Opioid Response Research Articles

Cooperative Extension professionals' knowledge and attitudes toward the opioid epidemic: Implications for capacity development and outreach.

IntroductionWorsening of the opioid epidemic amplifies calls for involvement of the nationwide Cooperative Extension System (Extension) in addressing this crisis. Understanding knowledge and attitudes among Extension professionals who directly interact with communities is critical given identified needs for increased capacity and substantial federal investments supporting Extension's opioid response. This study explored opioid knowledge and attitudes among Extension professionals in one state to identify attitudes and perceptions that may influence community-level efforts.MethodsAn online survey including 25 Likert scale questions about attitudes and beliefs related to substance use was administered to Extension professionals. Questions were categorized into five concept areas: treatment and community support, legal and punitive approaches, substance use as an illness, external causes of substance use, and personal causes of substance use. Descriptive statistics and response frequencies for all variables were calculated. One-way ANOVAs were used to calculate geographic differences between the state's three Extension regions.ResultsSurvey responses (n = 236) indicated respondents recognized the complexity of the opioid crisis and had favorable attitudes toward treatment and community support approaches. Support for legal and punitive approaches was mixed, as were attitudes toward external and personal causes of substance use. Most indicated needing better resources and more knowledge to engage in work locally.ConclusionIncreased capacity is needed in Extension to adequately support families and communities dealing with substance use disorder. Findings suggest areas of focus and provide insight for others seeking to develop capacity in opioid response by engaging Extension professionals or other community outreach workers in substance use prevention efforts.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter‐patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6‐guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype‐guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient‐reported pain‐related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype‐guided opioid selection for improving postoperative pain control and reducing opioid‐related risks.

Addressing stimulant use disorder through state opioid response grants from the substance abuse and mental health services administration: Missouri’s initial approach

ABSTRACT Background: The alarming growth of stimulant-involved deaths underscores the urgent need for states to expand existing opioid-specific approaches to intentionally reach and serve people who use stimulants. Recent permission from federal agencies has allowed states to spend grant funding that was previously restricted to opioid-related activities on approaches addressing stimulant use. Objectives: This manuscript describes the rationale, methods, and initial results supporting the implementation of Missouri’s recent stimulant-focused efforts – including previously-prohibited activities such as Contingency Management and fentanyl test strip distribution. Methods: Missouri’s State Opioid Response team facilitated the design and implementation of Contingency Management pilot programming abiding by federal spending limits of no more than $75 of incentives per client, mass distribution of fentanyl test strips, and publicly accessible harm reduction trainings and materials specific to stimulant use. Data sources used for initial evaluations included state-level treatment claims, fentanyl test strip distribution counts by type and region of organizations receiving them, and qualitative feedback from stakeholders. Results: Six substance use treatment agencies developed Contingency Management programs, serving 29 individuals in the first nine months. Over 20,000 fentanyl test strips were distributed using a prioritization system designed to reach those most likely to benefit from their use. Conclusions: Recent federally funded efforts to better address stimulant use in Missouri have increased access to evidence-based treatment and harm reduction resources. Lessons learned from early implementation, especially those regarding time allowed for program development and how best to ensure equitable resource distribution, will inform future stimulant-focused program efforts.

Paroxetine increases delta opioid responsiveness in sensory neurons.

There are currently no Food and Drug Administration (FDA)-approved δ-opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and nonhuman primates compared with traditional μ-opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in noninflammatory pain patients (Stein et al., 1989). It was recently identified that G-protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in noninflamed nociceptors (Brackley et al., 2016, 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor (SSRI) and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine’s effects on GRK2 in vivo are limited to peripheral tissues in the male rat. The effects of paroxetine on DOR competence are notably antagonized by GRK2 overexpression. This is the first study to suggest that paroxetine induces peripheral DOR analgesic competence through a GRK2-dependent mechanism, improving analgesic efficacy in noninflamed tissue. Because paroxetine targets the protein that governs peripheral opioid receptor responsiveness, and does so in the absence of inflammation, we propose that paroxetine may be suitable as a co-therapy with peripherally-restrictive doses of opioids to improve analgesic efficacy in noninflammatory pain conditions.

Evaluation of workplace opioid prevention and response training for union and employer instructors and leadership

Objective: Opioids and the Workplace Prevention and Response (OWPR) Train-the-Trainer (TTT) and Leadership programs were piloted to improve trainees’ abilities to conduct opioid awareness training and to introduce policies and programs in their workplaces.Methods: The TTT (N = 54) and Leadership (N = 19) pilot trainees were administered voluntary pre- and post-training surveys and observed for discussion on knowledge and confidence regarding teaching and on workplace policies and workplace injury prevention related to opioids.Results: Percentage agreement with correct responses for all TTT and 10 out of 14 (71.4 percent) Leadership knowledge and confidence questions increased significantly from pre- to post-test.Conclusion: We found some evidence that the OWPR TTT and Leadership training programs and materials were effective in improving trainee's abilities to conduct opioid awareness training and to introduce policies and programs to address opioids and the workplace.

State Opioid Response Grants (SAMHSA)

Federal Grants & ContractsVolume 46, Issue 14 p. 7-7 Grants alerts State Opioid Response Grants (SAMHSA) First published: 13 June 2022 https://doi.org/10.1002/fgc.32447Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume46, Issue1416 June 2022Pages 7-7 RelatedInformation

Rejection sensitivity and mu opioid receptor dynamics associated with mood alterations in response to social feedback

Rejection sensitivity (RS) is the heightened expectation or perception of social rejection and is a feature of many psychiatric disorders. As endogenous opioid pathways have been implicated in response to social rejection and reward, we hypothesize that RS will be negatively associated with mu opioid receptor (MOR) baseline binding and activity during rejection and acceptance stimuli. In exploratory analyses, we assessed the relationships between MOR activity and changes in mood and self-esteem before and after stimuli. Healthy participants, N = 75 (52% female), completed rejection and acceptance tasks during [11C]carfentanil positron emission tomography (PET) scans. MOR activity in the amygdala, midline thalamus, anterior insula, and nucleus accumbens (NAc) was evaluated. RS was not related to MOR baseline binding potential or activity during acceptance or rejection tasks in any region. Increased MOR activity in the NAc was associated with increase in ratings of self-esteem and positive mood during the period between acceptance task administration and approximately 5 min after the task completion. Our results suggest that endogenous opioid response to social rejection is independent of RS in healthy individuals. MOR activity in the NAc was associated with increase self-esteem and positive mood after experiencing social feedback, warranting further investigation.

Modeling the evolution of the US opioid crisis for national policy development.

The opioid crisis is a major public health challenge in the United States, killing about 70,000 people in 2020 alone. Long delays and feedbacks between policy actions and their effects on drug-use behavior create dynamic complexity, complicating policy decision-making. In 2017, the National Academies of Sciences, Engineering, and Medicine called for a quantitative systems model to help understand and address this complexity and guide policy decisions. Here, we present SOURCE (Simulation of Opioid Use, Response, Consequences, and Effects), a dynamic simulation model developed in response to that charge. SOURCE tracks the US population aged ≥12 y through the stages of prescription and illicit opioid (e.g., heroin, illicit fentanyl) misuse and use disorder, addiction treatment, remission, and overdose death. Using data spanning from 1999 to 2020, we highlight how risks of drug use initiation and overdose have evolved in response to essential endogenous feedback mechanisms, including: 1) social influence on drug use initiation and escalation among people who use opioids; 2) risk perception and response based on overdose mortality, influencing potential new initiates; and 3) capacity limits on treatment engagement; as well as other drivers, such as 4) supply-side changes in prescription opioid and heroin availability; and 5) the competing influences of illicit fentanyl and overdose death prevention efforts. Our estimates yield a more nuanced understanding of the historical trajectory of the crisis, providing a basis for projecting future scenarios and informing policy planning.

Capsaicin Reduces Ethanol Consumption in C57BL/6 but not DBA/2 Mice.

ObjectiveCapsaicin, the pungent analgesic substance of hot peppers which produces a burning sensation and pain is known to affect Substance P and central opioid activities. This experiment was designed to test the effect of capsaicin on alcohol consumption in C57BL/6 and DBA/2 mice. These two strains are known to differ in both their alcohol consumption and their endogenous opioid distribution and response to alcohol. It is hypothesized that this effect may be mediated by both increases Substance P and decreases beta-endorphin.MethodsAfter i.p. administration of 0.01 and 0.001 mg/kg of capsaicin with a vehicle or the vehicle alone as the control for eight days in C57BL/6 and DBA/2 mice on limited access alcohol model, Capsaicin’s effects on 2-hour alcohol, 22-hours water, 24-hours food intake and body weight were studied.ResultsIn this study, as expected, C57BL/6 mice drank significantly more alcohol than DBA/2 mice under baseline conditions. Capsaicin at both doses tested significantly reduced baseline alcohol consumption in C57BL/6 but not DBA/2 mice. These effects were selective for alcohol as capsaicin did not disrupt food or water consumption.ConclusionThese results demonstrate that capsaicin differentially affects those mechanisms underlying alcohol consumption in two strains of mice known to differ in their preference for and consumption of alcohol. This effect is hypothesized to be related to differences in the response of the endogenous opioid system.

SAMHSA announces almost $1.5 billion in new SOR grants

On May 19, the Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment (CSAT), announced that it is accepting applications for the fiscal year (FY) 2022 cohort of the State Opioid Response (SOR). Only single state agencies (NASADAD members) and territories can apply. From the funding opportunity announcement: “The purpose of this program is to address the opioid overdose crisis by providing resources to states and territories for increasing access to FDA‐approved medications for the treatment of opioid use disorder (MOUD), and for supporting the continuum of prevention, harm reduction, treatment, and recovery support services for opioid use disorder (OUD) and other concurrent substance use disorders. The SOR program also supports the continuum of care for stimulant misuse and use disorders, including for cocaine and methamphetamine. The SOR program aims to help reduce unmet treatment needs and opioid‐related overdose deaths across America.” There will be 59 awards for the grants, which are for up to 2 years. No cost sharing is required. Applications are due July 18. For more on the grant, go to https://www.samhsa.gov/grants/grant‐announcements/ti‐22‐005.

Opioid Literacy Among African Americans Living in Rural Alabama: Findings From a Social Determinants of Health (SDH) Framework

Limited research examining opioid literacy among African Americans (AAs) have been conducted. The current study examined the association between opioid literacy levels among AAs in rural Alabama using the social determinants of health framework. Three subscales in the Brief Opioid Overdose Knowledge questionnaire were used to measure opioid literacy. Among a sample of 253, limited opioid literacy was found. Social contact was found to be significantly associated with overall opioid literacy (B = .36, p < .05) and opioid general knowledge subscale (B = .14, p < .05). For the subscale of opioid overdose response knowledge, health insurance (B =−.59, p = .06) and social contact (B = .13, p = .07) emerged as marginally significant. The findings suggest that educational interventions are needed to increase opioid literacy among rural AAs, especially among those with limited social contact.

Design to Action: Community Capacity Building for Opioid Response

The International Journal of Integrated Care (IJIC) is an online, open-access, peer-reviewed scientific journal that publishes original articles in the field of integrated care on a continuous basis.IJIC has an Impact Factor of 5.120 (2020 JCR, received in June 2021)The IJIC 20th Anniversary Issue was published in 2021.

SAMHSA announces $55 million for most recent Tribal Opioid Response grant program

The Substance Abuse and Mental Health Services Administration (SAMHSA) has announced $55 million in funding for its Tribal Opioid Response (TOR) grant program. “Every five minutes, someone in the U.S. dies from a drug overdose,” said U.S. Department of Health and Human Services Secretary Xavier Becerra in announcing the funding opportunity May 4. “The TOR program ensures this country's Native American communities get connected to effective, culturally relevant treatment and recovery support services, which is critical to our work to advance health equity and address addiction and overdose.” And from Miriam E. Delphin‐Rittmon, leader of SAMHSA and assistant secretary for mental health and substance use for the U.S. Department of Health and Human Services (HHS): “The TOR grant program recognizes the full continuum of integrated care and services that are needed to help prevent substance use, expand quality treatment, and sustain recovery for people battling substance misuse.” The TOR grant program is increasing access to FDA‐approved medications for the treatment of opioid misuse, and supporting prevention, harm reduction, treatment and recovery support services for opioid and stimulant misuse and co‐occurring mental and substance use conditions. Funding will be provided each year for up to 150 grantees over a two‐year project period, beginning late FY 2022. According to the Centers for Disease Control and Prevention, the rate of drug overdose deaths among American Indians and Alaska Natives is above the national average. TOR supports the American Indian and Alaska Native Cultural Wisdom Declaration, which elevates the importance of tribal identities, culture, spiritual beliefs and practices for improving well‐being. Tribal entities are encouraged to include the following elements into grant applications as appropriate: ancestral cultural knowledge, wisdom, ceremony and practices of American Indian and Alaska Native tribes. To apply, see TOR Notice of Funding Opportunity.

Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function.

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [11C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential(BPND) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS bothat baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly.

Model-Based Analysis of the Influence of Alcohol Use and Age on Pharmacokinetics-Pharmacodynamics of Oral Oxycodone in Middle-Age and Older Community-Dwelling Adults.

Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours. Cold pressor test was administered at 1.5, 5, and 8 hours after oxycodone dosing. The study population consisted of 62 older adults (aged ≥60) and 66 middle-aged adults (aged 35-59), with 82% meeting the unhealthy drinking criteria. Oral oxycodone PK were well described using a 1-compartment model with a sequential 0 to first-order absorption process. Inhibitory maximum effect and linear direct effect PD models described the respective pupillometry and cold pressor test data using simultaneous PK-PD analysis in MONOLIX. Recent alcohol use measures were selected a priori as covariates. This analysis demonstrated an influence of age on clearance and body weight on the distribution volume of oxycodone; alcohol consumption was not noted to alter oxycodone PK. Oxycodone pupillometry PD were influenced by the level of subject-reported alcohol consumption (Alcohol Use Disorders Identification Test for Consumption), alcohol use biomarker-blood phosphatidylethanol, previous cannabis use, and age. Over the opioid exposure range of the study, none of the covariables including alcohol and age were noted to affect cold pressor test pharmacodynamics. Additional clinical studies are needed to further investigate the clinical consequences of opioid-alcohol-age interaction.

Who doesn’t fit? A multi-institutional study using machine learning to uncover the limits of opioid prescribing guidelines

BackgroundMany U.S. institutions have adopted postsurgical opioid-prescribing guidelines to standardize prescribing practices, and yet there is inherent variability in patients’ opioid consumption after surgery. The utility of these guidelines is limited by the fact that some patients’ needs will inevitably exceed them, and yet there are no evidence-based tools to help providers identify these patients. In this study we aimed to maximize the value of these guidelines by training machine learning models to predict patients whose needs will be met by these smaller recommended prescriptions, and patients who may require an additional degree of personalization. The aim of the present study was to develop predictive models for determining whether a surgical patient's postdischarge opioid requirement will fall above or below common opioid prescribing guidelines. MethodsWe conducted a retrospective cohort study of surgical patients at one institution from 2017 to 2018. Patients were called after discharge to collect opioid consumption data. Machine learning models were used to identify outlier opioid consumers (ie, exceeding our institutional prescribing guidelines) using diagnosis codes, medical history, in-hospital opioid use, and perioperative factors as predictors. External validation was performed on opioid consumption data collected at a second institution from 2020 to 2021, and sensitivity analysis was performed using a third institution’s prescribing guidelines. ResultsThe development and external validation cohorts included 1,867 and 498 patients, respectively. Age, body mass index, tobacco use, preoperative opioid exposure, and in-hospital opioid consumption were the strongest predictors of postdischarge consumption. A lasso regression model exhibited an area under the receiver operating characteristic curve of 0.74 (95% confidence interval 0.67–0.81) in predicting postdischarge opioid consumption. External validation of a limited lasso model yielded an area under the receiver operating characteristic curve of 0.67 (0.60–0.74). Performance was preserved when evaluated on another institution’s guidelines (area under the receiver operating characteristic curve 0.76 [0.72–0.80]). ConclusionPatient characteristics reliably predict postdischarge opioid consumption in relation to prescribing guidelines for both opioid-naive and exposed populations. This model may be used to help providers confidently follow prescribing guidelines for patients with typical opioid responsiveness and correctly pursue more personalized prescribing for others.

Neonatal Opioid Withdrawal Syndrome in Mice: Acute Molecular and Long‐Term Behavioral Consequences

Populations affected by the ongoing opioid epidemic include pregnant women and their offspring. Infants exposed to opioids in utero are at risk of developing Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of somatic withdrawal symptoms including high pitched crying, sleeplessness, irritability, and potentially seizures. Confounding environmental factors and difficulty in conducting longitudinal clinical studies have made it challenging to elucidate the long‐term consequences of NOWS. In order to investigate the molecular mechanisms and long‐term effects of NOWS, we have developed a mouse model of opioid exposure and withdrawal that encompasses the developmental equivalent of all three trimesters of the human pregnancy. Female mice are implanted with morphine minipumps (10 mg/kg/day) before mating, ensuring that pups are exposed to morphine in utero for the entirety of embryonic development. Mice are then given twice daily morphine injections (10 mg/kg/day, SC) for post‐natal days 1‐14. Mice are tested for developmental milestones during this period, including eye opening, extinguishing pivoting, surface righting, and forelimb grasp. Following the final morphine injection withdrawal behaviors were measured by ultrasonic vocalizations, 55°C hotplate analgesia latency, and somatic withdrawal signs. After reaching adulthood, mice were tested for changes in affective behavior (elevated zero maze, tail suspension test and learned helplessness), opioid response (conditioned place preference and intravenous self‐administration), social behavior (three‐chamber social behavior test), and sleep patterns. Mice exposed to this paradigm show delayed latency to reach developmental milestones and acute withdrawal phenotypes. In adulthood, social behavior and sleep patterns were affected in a sex‐dependent manner, while affective behavior and opioid response was unchanged. Bulk RNA sequencing of mice at post‐natal day 1 revealed changes in gene expression related to synapse development and function, the GABAergic system, and mitochondrial function. These transcriptome changes may underlie the behavioral long‐term effects of NOWS.

Effects of prenatal opioid exposure and early life adversity on opioid‐induced antinociception

Diagnoses of maternal opioid use disorder (MOUD) at delivery increased more than 500% between 1999 and 2017 in the United States. Today, cases of in utero opioid exposure due to MOUD exceed cases of the most common birth defects, including cleft lip, cleft palate, clubfoot, and Down syndrome, combined. Children exposed to opioids in utero are at increased risk of adverse childhood experiences (ACEs) due to parental care being compromised by SUDs. These ACEs include abuse, neglect, loss of a parent from death or incarceration, parental divorce, and household domestic violence. Altered sensitivity to opioid analgesia later in life is one potential outcome shared by in utero opioid exposure and ACEs that may contribute to poorly controlled pain and increased risk of opioid addiction. Studies using rat models of prenatal opioid exposure (POE) or early life adversity (ELA) have shown that each decreases opioid‐induced antinociception long after exposure has ceased. However, the contributions of POE and ELA, alone and in combination, to opioid analgesic response in humans remains unknown. In this study, we used a rodent model of combined POE and ELA to disambiguate their long‐term effects more quickly and with greater experimental control than human studies. We hypothesized that combined POE and ELA will decrease morphine‐induced antinociception in adolescence relative to POE or ELA alone. We used a two‐by‐two between‐subjects factorial design in which timed‐pregnant Long‐Evans rats were exposed to morphine (15 mg/kg/day; “POE” group) or saline (“vehicle” group) via subcutaneous osmotic minipump from gestation day 9 until delivery. Litters were fostered to untreated dams then randomly assigned to normal housing or ELA conditions using a limited bedding and nesting procedure from postnatal days 3‐11. Morphine‐induced antinociception was measured between postnatal days 30 and 54 using a warm‐water tail withdrawal (WWTW) assay. Cumulative dose‐response of morphine‐induced antinociception was determined on test day 0 (1.0‐30 mg/kg morphine, s.c.) and test day 13 (3.0‐100 mg/kg, s.c.). On test days 1‐12, rats were dosed with 18 mg/kg, s.c., every 12 hours, and WWTW was conducted on odd test days. Interesting, preliminary results of this ongoing study indicate that morphine‐induced antinociception was enhanced on test day 0 in POE + normal‐housed males (n = 2). These rats exhibited 100% maximum possible effect (MPE) and significantly higher potency (mean ED50=5.96 mg/kg; 95% CI = ‐12.12, 24.05), while mean MPE for the other groups (n=2‐3) was less than 70% and mean ED50>17 mg/kg. Males exhibited partial tolerance throughout the 12‐day chronic morphine treatment period. In the POE + normal‐housed males, MPE decreased from 100% on test day 1 to 58% on test day 11. For the remaining groups, MPE decreased from 44‐57% on test day 1 to 12‐23% on test day 11. Morphine was more potent in the POE + normal‐housed males on test day 13 (mean ED50=66.21 mg/kg; 95% CI = ‐281.6, 414) than in other males (mean ED50>104.4 mg/kg). No clear group effect was observed in females. These unexpected results suggest a complex sex‐dependent interaction between POE and ELA on opioid antinociception.

Chronic Cancer Pain: Opioids within Tumor Microenvironment Affect Neuroinflammation, Tumor and Pain Evolution.

Simple SummaryPain is a worrisome symptom that 60–80% of patients with cancer experience chronically. In the last twenty years, immunological and pain research have shown that cancer pain is attributable to the neuroinflammatory response driven by the cellular and soluble components of the tumor microenvironment, with features similar to that induced in many other painful chronic non-cancer diseases. Neuroinflammation leads to central sensitization and neuroplastic remodeling of the central nervous system with alteration of pain sensitivity (hyperalgesia), responsiveness (behavior), and drive (centralization). Engagement of opioid receptors by both endogenous and exogenous opioids, namely, the cornerstone of pain therapy morphine, results in modulation of pain intensity and quality, in addition to cancer growth and progression. The effects of opioids on the evolution of pain, (relief or immune-mediated hyperalgesia) and cancer (promotion or inhibition), are dual and ambiguous. This ambiguity currently represents a major limitation of long-term opioid therapy, and encourages novel immunotherapeutic strategies.Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.

Promoting sustainable responses to the US opioid epidemic with community-academic partnerships: qualitative outcomes from a statewide program

BackgroundDrug overdose deaths in the United States have continued to increase at an alarming rate. The Substance Abuse and Mental Health Services Administration (SAMHSA) distributed more than $7 billion between January 2016 and June 2020 to address the drug overdose crisis. The funds support evidence-based responses, including medications for opioid use disorder, and other prevention, treatment and recovery activities. Although the State Opioid Response (SOR) grants finance much-needed community level interventions, many of the services they support may not be sustainable, without ongoing assessment, evaluation and planning for continuation.MethodsThis paper describes a statewide effort to support local entities through SAMHSA’s SOR grants in Virginia. Community agencies across the state participated in detailed needs assessment exercises with VHEOC investigators, and developed requests for proposals (RFPs) to sustain their SOR programs. The RFPs were then distributed to prospective academic partners at the five VHEOC universities, based on the required subject matter expertise identified in the RFP. All responsive proposals were then provided to the local agencies who selected the proposal most likely to meet their needs. VHEOC investigators also conducted an inductive, three-phase content analysis approach to examine the RFPs submitted to the VHEOC to identify nominal categories of support requested of the VHEOC investigators.ResultsVHEOC Investigators received and coded 27 RFPs from ten community agencies representing four of five regions of the state. We identified six nominal categories of academic assistance with high inter-coder agreement. The six categories of support requested of the academic partners were program development and support, literature review and best practices, outreach and education, data analysis and interpretation, program evaluation, and grant writing assistance. Several RFPs requested up to three categories of support in a single project.ConclusionsOur analysis of the requests received by the consortium identified several categories of academic support for SOR-grantees addressing the drug overdose crisis. The most common requests related to development and maintenance of supportive collaborations, which existing research has demonstrated is necessary for the long-term sustainability of SOR-funded services. In this way, the academic partners reinforced sustainable SOR-funded programs. As the state opioid response program is implemented nationally, we hope that other states will consider similar models in response to the opioid crisis.