. When administered with naloxone, the C max value of naltrexone decreased 62% and the area under the concentration-time curve from time zero to infinity (AUC0-inf) decreased 38% compared with when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes postdose. In contrast, the C max and AUC0-inf values of naloxone decreased only 18% and 16%, respectively, when given with naltrexone. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a transporter. Neither compound was a substrate for organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter when they were tested separately or in combination at concentrations of 10 and 500 µM using Madin-Darby canine kidney II cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to six or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity; there was no apparent interaction when the two were coincubated. The importance of understanding how opioid antagonists are absorbed by the nasal epithelium is magnified by the rise in overdose deaths attributed to long-lived synthetic opioids and the realization that better strategies are needed to treat opioid overdoses.

The role of take-home naloxone in the epidemic of opioid overdose involving illicitly manufactured fentanyl and its analogs.

INTRODUCTION: There has been an exponential increase in overdose fatalities as illicitly manufactured fentanyl and its analogs (IMF) are becoming more prevalent in the illicit drug supply. In response, overdose education and naloxone distribution (OEND) programs have been implemented throughout the United States as a harm reduction strategy. However, there are increasing reports that higher naloxone doses or repeat administration might be required for overdose victims involving IMF. AREAS COVERED: In this article, we provide a comprehensive review of the epidemiology, public health impact, and pharmacologic properties of IMF. The pharmacokinetic properties of currently available take-home naloxone (THN) kits, the role of THN as a harm reduction strategy and available data on its clinical use are discussed. Implications of occupational IMF exposure for first responders are also described. EXPERT OPINION: THN administration by a bystander is an effective harm reduction intervention. However, there is growing evidence that higher dose or multiple administrations of naloxone are required to fully reverse IMF related toxicity. Recently, the US Food and Drug Administration approved THN kits with a concentrated naloxone dose that produce high bioavailability. However, limited presence of OEND programs and cost of these new devices impede their accessibility to the general public.

Consumption of Movantik™ (Naloxegol) results in detection of naloxone in the patient's urine evaluated by confirmatory urine drug testing.

BACKGROUND: Many patients on chronic opioid therapy suffer from constipation, one of the most common side effect of opioids. Movantik™ (naloxegol) is an opioid antagonist that is recently introduced in the market to treat opioid-induced constipation and contains naloxegol as the active ingredient. Naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Detection of naloxone in the patients urine after consumption of naloxegol was not reported by the manufacturer and may mislead the prescribing clinicians. This study was conducted to investigate the presence of naloxone in the urine of patients that consume movnatik in pain management clinics. METHODS: The presence of naloxone and naloxol in the urine of 45 patients that consumed naloxegol and 25 patients that consumed suboxone™ were investigated using a liquid chromatography mass spectrometry (LCMS) method. The urinary concentration of naloxone, naloxol, and their glucuronide conjugates were evaluated in five volunteers that took one pill of naloxegol for one day and one volunteer who took the pill for three days. RESULTS: Naloxone was detected in the urine of 45 individuals that were prescribed naloxegol. Urinary concentration of naloxone showed a distribution with a mean of 25 ±â€¯18 ng/ml. Consumption of one pill of 25 mg naloxegol resulted in the detection of naloxol and naloxone in the urine of 5 volunteers 1 h after taking the pill. Evaluation of urine specimens from 25 patients that consumed suboxone™, resulted in the detection of naloxone (180 ±â€¯187 ng/ml) and naloxol (6.3 ±â€¯7.2 ng/ml). CONCLUSIONS: This study demonstrated that consumption of naloxegol leads to appearance of naloxone in the urine of patients receiving opioid therapy in pain management clinics.

High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

BACKGROUND: Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. METHODS: Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg-1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. RESULTS: Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were -32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. CONCLUSIONS: A parent-metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. CLINICAL TRIALS REGISTRATION: NCT01992146.

Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects.

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.