An Autonomous Implantable Device for the Prevention of Death from Opioid Overdose

Abstract

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.

Fig. 1.. Autonomous operational scheme of Naloximeter for continuous sensing, triggered drug delivery and rescue from opioid overdose.

(A) Implanted device (Naloximeter) detects respiratory depression leading to hypoxia, a signature of opioid overdose, delivers the rescue drug naloxone (NLX) and sends an emergency alert to first responders. (B) Operational diagram including transdermal wireless power transfer, bidirectional communication via Bluetooth Low Energy (BLE) protocols, and cellular communication that delivers an emergency alert. (C) Optical images of a Naloximeter, inset: side (top) and top view (bottom) of the device. Scale bars, 1 cm.

Fig. 2.. Device design and in-vivo validation studies.

(A) Exploded view illustration of a Naloximeter for intravenous drug delivery via catheter and electrolytic pump, inset: printed-circuit board (PCB) layout with critical components labeled including the dual-wavelength optical sensor, mounted on the backside of the assembled pump device. (B) Cross sectional illustration showing deformation of a flexible membrane under pressure from gas generated via electrolytic water splitting. This process drives naloxone (NLX) through a catheter port to a vein. (C) Drug release from the electrolytic device, N = 3 devices, error bars are SD. (D) Exploded view illustration of a Naloximeter for drug injection via a needle and motor-driven actuator, inset: Huber needle and PTFE septum at the outlet of the housing. (E) Drug release from the injector device in single- or dual-injection mode (N = 3 devices). (F) Schematic illustrations of dual-injection operation, namely: needle deployment (–2), delivery of first dose (3), retraction (4), delivery of second dose (5), and final retraction once empty (6). (G) Validation of the dual-wavelength optical sensor for determining StO₂ via sequential exposure to hypoxic gas mixtures (21, 14, 12, 10, 8, 21% O₂, denoted as colored bars) in a rodent model; SpO₂ data collected using a gold standard device (GSD; MouseOx collar). (H) Correlation plot for SpO₂ (GSD) and StO₂ (Naloximeter) resulting from rodent hypoxia validation studies (R² = 0.95). Colors signify individual animals. (I) Correlation plot for SO₂ from blood gases and StO₂ from the dual-wavelength optical sensor validated in porcine hypoxia studies (R² = 0.65). Colors signify individual devices. (J) Pharmacokinetics of naloxone (NLX) delivered using the intravenous device in a porcine model, dose: 3 mL (2.7 mg NLX), N = 3 animals. Inset: Optical image of a catheter tunneled subcutaneously from a device and secured in the jugular vein, scale bar is 1 cm.

Fig. 3.. Physiological signs of opioid overdose and an algorithm for overdose detection in freely moving subjects.

(A) StO₂ recorded with a Naloximeter during a fentanyl overdose (OD; 10 μg/kg) in an anesthetized pig and its comparison with SO₂ measured by arterial blood gas (ABG) analysis and SpO₂ measured by a pulse oximeter (ear clip-on). (B) Decline of respiration rate, (C) elevation of end-tidal carbon dioxide (EtCO₂), (D) bradycardia, and (D) reduction in blood pressure after fentanyl injection (at time = 0) represent clinical signs of overdose. (F) StO₂ recorded from Naloximeters during fentanyl overdose quantify the rate of desaturation: (left) 10 μg/kg, −10.3 ± 6.8 %/min, n = 9 devices; and (right) 100 μg/kg, −6.1 ± 2.2 %/min, n = 4 devices. (G) Desaturation rates following fentanyl administration, estimated with data from Naloximeters and ABG analysis at different dosages. N = 29 subjects and n = 52 devices; 100 μg/kg [N, n] = [4, 4], 30 μg/kg [N, n] = [6, 10], 10 μg/kg [N, n] = [9, 9], 5 μg/kg [N, n] = [4, 12], and 2.5 μg/kg [N, n] = [6, 17]. (H) Schematic illustration of the analytical approach for overdose detection based on data from the Naloximeter dual-wavelength optical sensor. Various metrics associated to optical absorption and its rate of change (M1), desaturation rate (M2), tissue oxygenation levels (M3), and signal power density (M4) serve as the basis for a multivariable algorithm that discriminates physiological signs of opioid overdose from confounding events associated with physical activity, postural changes, and sleep apnea events. (I) Operation of the algorithm on data from a Naloximeter implanted in an ambulatory pig, including (J) StO₂ during opioid overdose (30 μg/kg), and the rates of change of (K) the red optical signal (∂λ₁), (L) the difference between the red and infrared optical signals (∂Δλ) of the dual-wavelength optical sensor, and (M) the tissue oxygenation (∂StO₂). Fentanyl was administered at time = 0. (O) Application of the overdose detection algorithm in a healthy, normally ambulating pig for 24 hours. Although several instances of synchronous positive metrics, i.e. EVENTs (EVENT = M1 & M2 & M3 & M4) were registered, none of them led to a WARNING. Colored bars in J and O indicate time stamps where individual metrics (M1, M2, M3, and M4) or compound logical metrics (EVENT) are true.

Fig. 4.. Demonstration of autonomous rescue from life-threatening opioid overdose in rodents and freely moving porcine models.

(A) Subcutaneous implant location for a miniaturized, battery-free wireless NFC Naloximeter designed for use in rodents and corresponding fentanyl overdose experiment grouping by naloxone (NLX) treatments, inset: optical image of the device, scale bar is 1 cm. (B) Oxygenation in a rodent model following fentanyl overdose and manual subcutaneous administration of NLX (manual rescue), autonomous rescue enabled by administration of NLX with a Naloximeter, or self-recovery without administration of NLX. Error bars depict SD at each point. Sample sizes are in the legend. (C) Comparison of recovery time between self-recovery and NLX treatments, P<0.0001 for manual and closed-loop rescue. Data points correspond to individual animals. The bars depict the mean and the error bars are SD. (D) Experimental setup for demonstrations of overdose (OD) rescue in an anesthetized pig model (E) with and (F) without a Naloximeter, the latter of which required manually administered NLX to rescue. Oxygenation (top), respiratory vitals (center), and pharmacokinetic data (bottom) for each fentanyl overdose. (G) Experimental setup for demonstrations of OD rescue in ambulatory pigs (H) with and (I) without a Naloximeter. (J) Demonstration of subcutaneous drug delivery from (K) a Naloximeter without venous access in a freely moving pig, insufficient to recover from OD, requiring manual administration of NLX to rescue. Panels (H, I, and K) show oxygenation (top) and pharmacokinetic (bottom) data for each experiment. The oxygenation in E, F, H, I and K was measured with blood gases (SO₂), a commercial pulse oximeter (SpO₂), and the Naloximeter (StO₂). (L) Longitudinal pharmacokinetic studies with an intravenous Naloximeter at 1 to 13 days post-implantation, and comparison to delivery of NLX with a continuous infusion pump as a control (CTRL I.V.). Dose is 1.5 mL. (M) Gadolinium pharmacokinetics when delivered via a Naloximeter (Device) at 14 days post-implantation in the jugular or mammary vein, or continuous infusion pump (CTRL) in the auricular vein. Dose is 2 mL. (N) Gadolinium pharmacokinetic profile when delivered by a Naloximeter intravenously (jugular vein) or subcutaneously. Dose is 3 mL.