Pharmacokinetic Properties of an FDA-approved Intranasal Nalmefene Formulation for the Treatment of Opioid Overdose.

Nalmefene is a high-affinity, long-duration opioid antagonist that was approved in 1995 as an injection for the treatment of opiate overdose, but subsequently withdrawn (2008) for reasons other than safety or effectiveness. The dramatic rise in opioid overdose deaths over the past 7-8 years catalyzed the development of an intranasal (IN) formulation of nalmefene for the emergency treatment of opioid overdose. The studies described here compare the pharmacokinetic properties and safety profiles of an IN formulation containing nalmefene (2.7 mg in 0.1 mL) to an approved 1 mg intramuscular (IM) dose. IN nalmefene produced maximum plasma concentrations that were significantly higher than observed following the IM dose (12.2 and 1.77 ng/mL, respectively). The time to reach maximum plasma concentrations was also faster following IN administration (0.25 and 0.33 hours, respectively) with significant differences in plasma concentrations manifested as early as 2.5 minutes after administration (NCT04759768). The plasma half-life of nalmefene was similar following IM and IN administration (10.6-11.4 hours). Furthermore, dose-normalized nalmefene exposure was similar for both 1 spray in each nostril and 2 sprays in the same nostril compared to a single spray in each nostril (NCT05219669). There were no sex differences in the pharmacokinetic properties of either IN or IM nalmefene. In an era when almost 90% of opioid overdose deaths have been linked to high-potency synthetic opioids, the ability to rapidly deliver high concentrations of nalmefene could represent an important tool for reducing both morbidity and mortality.

Cannabinoid1 (CB-1) receptor antagonists: a molecular approach to treating acute cannabinoid overdose.

The legalization of cannabis for both recreational and medical use in the USA has resulted in a dramatic increase in the number of emergency department visits and hospital admissions for acute cannabinoid overdose (also referred to as cannabis intoxication and cannabis poisoning). Both "edibles" (often sold as brownies, cookies, and candies) containing large amounts of Δ9-tetrahydrocannabinol and synthetic cannabinoids (many possessing higher potencies and efficacies than Δ9-tetrahydrocannabinol) are responsible for a disproportionate number of emergency department visits relative to smoked cannabis. Symptoms of acute cannabinoid overdose range from extreme lethargy, ataxia, and generalized psychomotor impairment to feelings of panic and anxiety, agitation, hallucinations, and psychosis. Treatment of acute cannabinoid overdose is currently supportive and symptom driven. Converging lines of evidence indicating many of the symptoms which can precipitate an emergency department visit are mediated through activation of cannabinoid1 receptors. Here, we review the evidence that cannabinoid1 receptor antagonists, originally developed for indications ranging from obesity to smoking cessation and schizophrenia, provide a molecular approach to treating acute cannabinoid overdose.

Treating gambling disorder with as needed administration of intranasal naloxone: a pilot study to evaluate acceptability, feasibility and outcomes.

BACKGROUND AND AIM: There is growing interest in the use of medication-assisted treatments for gambling disorder (GD). Opioid receptor antagonists are hypothesised to blunt the craving associated with gambling. This study was designed to assess the feasibility of using an intranasal naloxone spray to treat GD. DESIGN: An 8-week, open-label, uncontrolled pilot study. SETTING: A single study site in the capital region of Finland. SUBJECTS: Twenty problem gamblers (nine men) were randomised into two groups. Group A (n=10) took one dose into one nostril (2 mg naloxone), as needed, with a maximum of 4 doses/day (max. 8 mg/day). Group B (n=10) took one dose into each nostril (4 mg naloxone) as needed, with a maximum of 4 doses/day (max. 16 mg/day). INTERVENTION: Naloxone hydrochloride nasal spray. MEASURES: Acceptability and feasibility of the intervention were assessed. Use of study medication, adverse events, gambling frequency and gambling expenditure were recorded in a mobile diary. Problem gambling: South Oaks Gambling Screen (SOGS), depressive symptoms: Beck Depression Inventory (BDI) and alcohol use: Alcohol Use Disorders Identification Test were recorded. RESULTS: Study completion rate was 90%. Acceptability and feasibility scores were high. Group B used intranasal naloxone more frequently than group A, and consequently used more naloxone. No serious adverse events were reported. The postintervention SOGS scores were lower (median=4 (IQR=3.75) versus preintervention scores (median=12 (IQR=4.75)). Depressive symptoms were reduced during the trial (preintervention BDI median=9, IQR=9 vs postintervention BDI median=6, IQR=6). CONCLUSIONS: The acceptability and feasibility of using intranasal naloxone were high, and no serious adverse events were reported. Preliminary results suggest mixed results in terms of gambling behaviour (ie, reduced frequency but not expenditure) and decreased depressive symptoms. TRIAL REGISTRATION NUMBER: EudraCT2016-001828-56.

Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose.

The dramatic rise in overdose deaths linked to synthetic opioids (e.g., fentanyl, carfentanil) may require more potent, longer-duration opiate antagonists than naloxone. Both the high affinity of nalmefene at µ opiate receptors and its long half-life led us to examine the feasibility of developing an intranasal (IN) formulation as a rescue medication that could be especially useful in treating synthetic opioid overdose. In this study, the pharmacokinetic properties of IN nalmefene were compared with an intramuscular (i.m.) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median time to reach Cmax (Tmax) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced Tmax to 0.25 hour and increased Cmax by ∼2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltoside has characteristics consistent with an effective rescue medication: its onset of action is comparable to an i.m. injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the Cmax following IN administration was ∼3-fold higher than following i.m. dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 minutes following a 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life (>7 hours) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.

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.

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose.

Based on its high affinity for µ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased Cmax by ∼3-fold and reduced the Tmax from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half-life following intranasal administration (∼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer-lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as-needed dosing strategy to treat alcohol use disorder.

Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose.

Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.

Optimal injection points for the neuromuscular blockade of forearm flexor muscles: a cadaveric study.

Botulinum toxin acts at neuromuscular junctions close to muscle motor points and is used to help manage spastic upper-limb deformities. To develop a system allowing clinicians to identify optimal injection sites by an easily reproducible technique, forearm flexor muscles were dissected in 20 formalin-preserved human limbs. Motor points for flexor carpi ulnaris, flexor carpi radialis, flexor digitorum superficialis and pronator teres were (1) identified, (2) related to a reference grid based on lines (proximal, distal, lateral, medial and diagonals) drawn between forearm anatomical landmarks, and (3) defined in terms of their percentage distances along the established grid lines.

Ambulance alerting of paediatric emergencies to a general hospital.

BACKGROUND: There are at present only a small number of dedicated paediatric emergency departments in the UK. Severely ill and injured children are often taken by ambulance to the nearest general hospital. Efforts have been made to provide better care for these sickest children pending the establishment of dedicated paediatric emergency services within general emergency departments by 2004 [Royal College of Paediatrics and Child Health; Accident and Emergency Services for Children-Report of a Multidisciplinary Working Party, June 1999]. To learn more of the staffing implications for the establishment of dedicated paediatric emergency units within the general hospital, 30 months of paediatric alert call data are presented. METHODS: A prospective review of paediatric alert calls over 30 months, (from January 1999 until June 2001). All alert calls from the ambulance service to a large urban emergency department were recorded on a specific form. Data from these forms is presented. RESULTS: There were 1754 alert calls of all types during this 30-month period, of which 153 (9%) were for patients under the age of 16 (mean 1.2 each week). Of these, 102 (66%) were for medical conditions and 51 (34%) were for trauma. The mean estimated time of arrival from the time of the alert call was 6 min. The majority of both medical and trauma paediatric alert calls occur in the afternoon and progress well into the night. The 51.6% of paediatric medical alert calls and 64.4% of paediatric trauma alert calls occur 'out of normal hours'. There was little reduction in the frequency of alert calls at the weekend. There were no paediatric trauma alert calls between 2 a.m. and 10 a.m., although medical paediatric alert calls continued throughout the night. CONCLUSIONS: Resident senior trauma personnel to manage injured children should be provided until at least midnight. Hospitals that maintain a facility for the reception of sick children must be able to provide a rapid response to paediatric medical emergencies on a 24 h basis. Guidelines for alert calls for ambulance crews are required.

Ambulance crew assessment of trauma severity and alerting practice for trauma patients brought to a general hospital.

INTRODUCTION: Ambulance crews may alert hospitals for patients who are severely unwell. This allows the hospital time to prepare space and equipment, and to assemble an appropriate clinical team to receive and manage the patient immediately on arrival. Over and under alerting by ambulance crews is to be avoided to avoid complacency on one hand, and inadequate reception of severely injured patients on the other. There are currently no formal guidelines for the ambulance service to alert hospitals in appropriate cases. AIMS: To describe the current alerting practice for trauma patients by ambulance crews to a large urban hospital. METHODS: Details of each trauma alert for the hospital for the year 2000 were identified. The Injury Severity Score (ISS) was determined for all trauma patients who were eligible for inclusion into the Trauma Audit Research Network (TARN) for the same year. The two populations were compared. RESULTS: There were 145 trauma patients for whom an alert was made during the year 2000, and there were 504 patients eligible for inclusion into TARN. Ten percent (49) of the TARN patients had an ISS > 15. Twenty-five percent (35/135) of the trauma patients with alerts had been entered into TARN. Seventy-five percent (100/135) of the trauma patients with alerts did not meet the criteria for inclusion into TARN. Forty-three percent (15/35) of the trauma patients with alerts who appeared in TARN had an ISS > 15 (11% of all trauma alerts). Thirty-four TARN-eligible patients with an ISS > 15 were not the subject of a hospital alert. CONCLUSIONS: The majority of patients with major trauma (ISS > 15) were not the subject of a hospital alert by the ambulance service. Seventy-five percent of the patients who were the subject of an alert were not eligible for inclusion into TARN, implying that they did not have serious injury. Pre-hospital trauma severity assessment needs developing with appropriate ambulance protocols, to ensure appropriate alert calls.