Naloxone for opioid overdose - Pharmacological aspects and dosing in clinical practice

Dødsfall fra opioidoverdoser er et stort folkehelseproblem og utdeling av nesespray med motgiften nalokson var foreslått som et tiltak for å redde liv. I 2012 fantes det ingen godkjente nesesprayer på markedet. Istedenfor var improviserte, ikke-godkjente sprayer uten vitenskapelig evidens i utstrakt bruk. NTNU startet derfor utviklingen av en slik nesespray. Det overordnede målet med denne doktorgraden var å bidra til evidensbasert behandling av opioidoverdoser med nalokson som nesespray. Nesesprayens opptak ble undersøkt ved at friske frivillige deltok i en åpen, randomisert, treveis overkrysningsstudie. Nesesprayen ble undersøkt i to ulike doser, 0,8 mg og 1,6 mg, og ble sammenlignet med 1,0 mg nalokson intravenøst ved å se på legemiddelkonsentrasjonen i blodet. For å undersøke effekten av nalokson ble det utviklet en modell hvor friske frivillige fikk 1,0 mg nalokson intravenøst samtidig som de fikk en målstyrt infusjon med opioidet remifentanil. Slik kunne effekten av nalokson måles med endring av pupillestørrelse, samtidig som vi tok både arterielle og venøse blodprøver for å måle konsentrasjonen av legemidlene. Gjennom en 5-års observasjonsstudie i ambulansetjenesten i Oslo undersøkte vi også den nåværende bruken av nalokson ved overdoser, og koblet disse dataene mot dødsårsaksregistret. Opptaket av legemidlet gikk raskt og biotilgjengeligheten av nesesprayen var 52-54%. Nesesprayen var godt tolerert og det var ingen alvorlige bivirkninger. Remifentanilinfusjonen gav stabile blodkonsentrasjoner gjennom forsøket. Intravenøs nalokson reverserte raskt effekten av opioidet og effekten varte i 118 minutter. Av 2215 overdosepasienter i Oslo fikk 92% intramuskulær nalokson og startdosene var 0,4 og 0,8 mg. En ukes mortalitet for narkotikautløste dødsfall var 4,1/1000 tilfeller. Ingen av dødsfallene var på grunn av reintoksikasjon. Nesesprayen hadde raskt, systemisk opptak og høyere biotilgjengelighet enn improviserte nesesprayer. Dette indikerer at en optimalisert nesespray kan gi en terapeutisk dose nalokson. En målstyrt remifentanil infusjon gav stabile konsentrasjoner av opioidet i blodet og kan være en nyttig modell for å teste nye naloksonprodukter. I ambulansetjenesten var intramuskulær nalokson i dosene 0,4-0,8 mg effektivt og trygt

Nasal naloxone - A pilot study of the pharmacokinetics of a concentrated formulation

Introduction: Naloxone is the antidote against heroin and other opioids. As a measure to combat overdose deaths, nasal naloxone is wanted for bystander administration by lay people. The objective of this study was to investigate the pharmacokinetic profile of nasal naloxone delivered as in a high-concentration/low-volume formulation. The primary objective was to get a preliminary estimation of bioavailability of intranasal naloxone in human, healthy volunteers. Secondary objectives were a preliminary estimation of maximum serum concentration (Cmax) and time to maximum serum concentration (Tmax), and also to investigate the safety of the formulation. Materials and methods: This was a phase 1, single centre, open-label, randomised, two-way crossover trial in healthy male volunteers, n=5, age 18-45 years. 1.0 mg intravenous naloxone was compared to 2 mg intranasal naloxone given as 0.1 ml of 20 mg/ml nasal spray. Blood samples were drawn at predetermined intervals, and serum concentrations of naloxone was determined by a validated liquid chromatography-mass spectrometry method, and analysed by non-compartmental techniques. A 72-hour washout period was enforced between treatments. A post-study interview was performed. Results: Bioavailability (mean (95% confidence interval) were 47.1% (38.4-55.8) for the intranasal naloxone. Cmax were 4.24 (1.48-7.00). Tmax was reached after 16.0 min (5.80- 26.2). The mean half-lives varied from 80-90 min. No clinically significant adverse event was observed. Moreover, the spray provoked no unexpected adverse events. The only reported adverse drug reaction was taste of the nasal spray. Conclusions: The nasal sprayer resulted in a rapid systemic uptake, and a higher bioavailability than previously reported for low-concentration/high-volume formulations. The nasal spray provided serum concentration that surpassed the intravenous after 10 min, and stayed above until 240 min. The spray did not elicit worrying side effects in the exposed subjects. The results are promising and further development of the product is warranted. Based on these results we have chosen to study 8 and 16 mg/ml in the next study. Further trials comparing the nasal spray with clinically relevant doses of intramuscular naloxone, and studies investigating the pharmacodynamic properties of the product, is also needed

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 naloxone3-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 signifcantly 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 signifcantly 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 efect gradually diminished. From 240 min there was no signifcant diference 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

Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil

Purpose Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying pharmacokinetic/pharmacodynamic aspects of naloxone and to explore whether a significant arteriovenous concentration difference for naloxone in humans was present. Methods Relevant authorities approved this study. Healthy volunteers (n = 12) were given 1.0 mg intravenous (IV) naloxone after steady state opioid agonism was obtained by TCI of remifentanil (1.3 ng/ml). Opioid effect was measured by pupillometry. Arterial and venous samples were collected simultaneously before and for 2 h after naloxone administration for quantification of naloxone and remifentanil. Results Arterial remifentanil was in steady state at 12 min. One milligram IV naloxone reversed the effect of remifentanil to 93% of pre-opioid pupil-size within 4 min. The estimated duration of antagonism was 118 min. At that time, the concentration of naloxone was 0.51 ng/ml. The time course of arterial and venous serum concentrations for naloxone was similar, although arterial AUC (area under the curve) was slightly lower (94%) than the venous AUC (p = 0.03). There were no serious adverse events. Conclusion Onset of reversal by IV naloxone was rapid and lasted 118 min. The minimum effective concentration was 0.5 ng/ml. Using TCI remifentanil to obtain a steady-state opioid agonism may be a useful tool to compare new naloxone products

Pharmacokinetics of a new, nasal formulation of naloxone

Purpose Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone. Methods This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method. Results Bioavailability was 0.54 (0.45–0.63) for the 0.8 mg and 0.52 (0.37–0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (Cmax) were 1.45 ng/ml (1.07–1.84) for 0.8 mg and 2.57 ng/ml (1.49–3.66) for the 1.6 mg. Time to maximum concentrations (Tmax) were reached at 17.9 min (11.4–24.5) and 18.6 min (14.4–22.9) for the 0.8 mg and the 1.6 mg doses, respectively. Conclusion This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15–20 min and stayed above for the rest of the study period

Pharmacokinetics of a novel, approved, 1.4-mg intranasal naloxone formulation for reversal of opioid overdose—a randomized controlled trial

Background and aims Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. Design Open, randomized four‐way cross‐over trial. Setting Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. Participants Twenty‐two healthy human volunteers, 10 women, median age = 25.8 years. Intervention and comparator One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. Measurements Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non‐compartment analyses were used for the main analyses. A non‐parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. Findings Area under the curve from administration to last measured concentration (AUC0‐last) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 ± 0.94 and 3.09 ± 0.64 h × ng/ml, respectively (P = 0.33). Maximum concentration (Cmax) was 2.36 ± 0.68 ng/ml for i.n. 1.4 mg and 3.73 ± 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 ± 1.53 ng/ml. Tmax was reached after 20.2 ± 9.4 minutes for i.n. 1.4 mg and 13.6 ± 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). Conclusion Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals

REBOARREST, resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest: a study protocol for a randomised, parallel group, clinical multicentre trial

Background Survival after out-of-hospital cardiac arrest (OHCA) is poor and dependent on high-quality cardiopulmonary resuscitation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be advantageous in non-traumatic OHCA due to the potential benefit of redistributing the cardiac output to organs proximal to the aortic occlusion. This theory is supported by data from both preclinical studies and human case reports. Methods This multicentre trial will enrol 200 adult patients, who will be randomised in a 1:1 ratio to either a control group that receives advanced cardiovascular life support (ACLS) or an intervention group that receives ACLS and REBOA. The primary endpoint will be the proportion of patients who achieve return of spontaneous circulation with a duration of at least 20 min. The secondary objectives of this trial are to measure the proportion of patients surviving to 30 days with good neurological status, to describe the haemodynamic physiology of aortic occlusion during ACLS, and to document adverse events. Discussion Results from this study will assess the efficacy and safety of REBOA as an adjunctive treatment for non-traumatic OHCA. This novel use of REBOA may contribute to improve treatment for this patient cohort.publishedVersio

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers

Purpose This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. Methods Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. Results The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02–p < 0.001). Heat pain threshold showed no statistical difference. Conclusions A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use

Abstract Introduction Intranasal naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared to injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved intranasal naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 millilitres per dose is non- inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose. Methods and analysis Sponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration ≥10 breaths/minute based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked. Ethics and dissemination The study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the NTNU Open repository. De-identified individual participant data will be made available to recipients conditional of data processor agreement being entered. Trial registrations: EudraCT number: 2016-004072-22 and Clinicaltrials.gov NCT0351802

NTNU intranasal naloxone trial (NINA-1) study protocol for a double-blind, double-dummy, non-inferiority randomised controlled trial comparing intranasal 1.4 mg to intramuscular 0.8 mg naloxone for prehospital use

Abstract Introduction Intranasal naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared to injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved intranasal naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 millilitres per dose is non- inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose. Methods and analysis Sponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration ≥10 breaths/minute based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked. Ethics and dissemination The study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the NTNU Open repository. De-identified individual participant data will be made available to recipients conditional of data processor agreement being entered. Trial registrations: EudraCT number: 2016-004072-22 and Clinicaltrials.gov NCT0351802