Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects.

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.

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.

Pharmacokinetic considerations for community-based dosing of nasal naloxone in opioid overdose in adults.

INTRODUCTION: The administration of the opioid antagonist naloxone in the community is a measure to prevent death from opioid overdose. Approved nasal naloxone sprays deliver initial doses of 0.9 to 8 mg. The level of the initial community dose is controversial, as the scientific base is weak.In this review knowledge of the pharmacokinetics of nasal, both approved and improvised nasal sprays, and intramuscular naloxone will be utilized to evaluate dose-effect relationships in previous studies of opioid overdose outcomes. AREAS COVERED: The aim was to present scientifically based considerations on the initial nasal naloxone doses currently available, which reasonably balances the effect and adverse outcomes, given that at least two doses are at hand. Also included in these considerations is the challenge by illicitly manufactured fentanyl and analogs.This paper is based on both peer-reviewed and grey literature identified by several searches, of such as naloxone pharmacokinetics/formulations/outcomes/emergency medical services, in PubMed and Embase. EXPERT OPINION: There is little scientific evidence that supports the use of initial systemic dosing that exceeds 0.8 mg in the community. Higher doses increase the risk of withdrawal symptoms feared in people who use opioids. Many obstacles may reduce the potential of community-administered naloxone.

Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial.

AIMS: To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre-hospital environment. DESIGN: Randomised, controlled, double-dummy, blinded, non-inferiority trial, and conducted at two centres. SETTING: Participants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred. PARTICIPANTS: Men and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred-consent procedure. INTERVENTION AND COMPARATOR: A commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly. MEASUREMENTS: The primary end-point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events. FINDINGS: In total, 201 participants were analysed in the per-protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% (95% CI, 8.9%-26.1%) in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% (95% CI, 9.0%-29.7%) higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% (95% CI, 0.2%-13%) in favour of the intranasal group in a post hoc analysis. CONCLUSION: Intranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre-hospital environment when compared head-to-head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.

A Clinical Description of Chronic Pain in a General Population Using ICD-10 and ICD-11 (The HUNT Pain Examination Study).

The purpose was to present a total description, distribution, and ranking of chronic pain conditions in the general population. This was based on structured clinical examinations of a random sample from a population-based survey (HUNT3) with a calculated oversampling of participants with chronic pain. Supplemented with access to hospital reports, the examination was performed by experienced physicians and psychologists using a consistent definition of chronic pain as well as ICD-10- and the new ICD-11-classification. The main findings were that a higher proportion of the 551 participants had chronic pain assessed by clinical examination (399) than by self-report in a survey the same day (337). Among those with examination-verified chronic pain estimated from HUNT3 to represent 27.9% of the general population, 63% had chronic primary pain, 81% musculoskeletal pain, and 77% more than one chronic pain condition. When separating chronic primary from chronic secondary pain according to ICD-11, the weighted prevalence was 17.7% for chronic pain conditions of unknown and 10.2% of known cause. When all the participants' conditions were accounted for, the most prevalent was nonspecific low back (10.8%) and neck pain (7.6%). Participants with chronic primary pain did not have significantly more psychopathology than those with chronic secondary pain: 14.5% versus 12.5%. PERSPECTIVE: Since this study confirms the high prevalence in self-report surveys and indicates that two thirds of chronic pain conditions cannot be explained by underlying diseases, this huge health and societal problem should be solved primarily on a public health level directed toward prevention and rehabilitation.

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.

European survey on national harmonization in clinical research.

BACKGROUND: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. METHODS: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. RESULTS: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far. CONCLUSIONS: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

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.

INTRODUCTION: Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with 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 IN naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 mL 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/min 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 Norwegian University of Science and Technology Open repository. Deidentified individual participant data will be made available to recipients conditional of data processor agreement being entered. TRIAL REGISTRATION NUMBERS: EudraCT Registry (2016-004072-22) and Clinicaltrials.gov Registry (NCT03518021).

Prehospital naloxone administration - what influences choice of dose and route of administration?

BACKGROUND: Amidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration and emergency medical services, and in the development of new naloxone products. We examined the characteristics of naloxone administration, including predictors of dosages and multiple doses during patient treatment by emergency medical service staff in order to enlighten this debate. METHODS: This was a prospective observational study of patients administered naloxone by the Oslo City Center emergency medical service, Norway (2014-2018). Cases were linked to The National Cause of Death Registry. We investigated the route of administration and dosage of naloxone, clinical and demographic variables relating to initial naloxone dose and use of multiple naloxone doses and one-week mortality. RESULTS: Overall, 2215 cases were included, and the majority (91.9%) were administered intramuscular naloxone. Initial doses were 0.4 or 0.8 mg, and 15% of patients received multiple dosages. Unconscious patients or those in respiratory arrest were more likely to be treated with 0.8 mg naloxone and to receive multiple doses. The one-week mortality from drug-related deaths was 4.1 per 1000 episodes, with no deaths due to rebound opioid toxicity. CONCLUSIONS: Intramuscular naloxone doses of 0.4 and 0.8 mg were effective and safe in the treatment of opioid overdose in the prehospital setting. Emergency medical staff appear to titrate naloxone based on clinical presentation.

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.

Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine.

Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of 'take-home naloxone' has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40-50%. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved.

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.

Ambulance-attended opioid overdoses: An examination into overdose locations and the role of a safe injection facility.

Background: Although the United States and numerous other countries are amidst an opioid overdose crisis, access to safe injection facilities remains limited. Methods: We used prospective data from ambulance journals in Oslo, Norway, to describe the patterns, severity, and outcomes of opioid overdoses and compared these characteristics among various overdose locations. We also examined what role a safe injection facility may have had on these overdoses. Results: Based on 48,825 ambulance calls, 1054 were for opioid overdoses from 465 individuals during 2014 and 2015. The rate of calls for overdoses was 1 out of 48 of the total ambulance calls. Males made up the majority of the sample (n = 368, 79%), and the median age was 35 (range: 18-96). Overdoses occurred in public locations (n = 530, 50.3%), the safe injection facility (n = 353, 33.5%), in private homes (n = 83, 7.9%), and other locations (n = 88, 8.3%). Patients from the safe injection facility and private homes had similarly severe initial clinical symptoms (Glasgow Coma Scale median =3 and respiratory frequency median =4 breaths per minute) when compared with other locations, yet the majority from the safe injection facility did not require further ambulance transport to the hospital (n = 302, 85.6%). Those overdosed in public locations (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.17-2.35), and when the safe injection facility was closed (OR =1.4, 95% CI =1.04-1.89), were more likely to receive transport for further treatment. Conclusions: Our findings suggest that the opening hours at the safe injection facility and the overdose location may impact the likelihood of ambulance transport for further treatment.

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 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. TRIAL REGISTRATION: clinicaltrials.gov : NCT02307721.

International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database.

ISSUES: Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. APPROACH: (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. KEY FINDINGS: Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL-1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL-1 ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL-1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted Cmax  = 0.8-1.7 ng mL-1 ) reached in 19-30 min (tmax ). IMPLICATIONS: Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. CONCLUSION: We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000].