Countermeasures for Preventing and Treating Opioid Overdose

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic “nanosponge” decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.</p

Deep Brain Stimulation for Obesity: From a Theoretical Framework to Practical Application

Obesity remains a pervasive global health problem. While there are a number of nonsurgical and surgical options for treatment, the incidence of obesity continues to increase at an alarming rate. The inability to curtail the growing rise of the obesity epidemic may be related to a combination of increased food availability and palatability. Research into feeding behavior has yielded a number of insights into the homeostatic and reward mechanisms that govern feeding. However, there remains a gap between laboratory investigations of feeding physiology in animals and translation into meaningful treatment options for humans. In addition, laboratory investigation may not be able to recapitulate all aspects of human food consumption. In a landmark pilot study of deep brain stimulation (DBS) of the lateral hypothalamic area for obesity, we found that there was an increase in resting metabolic rate as well as a decreased urge to eat. In this review, the authors will review some of the work relating to feeding physiology and research surrounding two nodes involved in feeding homeostasis, nucleus accumbens (NAc) and hypothalamus, and use this to provide a framework for future investigations of DBS as a viable therapeutic modality for obesity

Movement disorder Deep brain stimulation Hybridization: Patient and caregiver outcomes

Background and Objectives: Deep brain stimulation (DBS) is a well-established surgical treatment for certain movement disorders and involves the implantation of brain electrodes connected to implantable pulse generators (IPGs). As more device manufacturers have entered the market, some IPG technology has been designed to be compatible with brain electrodes from other manufacturers, which has facilitated the hybridization of implant technology. The aim of this study was to assess the benefits of hybridization of non-rechargeable, constant voltage IPGs to rechargeable, constant current IPGs. Methods: A list of DBS movement disorder patients who had their non-rechargeable, constant voltage IPGs replaced with rechargeable, constant current IPGs from a different manufacturer was compiled. Structured surveys of these patients, and their caregivers when applicable, were undertaken to determine both patient and caregiver satisfaction in this DBS hybridization strategy. Results: Eighteen patients met inclusion criteria and twelve patients or their caregivers completed the structured survey (67% response rate). Nine patients had Parkinson’s disease (75%), three had essential tremor (25%). Nine (75%) were converted from bilateral single-channel IPGs, and three (25%) were converted from a unilateral dual-channel IPGs. Overall, 92% of patients and caregivers surveyed reported improvement or no change in their symptoms, 92% reported a decrease or no change in their medication requirements, and 92% report they are satisfied or very satisfied with their IPG hybridization and would recommend the surgery to similar patients. There were no immediate surgical complications. Conclusion: In this series of movement disorder DBS patients, surgery was safe and patient and caregiver satisfaction were high with a hybridization of non-rechargeable, constant voltage IPGs to rechargeable, constant current IPGs

Fentanyl Initiated Polymers Prepared by ATRP for Targeted Delivery

The targeted delivery of polymers to neurons is a challenging yet important goal for polymer based drug delivery. We prepared a fentanyl based atom transfer radical polymerization (ATRP) initiator to target the Mu opioid receptor (MOR) for neuronal targeting. We incorporated our recently discovered rigid acrylate linking group into the initiator to retain a high degree of binding to the MOR and grafted random or block copolymers of poly­(oligo­(ethylene oxide) methacrylate)-<i>block</i>-(glycidyl methacrylate). Trifluoroethanol promoted amine ring opening of the glycidyl methacrylate was used for post-polymerization modification of the fentanyl initiated polymers to attach a near-infrared fluorescent dye (ADS790WS) or to build a targeted siRNA delivery system via modification with secondary amines. We examined the biocompatibility, cellular internalization, and siRNA binding properties of our polymer library in a green fluorescent protein expressing SY SH5Y neuroblastoma cell-line

Countermeasures for Preventing and Treating Opioid Overdose

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)(1A) receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic “nanosponge” decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease. Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life. The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period. Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians

The American Society of Pain and Neuroscience (ASPN) Evidence-Based Clinical Guideline of Interventional Treatments for Low Back Pain

INTRODUCTION: Painful lumbar spinal disorders represent a leading cause of disability in the US and worldwide. Interventional treatments for lumbar disorders are an effective treatment for the pain and disability from low back pain. Although many established and emerging interventional procedures are currently available, there exists a need for a defined guideline for their appropriateness, effectiveness, and safety. OBJECTIVE: The ASPN Back Guideline was developed to provide clinicians the most comprehensive review of interventional treatments for lower back disorders. Clinicians should utilize the ASPN Back Guideline to evaluate the quality of the literature, safety, and efficacy of interventional treatments for lower back disorders. METHODS: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations. Experts from the fields of Anesthesiology, Physiatry, Neurology, Neurosurgery, Radiology, and Pain Psychology developed the ASPN Back Guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Scopus, and meeting abstracts to identify and compile the evidence (per section) for back-related pain. Search words were selected based upon the section represented. Identified peer-reviewed literature was critiqued using United States Preventive Services Task Force (USPSTF) criteria and consensus points are presented. RESULTS: After a comprehensive review and analysis of the available evidence, the ASPN Back Guideline group was able to rate the literature and provide therapy grades to each of the most commonly available interventional treatments for low back pain. CONCLUSION: The ASPN Back Guideline represents the first comprehensive analysis and grading of the existing and emerging interventional treatments available for low back pain. This will be a living document which will be periodically updated to the current standard of care based on the available evidence within peer-reviewed literature