We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immunostaining, in situ hybridization, and patch-clamp recordings in acute brain slices to study the release mechanism and μ-opioid modulation of the dual glutamatergic/GABAergic inputs from the ventral tegmental area and supramammillary nucleus to the granule cells of the dorsal hippocampus of male and female mice. In keeping with previous reports showing that the two transmitters are released by separate active zones within the same terminals, we found that the short-term plasticity and pharmacological modulation of the glutamatergic and GABAergic currents are indistinguishable. We further found that glutamate and GABA release at these synapses are both virtually completely mediated by N- and P/Q-type calcium channels. We then investigated μ-opioid modulation of these synapses and found that activation of μ-opioid receptors (MORs) strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by MORs of these dual synapses is complex, as it likely includes also a disinhibition due to downmodulation of local GABAergic interneurons which make direct axo-axonic contacts with the dual glutamatergic/GABAergic terminals. We discuss how this opioid modulation may enhance LTP at the perforant path inputs, potentially contributing to reinforce memories of drug-associated contexts.

As Week 3 of the provincial election campaign begins, there are questions about how Nova Scotia's major political parties plan to combat the rising number of opioid overdose deaths. 

Sault Ste. Marie has the highest rate of opioid deaths in Ontario so far this year, according to new numbers from the province's coroner's office.

Two Penn State Great Valley graduate students are collaborating with faculty — who received a University Presidential Public Impact Research Award — to conduct a research project that will use artificial intelligence and machine learning to analyze demographic data to help predict and prevent opioid deaths. 

DOVER – Revenue from a new opioid impact fee created by the Delaware General Assembly in 2019 will be used to prevent overdose deaths and provide new services to those seeking treatment for their substance use disorder, the Delaware Department of Health and Social Services (DHSS) and Sen. Stephanie Hansen announced Wednesday. DHSS Secretary Molly […]

Attorney General Kathy Jennings announced Thursday a $573 million multistate settlement with one of the world’s largest consulting firms, McKinsey & Company, resolving investigations into the company’s role in helping opioid companies promote their drugs and profiting from the opioid epidemic. “These are the first damages Delaware’s recovered from the people responsible for the opioid […]

The State Senate unanimously passed legislation Wednesday that would formalize a responsible, independent, and collaborative process to allocate the significant funds the State has received, and will continue to receive, from opioid settlements. Senate Bill 166, sponsored by Sen. Stephanie Hansen and House Speaker Pete Schwartzkopf, and supported by Attorney General Kathy Jennings, would establish […]

Jennings held out from a prior deal that would have been $4 billion less Attorney General Jennings announced a historic $26 billion settlement with the nation’s three major pharmaceutical distributors and one of its largest opioid manufacturers, which will help bring desperately needed relief to those struggling with opioid addiction. The agreement resolves investigations and […]

Attorney General Kathy Jennings and fellow attorneys general have reached an agreement in principle with opioid maker Endo International plc and its lenders that would provide up to $450 million to participating states and local governments, ban promotion of Endo’s opioids, and require Endo to turn over documents related to its role in the opioid […]

Attorney General Kathy Jennings today announced that Delaware has reached a settlement with Walmart to resolve allegations that the company contributed to the opioid addiction crisis by failing to appropriately oversee the dispensing of opioids at its stores. The settlement will provide $3.1 billion nationally and will require significant improvements in how Walmart’s pharmacies handle […]

Together with prior deals, Delaware now expects to recover a quarter-billion dollars to combat opioid crisis Attorney General Kathy Jennings today announced that she has finalized settlement agreements with CVS and Walgreens, bringing the national amount from investigations and litigation against the pharmaceutical industry for its role in the opioid crisis to more than $50 billion. Delaware’s […]

Delaware to receive nearly $70 million to fight the opioid crisis Delaware Attorney General Kathy Jennings today announced the final approval of $17.3 billion in opioid agreements with drug makers Teva and Allergan and pharmacies CVS and Walgreens. Following successful state sign-on and subdivision sign-on periods, the defendants have committed to the deal and will start releasing funds […]

Attorney General Kathy Jennings announced today a $150 million multistate settlement in principle with opioid manufacturer Hikma Pharmaceuticals (Hikma) for its role in fueling the opioid crisis. Hikma produces a range of generic opioid products and sells hundreds of millions of opioid doses every year. The attorneys general allege that from 2006 to 2021, Hikma […]

Attorney General Kathy Jennings today announced a $350 million national settlement with Publicis Health to resolve investigations into the global marketing and communications firm’s role in the prescription opioid crisis. Delaware will receive over $1.5 million from the settlement to help address the opioid crisis.  In agreeing to the terms of the settlement, Publicis recognized the harm its conduct caused, and the agreement […]

DOVER, DE (March 15, 2022) – The Division of Public Health’s (DPH) Office of Health Crisis Response (OHCR), has initiated a Restaurant Accolade Program to train and educate restaurant industry staff on how to reverse an opioid overdose and support coworkers with substance use disorder (SUD). The program was developed to assist restaurants, hospitality groups, and […]

NEW CASTLE (Feb. 8, 2023) – Divisions from the Delaware Department of Health and Social Services (DHSS) and the Department of Services for Children, Youth & Their Families (DSCYF) are working together to prevent opioid abuse among young athletes by funding innovative prevention programs in the community. The Delaware Division of Substance Abuse and Mental […]

MILFORD (June 6, 2023) – Lieutenant Governor Bethany Hall-Long and leaders from the Department of Health and Social Services (DHSS), Department of Education (DOE), and Department of Services for Children, Youth and their Families (DSCYF) led a community response briefing on Friday to provide the latest information regarding the state’s efforts to address substance use […]

Delaware Attorney General Kathy Jennings today announced a multistate settlement in principle with opioid manufacturer Amneal Pharmaceuticals (Amneal) for its role in fueling the nationwide epidemic of opioid addictions and overdoses. Amneal produces several generic opioid products and was one of the largest manufacturers of opioids from 2006 to 2019, selling nearly nine billion pills. […]

For Immediate Release: August 13, 2024 Contact: Samuel Barry, Policy Advisor (302) 382-0651, Samuel.Barry@delaware.gov The tracker is a publicly accessible tool for Delawareans to learn about how Prescription Opioid Abatement and Remediation Grants have been distributed to date. Dover, DE – Delaware Auditor of Accounts Lydia E. York published an official Prescription Opioid Settlement Tracker […]

WILMINGTON, Del. – As the first year of grantmaking comes to a close, Co-Chairs Attorney General Kathy Jennings and Lt. Governor Bethany Hall-Long shared the results of the third-party report from independent contractor Social Contract with recommendations to maximize the impact of the governing body overseeing Delaware’s opioid settlement funds.     The report, Enhancing Use […]

Delaware Attorney General Kathy Jennings, alongside a bipartisan coalition of thirty state attorneys general, announced today the completion of the $1.37 billion settlement agreement with Kroger, addressing the grocery chain’s role in the opioid crisis. Delaware will receive over $2.7 million for opioid abatement, all of which will be overseen by the Prescription Opioids Settlement Distribution Commission. Payments are […]

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Background

People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear.

BACKGROUND:Opioids are known to cause respiratory depression, aspiration, and to suppress the immune system. This study aimed to investigate the relationship between short- and long-term opioid use and the occurrence and clinical outcomes of pneumonia in South Korea.METHODS:The data for this population-based retrospective cohort analysis were obtained from the South Korean National Health Insurance Service. The opioid user group consisted of those prescribed opioids in 2016, while the non-user group, who did not receive opioid prescriptions that year, was selected using a 1:1 stratified random sampling method. The opioid users were categorized into short-term (1–89 d) and long-term (≥90 d) users. The primary end point was pneumonia incidence from January 1, 2017–December 31, 2021, with secondary end points including pneumonia-related hospitalizations and mortality rates during the study period.RESULTS:In total, 4,556,606 adults were enrolled (opioid group, 2,070,039). Opioid users had a 3% higher risk of pneumonia and an 11% higher risk of pneumonia requiring hospitalization compared to non-users. Short-term users had a 3% higher risk of pneumonia, and long-term users had a 4% higher risk compared to non-users (P < .001). Additionally, short-term users had an 8% higher risk of hospital-treated pneumonia, and long-term users had a 17% higher risk compared to non-users (P < .001).CONCLUSIONS:Both short- and long-term opioid prescriptions were associated with higher incidences of pneumonia and hospital-treated pneumonia. In addition, long-term opioid prescriptions were linked to higher mortality rates due to pneumonia.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, , and ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ~100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system.

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors.

Cannabinoid and opioid receptor activities can be modulated by a variety of post-translational mechanisms including the formation of interacting complexes. This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB₁ receptor (CB₁R), opioid receptor (DOR), and CB₁R-DOR interacting complexes. Focusing on endogenous protein chaperones, namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared with other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB₁R, DOR, and CB₁R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long-term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones. Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord. Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB₁R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO₂ were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

Background

In an evolving landscape of practices and policies, reviewing and incorporating the latest scientific evidence is necessary to ensure optimal clinical management for people with opioid use disorder. We provide a synopsis of the 2024 update of the 2018 National Guideline for the Clinical Management of Opioid Use Disorder, from the Canadian Research Initiative in Substance Matters.

Tech startups are stepping up to meet the needs of 60 million people worldwide who use opioids, representing about 1 percent of the world’s adult population. In the United States, deaths involving synthetic opioids have risen 1,040 percent from 2013 to 2019. The COVID-19 pandemic and continued prevalence of fentanyl have since worsened the toll, with an estimated 81,083 fatal overdoses in 2023 alone.

Innovations include biometric monitoring systems that help doctors determine proper medication dosages, nerve stimulators that relieve withdrawal symptoms, wearable and ingestible systems that watch for signs of an overdose, and autonomous drug delivery systems that could prevent overdose deaths.

Helping Patients Get the Dosage They Need

For decades, opioid blockers and other medications that suppress cravings have been the primary treatment tool for opioid addiction. However, despite its clinical dominance, this approach remains underutilized. In the United States, only about 22 percent of the 2.5 million adults with opioid use disorder receive medication-assisted therapy such as methadone, Suboxone, and similar drugs.

Determining patients’ ideal dosage during the early stages of treatment is crucial for keeping them in recovery programs. The shift from heroin to potent synthetic opioids, like fentanyl, has complicated this process, as the typical recommended medication doses can be too low for those with a high fentanyl tolerance.

A North Carolina-based startup is developing a predictive algorithm to help clinicians tailor these protocols and track real-time progress with biometric data. OpiAID, which is currently working with 1,000 patients across three clinical sites, recently launched a research pilot with virtual treatment provider Bicycle Health. Patients taking Suboxone will wear a Samsung Galaxy Watch6 to measure their heart rate, body movements, and skin temperature. OpiAID CEO David Reeser says clinicians can derive unique stress indications from this data, particularly during withdrawal. (He declined to share specifics on how the algorithm works.)

“Identifying stress biometrically plays a role in how resilient someone will be,” Reeser adds. “For instance, poor heart rate variability during sleep could indicate that a patient may be more susceptible that day. In the presence of measurable amounts of withdrawal, the potential for relapse on illicit medications may be more likely.”

Nerve Stimulators Provide Opioid Withdrawal Relief

While OpiAID’s software solution relies on monitoring patients, electrical nerve stimulation devices take direct action. These behind-the-ear wearables distribute electrodes at nerve endings around the ear and send electrical pulses to block pain signals and relieve withdrawal symptoms like anxiety and nausea.

The U.S. Food and Drug Administration (FDA) has cleared several nerve stimulator devices, such as DyAnsys’ Drug Relief, which periodically administers low-level electrical pulses to the ear’s cranial nerves. Others include Spark Biomedical’s Sparrow system and NET Recovery’s NETNeuro device.

Masimo’s behind-the-ear Bridge device costs US $595 for treatment providers.Masimo

Similarly, Masimo’s Bridge relieves withdrawal symptoms by stimulating the brain and spinal cord via electrodes. The device is intended to help patients initiating, transitioning into, or tapering off medication-assisted treatment. In a clinical trial, Bridge reduced symptom severity by 85 percent in the first hour and 97 percent by the fifth day. A Masimo spokesperson said the company’s typical customers are treatment providers and correctional facilities, though it’s also seeing interest from emergency room physicians.

Devices Monitor Blood Oxygen to Prevent Overdose Deaths

In 2023, the FDA cleared Masimo’s Opioid Halo device to monitor blood oxygen levels and alert emergency contacts if it detects opioid-induced respiratory depression, the leading cause of overdose deaths. The product includes a pulse oximeter cable and disposable sensors connected to a mobile app.

Opioid Halo utilizes Masimo’s signal extraction technology, first developed in the 1990s, which improves upon conventional oxygen monitoring techniques by filtering out artifacts caused by blood movement. Masimo employs four signal-processing engines to distinguish the true signal from noise that can lead to false alarms; for example, they distinguish between arterial blood and low-oxygen venous blood.

Masimo’s Opioid Halo system is available over-the-counter without a prescription. Masimo

Opioid Halo is available over-the-counter for US $250. A spokesperson says sales have continued to show promise as more healthcare providers recommend it to high-risk patients.

An Ingestible Sensor to Watch Over Patients

Last year, in a first-in-human clinical study, doctors used an ingestible sensor to monitor vital signs from patients’ stomachs. Researchers analyzed the breathing patterns and heart rates of 10 sleep study patients at West Virginia University. Some participants had episodes of central sleep apnea, which can be a proxy for opioid-induced respiratory depression. The capsule transmitted this data wirelessly to external equipment linked to the cloud.

Celero’s Rescue-Rx capsule would reside in a user’s stomach for one week.Benjamin Pless/Celero Systems

“To our knowledge, this is the first time anyone has demonstrated the ability to accurately monitor human cardiac and respiratory signals from an ingestible device,” says Benjamin Pless, one of the study’s co-authors. “This was done using very low-power circuitry including a radio, microprocessor, and accelerometer along with software for distinguishing various physiological signals.”

Pless and colleagues from MIT and Harvard Medical School started Celero Systems to commercialize a modified version of that capsule, one that will also release an opioid antagonist after detecting respiratory depression. Pless, Celero’s CEO, says the team has successfully demonstrated the delivery of nalmefene, an opioid antagonist similar to Narcan, to rapidly reverse overdoses.

Celero’s next step is integrating the vitals-monitoring feature for human trials. The company’s final device, Rescue-Rx, is intended to stay in the stomach for one week before passing naturally. Pless says Rescue-Rx’s ingestible format will make the therapy cheaper and more accessible than wearable autoinjectors or implants.

Celero’s capsule can detect vital signs from within the stomach. www.youtube.com

Autonomous Delivery of Overdose Medication

Rescue-Rx isn’t the only autonomous drug-delivery project under development. A recent IEEE Transactions on Biomedical Circuits and Systems paper introduced a wrist-worn near-infrared spectroscopy sensor to detect low blood oxygen levels related to an overdose.

Purdue University biomedical engineering professor Hugh Lee and graduate student Juan Mesa, who both co-authored the study, say that while additional human experiments are necessary, the findings represent a valuable tool in counteracting the epidemic. “Our wearable device consistently detected low-oxygenation events, triggered alarms, and activated the circuitry designed to release the antidote through the implantable capsule,” they wrote in an email.

Lee and Purdue colleagues founded Rescue Biomedical to commercialize the A2D2 system, which includes a wristband and an implanted naloxone capsule that releases the drug if oxygen levels drop below 90 percent. Next, the team will evaluate the closed-loop system in mice.

This story was updated on 27 August 2024 to correct the name of Masimo’s Opioid Halo device.

In 2018, opioid overdoses in the United States caused one death every 11 minutes, resulting in nearly 47,000 fatalities. The most effective treatments for opioid use disorder (OUD) are three medications approved by the Food and Drug Administration (FDA): methadone, buprenorphine, and naltrexone.

Few correctional facilities in the United States have treatment programs for individuals with opioid use disorder (OUD), despite clear evidence that certain medications reduce the risk of overdose and death. Even in facilities where treatment is available, the COVID-19 pandemic has complicated efforts to provide such care.

Between 1999 and 2014, opioid use disorder (OUD) among pregnant women more than quadrupled, risking the health of the women—before and after giving birth—and their infants. As states grapple with COVID-19’s exacerbation of the opioid crisis, several are taking innovative steps to address the needs of high-risk groups, including low-income, postpartum patients with OUD.