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

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.

The Neurostimulation Appropriateness Consensus Committee (NACC): Recommendations on Best Practices for Cervical Neurostimulation.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on the use of neurostimulation in the cervical region to improve outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for an often-overlooked area of neurostimulation practice. MATERIALS AND METHODS: Authors were chosen based upon their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to the present. Identified studies were graded using the US Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant. RESULTS: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The NACC recommends best practices regarding the use of cervical neuromodulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be utilized as a guide to assist decision making when clinically appropriate.

Development and Characterization of Novel Conductive Sensing Fibers for In Vivo Nerve Stimulation.

Advancements in electrode technologies to both stimulate and record the central nervous system's electrical activities are enabling significant improvements in both the understanding and treatment of different neurological diseases. However, the current neural recording and stimulating electrodes are metallic, requiring invasive and damaging methods to interface with neural tissue. These electrodes may also degrade, resulting in additional invasive procedures. Furthermore, metal electrodes may cause nerve damage due to their inherent rigidity. This paper demonstrates that novel electrically conductive organic fibers (ECFs) can be used for direct nerve stimulation. The ECFs were prepared using a standard polyester material as the structural base, with a carbon nanotube ink applied to the surface as the electrical conductor. We report on three experiments: the first one to characterize the conductive properties of the ECFs; the second one to investigate the fiber cytotoxic properties in vitro; and the third one to demonstrate the utility of the ECF for direct nerve stimulation in an in vivo rodent model.

Spinal Cord Stimulation for Loin Pain Hematuria Syndrome: Clinical Report.

Loin pain hematuria syndrome (LPHS) is a rare condition characterized by cryptogenic debilitating flank pain and microscopic or macroscopic hematuria. The pathophysiology of LPHS remains poorly understood, and diagnosis is made largely by exclusion of alternate pathology. Management strategies can vary widely and include chronic opioid medication and a variety of invasive procedures, including regional nerve blocks, transcutaneous electrical nerve stimulation, local capsaicin infusion, and surgical renal denervation. Neuromodulation may provide a new paradigm of treatment for LPHS, potentially sparing patients from long-term complications of opiate therapy and invasive surgery. This report demonstrates the first case of successful symptomatic management of LPHS using spinal cord stimulation.

Spinal Cord Stimulator Explantation: Motives for Removal of Surgically Placed Paddle Systems.

BACKGROUND: Despite requiring successful trials prior to implantation, spinal cord stimulation (SCS) systems for pain are often later removed. Removing surgically implanted hardware subjects patients to the risks and discomfort of a second surgery, threatens the cost-effectiveness of SCS, and limits the perceived durability of SCS technology for pain problems. OBJECTIVE: To investigate patterns of reasons given among patients who underwent SCS explant surgery (SCSES). METHODS: Retrospective review of SCSES cases over 17 years at Allegheny General Hospital, Pittsburgh, PA. RESULTS: 165 patients underwent SCSES between 1997 and 2014. The top 3 reasons for explantation were inadequate pain control (IPC; 73%), hardware discomfort (22%), and need for magnetic resonance imaging (MRI) (10%). Other less frequent reasons were infection (9%), painful dysesthesias (9%), electrical arcing (4%), resolution of inciting symptoms (4%), weakness (2%), pseudomeningocele (1%) and muscle spasms (1%). CONCLUSION: Inadequate pain control is the most common reason for SCSES. Advances in technology are needed to improve the quality and duration of pain control, as well as to design improvements to make the hardware more comfortable. A significant number of implants are removed due to need for MRI, a fact obviating the need for MRI-compatible systems. Patients considering SCS paddle lead placement should be counseled on the most common reasons for later explantation.

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)-block-(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.

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.

Deep brain stimulation for obesity: past, present, and future targets.

The authors review the history of deep brain stimulation (DBS) in patients for treating obesity, describe current DBS targets in the brain, and discuss potential DBS targets and nontraditional stimulation parameters that may improve the effectiveness of DBS for ameliorating obesity. Deep brain stimulation for treating obesity has been performed both in animals and in humans with intriguing preliminary results. The brain is an attractive target for addressing obesity because modulating brain activity may permit influencing both sides of the energy equation--caloric intake and energy expenditure.

Successful relief of central poststroke pain with BurstDR spinal cord stimulation: A case series.

Background: Central poststroke pain (CPSP) is a commonly undertreated condition that can negatively impact a patient's quality of life. The efficacy of spinal cord stimulation (SCS) for the treatment of CPSP is not established due to limited studies. Case Description: Here, two patients, ages 42 and 75, sustained strokes resulting in CPSP. After failed medical management, both underwent placement of paddle-lead SCS systems utilizing BurstDR stimulation that successfully resulted in pain resolution. Conclusion: Two patients with CPSP were successfully treated with paddle lead SCS with BurstDR programming.

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.

Deep brain stimulation for psychiatric diseases: a pooled analysis of published studies employing disease-specific standardized outcome scales.

BACKGROUND: Deep brain stimulation (DBS) has emerged in recent years as a novel therapy in the treatment of refractory psychiatric disease, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). Standardized outcome scales were crucial in establishing that DBS was an effective therapy for movement disorders. OBJECTIVE: In order to better characterize the evidence supporting DBS for various psychiatric diseases, we performed a pooled analysis of those studies which incorporated specific standardized rating scales. METHODS: A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. The search yielded a total of 49 articles, of which 24 were included: 4 related to MDD (n = 48), 10 to OCD (n = 64), and 10 to TS (n = 46). RESULTS: A meta-analysis of DBS for MDD, OCD, and TS in studies employing disease-specific standardized outcome scales showed that the outcome scales all improved in a statistically significant fashion for these psychiatric diseases. Our pooled analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS, followed by OCD and MDD. CONCLUSION: DBS for psychiatric diseases remains investigational; however, even when studies failing to incorporate standardized outcome scales are excluded, there is statistically significant evidence that DBS can improve symptoms in MDD, OCD, and TS. Standardized disease-specific outcome scales facilitate pooled analysis and should be a required metric in future studies of DBS for psychiatric disease.

Inactivation of spinal cord stimulator implanted pulse generators after elective surgery: an under-recognized problem.

STUDY DESIGN: We retrospectively analyzed a database of implanted pulse generators (IPGs) for spinal cord stimulation (SCS) implanted by a single surgeon (NDT). We additionally report a series of five illustrative patient cases. OBJECTIVES: The electronics of SCS IPGs are susceptible to damage when implanted patients undergo surgery. Some SCSs have a dedicated surgery mode, while others recommend turning the SCS off to protect it from damage. IPG inactivation may require resetting or replacement surgery. We aimed to explore the prevalence of this real-world problem which has not been studied. SETTING: Pittsburgh, Pennsylvania. METHODS: Using a single surgeon SCS database, we identified cases of IPG inactivation after a non-SCS surgery and analyzed the management. We then reviewed the charts of five illustrative cases. RESULTS: Among 490 SCS IPG implantations between 2016-2022, 15 (3%) of the 490 patients' IPGs became inactivated after another non-SCS surgery. 12 (80%) required surgical IPG replacement, while 3 (20%) were able to have their IPG function restored non-operatively. In cases analyzed thus far, surgery mode was often not activated prior to surgery. CONCLUSION: SCS IPG inactivation by surgery is not a rare problem and is presumably engendered by monopolar electrocautery. Premature IPG replacement surgery carries risks and reduces the cost-effectiveness of SCS. Awareness of this problem may prompt more preventative measures to be taken by surgeons, patients, and caretakers, and encourage technological advances to render IPGs less vulnerable to surgical tools. Further research is needed to determine what quality improvement measures could prevent electrical damage to IPGs.

Paddle Lead Spinal Cord Stimulation in the Morbidly Obese Patient Population: Outcomes and Complications in a Single-Surgeon Cohort.

BACKGROUND: Paddle lead spinal cord stimulation (SCS) is used to treat refractory chronic pain. Morbidly obese patients seek SCS to reduce chronic pain. However, these patients face worse surgical outcomes, and the SCS literature has not evaluated safety and efficacy in this patient population. This study is the largest single-surgeon case series to date on morbidly obese patients with paddle lead SCS implantations. The primary objective is to report postoperative complication rates in morbidly obese patients receiving SCS implants. The secondary objective is to report patient-reported pain scores and Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and physical function scores in these patients. METHODS: A retrospective chart review was conducted. The patient charts were reviewed from the day of procedure consent to 6 months postop. Demographic information, pain scores, PROMIS scores, neurological complications, infections, and wound complications were documented. RESULTS: Sixty-seven patients were included. The mean preoperative BMI was 44.47 ± 4.02 kg/m2. The mean age was 58.9 ± 11.4 years old. There were no neurological complications. 3/67 (4%) developed culture-positive infections. Nine out of sixty-seven (13%) patients developed superficial wound dehiscence without underlying infection. The mean postop PROMIS physical function score was 31.6 ± 6.2 (n = 16) and the mean post-op PROMIS pain interference score was 64.0 ± 6.4 (n = 16). There was a reduction in pain scores, from 7.9 ± 1.7 preop to 5.7 ± 2.5 postop (n = 22, P = 0.004). CONCLUSIONS: Paddle lead SCS implantation is safe for morbidly obese patients. The only minimal-risk complications present were postoperative infections and wound dehiscence. Surgical care can be modified to further reduce the rates of infection and dehiscence.

Spinal cord stimulation: A novel approach to pain management in Dercum's disease.

Background: Dercum's Disease (DD) is a rare chronic pain syndrome in which patients experience extreme burning pain associated with subcutaneous lipomatous tissue deposits. These patients may also present with; weakness, psychiatric symptoms, metabolic derangements, sleep disturbance, impaired memory, and easy bruising. Common risk factors for DD include: obesity, Caucasian race, and female sex. The etiology of DD remains under debate while it has proven highly resistant to treatment (i.e., requiring high doses of opioids for adequate pain management). Case Description: A 48-year-old female with DD and a prior spinal cord stimulator (SCS) placed for chronic back pain, presented with recurrent back pain, and increased falling. Surgery to replace her SCS resulted in improvement in her back pain and a decreased incidence of falls. Furthermore, she noticed significant improvement in the burning pain attributed to her subcutaneous nodules; this most markedly occurred at and below the level of stimulator placement. Conclusion: A 48-year-old female with the extremely rare condition, DD experienced dramatic reduction in her pain following the successful revision of her SCS.

Deep brain stimulation for obesity--from theoretical foundations to designing the first human pilot study.

Obesity is perhaps an evolutionary consequence of a species reared with intermittent caloric reward. Humans are hardwired to enjoy food, and our bodies voraciously extract and store energy from food as if each meal was the last. As an amalgam of behavioral and metabolic disturbance, obesity is an attractive target for deep brain stimulation (DBS) since neuromodulation may be able to influence both eating behavior and metabolism. The current pandemic proportions of obesity combined with the failures and morbidity of modern treatments remain the impetus behind the application of DBS to this complex disease. We review the rationale and scientific foundations for obesity DBS and explain how this preclinical evidence has helped sculpt the design of the first human pilot study.

Design, synthesis, and biological evaluation of C6-difluoromethylenated epoxymorphinan Mu opioid receptor antagonists.

The recent widespread abuse of high potency synthetic opioids, such as fentanyl, presents a serious threat to individuals affected by substance use disorder. Synthetic opioids generally exhibit prolonged in vivo circulatory half-lives that can outlast the reversal effects of conventional naloxone-based overdose antidotes leading to a life-threatening relapse of opioid toxicity known as renarcotization. In this manuscript, we present our efforts to combat the threat of renarcotization by attempting to extend the half-life of traditional MOR antagonists through the design of novel, fluorinated 4,5-epoxymorphinans possessing increased lipophilicity. Analogues were prepared via a concise synthetic strategy highlighted by decarboxylative Wittig olefination of the C6 ketone to install a bioisosteric 1,1-difluoromethylene unit. C6-difluoromethylenated compounds successfully maintained in vitro potency against an EC90 challenge of fentanyl and were predicted to have enhanced circulatory half-life compared to the current standard of care, naloxone. Subsequent in vivo studies demonstrated the effective blockade of fentanyl-induced anti-nociception in mice.

Best Practices for Minimally Invasive Lumbar Spinal Stenosis Treatment 2.0 (MIST): Consensus Guidance from the American Society of Pain and Neuroscience (ASPN).

Introduction: Lumbar spinal stenosis (LSS) is a common spinal disease of aging with a growing patient population, paralleling population growth. Minimally invasive treatments are evolving, and the use of these techniques needs guidance to provide the optimal patient safety and efficacy outcomes. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for guidance on the prudent use of the innovative minimally invasive surgical therapies for the treatment of symptomatic LSS. The executive board nominated experts spanning anesthesiology, physiatry, orthopedic surgery, and neurosurgery based on expertise, publications, research, diversity and field of practice. Evidence was reviewed, graded using the United States Preventive Services Task Force (USPSTF) criteria for evidence and recommendation strength and grade, and expert opinion was added to make consensus points for best practice. Results: 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 LSS-related pain. Search words were selected based upon the section represented. Identified peer-reviewed literature was critiqued using USPSTF criteria and consensus points are presented. Discussion: The algorithm for patient selection in the management of symptomatic spinal stenosis is evolving. Careful consideration of patient selection and anatomic architecture variance is critical for improved outcomes and patient safety. Conclusion: ASPN created a guidance for best practice for minimally invasive surgical treatment of symptomatic spinal stenosis.

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.

Cervicomedullary junction spinal cord stimulation for head and facial pain.

OBJECTIVE: To review our experience with cervicomedullary junction spinal cord stimulation (SCS), to alleviate head and facial pain. BACKGROUND: There is a dearth of literature regarding the use of spinal cord stimulation for treating head and facial pain. DESIGN: We performed a Boolean search of the electronic medical record (1990-2009) and identified 35 patients (9 men, 26 women) for whom the senior author (J.J.M) trialed paddle lead cervicomedullary junction stimulation (CMJ-S) for intractable head or facial pain. Twenty-five patients (71.4%) had a successful trial with subsequent implantation of SCS hardware and 10 patients (28.6%) experienced a failed trial. Pain syndromes were categorized into diagnostic groups: trigeminal deafferentation pain (TDP), trigeminal neuropathic pain (TNP), occipital pain/neuralgia, post-herpetic neuralgia (PHN), and post-stroke facial pain. Follow-up via structured telephone interview was obtained in 25 patients (71.4%). RESULTS: Among the 25 patients available for follow-up, 16 patients (64%) underwent implantation and 9 patients (36%) had a failed trial of CMJ-S. The mean patient age and length of follow-up was 47.3 years old (20-78 years old) and 53.4 months (2-120 months), respectively. On a 0-10 pain intensity scale (0 being no pain and 10 being the worst degree of pain), a mean pretrial pain level of 9.6 (range 7-10) had been reduced to a mean of 4.8 (0-10) at follow-up. Successful trial and subsequent implantation occurred in 7 patients with TDP (70%), 4 patients with TNP (80%), both patients with PHN (100%), and in the single patient with post-stroke facial pain (100%) but in only 2 patients (28.6%) with occipital neuralgia/pain. At the time of telephone interview, 4 of the implanted patents (25%) had their hardware removed because of loss of effectiveness (3) and infection (1). The other 12 implanted patients (75%) continue to use CMJ-S on a daily basis and insist that it has improved their quality of life. Six current users (50%) of CMJ-S have been able to decrease their use of oral pain medications. Complications in the implanted group included infection (1), uncomfortable paresthesias from breakdown of connecting wire insulation (1), and gradual loss of effectiveness (3). CONCLUSIONS: Our preliminary experience suggests that patients suffering from TDP, TNP, and PHN may respond favorably to CMJ-S whereas patients with occipital neuralgia/pain are rarely palliated by this neuromodulatory approach.

Covalently Loaded Naloxone Nanoparticles as a Long-Acting Medical Countermeasure to Opioid Poisoning.

The mu opioid receptor antagonist naloxone has been a vital, long-standing countermeasure in the ongoing battle against opioid use disorders (OUD) and toxicity. However, due to its distinctive short elimination half-life, naloxone has shown diminished efficacy in cases of synthetic opioid poisoning as larger or repeated doses of the antidote have been required to achieve adequate reversal of severe respiratory depression and prevent episodes of renarcotization. This report describes the synthesis, characterization, and in vivo evaluation of a novel, nanoparticle-based naloxone formulation that provides extended protection against the toxic effects of the powerful synthetic opioid fentanyl. The strategy was predicated on a modified two-step protocol involving the synthesis and subsequent nanoprecipitation of a poly(lactic-co-glycolic acid) polymer scaffold bearing a covalently linked naloxone chain end (drug loading ∼7% w/w). Pharmacokinetic evaluation of the resulting covalently loaded naloxone nanoparticles (cNLX-NP) revealed an elimination half-life that was 34 times longer than high dose free naloxone (10 mg/kg) in male Sprague-Dawley rats. This enhancement was further demonstrated by cNLX-NP in subsequent in vivo studies affording protection against fentanyl-induced respiratory depression and antinociception for up to 48 h following a single intramuscular injection. These discoveries support further investigation of cNLX-NP as a potential therapeutic to reverse overdose and prevent renarcotization from fentanyl and its potent analogs.