Treatment Of Opioid Abuse Research Articles

Scoping review of the role of equine assisted psychotherapy and learning in opioid abuse treatment

Opioid abuse is an epidemic in the United States with the number of deaths associated with this addiction growing each year, and yet, identification of a successful treatment plan is a major limitation to addressing this epidemic. Traditional treatment programs do not always fit for all addicts; however, equine assisted psychotherapy and learning (EAPL) shows promise as an alternative treatment option for those individuals where traditional treatment options have failed. Nevertheless, due to the novelty of this treatment option, literature concerning EAPL is limited. The purpose of this scoping review was to identify articles that address the characteristics and methodologies found in EAPL programs as it relates to opioid abuse treatment. Through the use of this scoping review, literature covering four key topics were gathered: 1) addiction treatment curriculums, 2) EAPL programs, 3) physiological effect of addiction treatment for humans, and 4) physiological effect of EAPL participation on the human and horse. Research associated with physiological effect was the most lacking of the topics covered during this review of literature. Reviewed literature pointed to a variety of populations that participate in addiction treatment programs that range from inpatient to long term recovery. EAPL programs offer an assortment of activity options to combat the challenges presented by the range of populations treated. Vital signs were mentioned in the literature reviewed as the leading way to track physiological changes but were not discussed in relation to addiction-specific treatment. Physiological measures showed change in both horses and humans who participated in equine programming but did not dictate concrete cause and effect instances. The limited literature identified through this scoping review validates the need to further explore the intentional relationship between EAPL and opioid abuse treatment programming.

Consensus Panel Recommendations for the Pharmacological Management of Breastfeeding Women with Postpartum Depression

Introduction: Our consensus statement aims to clarify the use of antidepressants and anxiolytics during breastfeeding amidst clinical uncertainty. Despite recent studies, potential harm to breastfed newborns from these medications remains a concern, leading to abrupt discontinuation of necessary treatments or exclusive formula feeding, depriving newborns of benefits from mother’s milk. Methods: A panel of 16 experts, representing eight scientific societies with a keen interest in postpartum depression, was convened. Utilizing the Nominal Group Technique and following a comprehensive literature review, a consensus statement on the pharmacological treatment of breastfeeding women with depressive disorders was achieved. Results: Four key research areas were delineated: (1) The imperative to address depressive and anxiety disorders during lactation, pinpointing the risks linked to untreated maternal depression during this period. (2) The evaluation of the cumulative risk of unfavorable infant outcomes associated with exposure to antidepressants or anxiolytics. (3) The long-term impact on infants’ cognitive development or behavior due to exposure to these medications during breastfeeding. (4) The assessment of pharmacological interventions for opioid abuse in lactating women diagnosed with depressive disorders. Conclusions: The ensuing recommendations were as follows: Recommendation 1: Depressive and anxiety disorders, as well as their pharmacological treatment, are not contraindications for breastfeeding. Recommendation 2: The Panel advocates for the continuation of medication that has demonstrated efficacy during pregnancy. If initiating an antidepressant during breastfeeding is necessary, drugs with a superior safety profile and substantial epidemiological data, such as SSRIs, should be favored and prescribed at the lowest effective dose. Recommendation 3: For the short-term alleviation of anxiety symptoms and sleep disturbances, the Panel determined that benzodiazepines can be administered during breastfeeding. Recommendation 4: The Panel advises against discontinuing opioid abuse treatment during breastfeeding. Recommendation 5: The Panel endorses collaboration among specialists (e.g., psychiatrists, pediatricians, toxicologists), promoting multidisciplinary care whenever feasible. Coordination with the general practitioner is also recommended.

3 Neuropsychiatric Change and Childhood Adversity Levels in an Opioid Treatment Population

Objective:Early life adversity is strongly correlated with a number of negative health outcomes, with some of the highest risks are related to later illicit drug use and substance use disorders (SUDs). Specifically, it has been found that an ACEs score of >4 confers a 7-10-fold risk of substance abuse. Subsequent research has identified a number of neurobiological effects of childhood trauma, including structural and functional disruptions of the LHPA axis, the brain's primary stress-response system. It has been hypothesized that various trauma-induced neurobiological changes may lead to later physical health, mental health, and psychosocial problems in persons with early life adversity. One area that such changes might affect is a person's ability to stop abusing substances, with factors such as trauma-related mood, self-efficacy, or cognitive functioning as considerations in early treatment success. This study followed a group of participants in a residential substance abuse treatment program across their first month of abstinence, to assess natural change in cognitive performance as well as potential effect of early life adversity on changes in neuropsychiatric outcomes.Participants and Methods:Participants were 37 adults (mean age=33.9 years, SD=6.7) who had completed detoxification and were first assessed during their first week of residential treatment. Follow-up assessment was completed 4 weeks later. Participants were primarily male (62%) and white (62%). They were all in treatment for opioid abuse, with a majority of participants reporting a history of polysubstance abuse. To measure adverse and protective factors, participants completed the Adverse Childhood Experiences scale and Protective And Compensatory Experiences Scale at baseline. Participants also completed the NIH Toolbox cognition battery and a set of self-report measures of cognitive functioning, mood, anxiety, and self-efficacy at baseline and follow up.Results:Results of paired samples t-test comparison between baseline and follow-up testing found a significant improvement in self-reported depression symptoms, anxiety symptoms, and self-efficacy (all p<.001). Interestingly, participants overall reported an increase in cognitive problems between baseline and retest, even though on objective cognitive testing (NIH Toolbox cognition battery) there was significant improvement in cognitive performance. Participants generally had a high level of childhood adversity (mean ACE score of 4.5), with an average level of childhood compensatory experiences. Considering the specific effect for childhood adversity, ACE score was found to be predictive in amount of anxiety and self-reported cognitive change but not for objective cognitive performance or change in other factors.Conclusions:Consistent with previous research, these patients had a high level of past trauma, which interacted with a number of other neuropsychiatric measures and support the importance of assessing for trauma history and integrating trauma-focused treatment into substance abuse treatment programs.

2 Pilot Study of a Cognitive Enhancement Intervention for Substance Abuse Recovery

Objective:This was a pilot study testing a cognitive enhancement program to improve rate of cognitive recovery in early substance abuse treatment. It is hypothesized that if patients were able to accelerate the rate of cognitive improvement, they may be able to better engage in substance abuse treatment and potentially have better long-term outcomes.Participants and Methods:Participants were 47 adults newly admitted to a residential substance abuse treatment facility (74.5% male, 76.6% white, mean age=34.5 years, education=12+ years). All were post-detox. All were being treated for opioid abuse, with the majority in treatment for polysubstance abuse. Participants were randomly assigned to either the intervention group (BrainHQ research cognitive training program) or active control group (inert computer games) and completed 34 training sessions per week for a minimum of 3 weeks. NIH Toolbox cognition battery was administered at baseline and endpoint.Results:Regardless of study group, most participants had a significant improvement in cognitive performance across most subtests and composite scores of the NIH Toolbox cognition battery. The RAVLT and Oral Symbol Digit subtests had the greatest change (p<.001) for both groups, as well as a significant improvement (p=.002) in Cognitive Function Composite Score for both groups. The only difference between the control and intervention group was on the Pattern Comparison subtest, with the intervention group scoring significantly higher at endpoint (p=.004).Conclusions:Although substance abuse is known to cause injury to the brain that may not be fully repaired by sobriety, cognitive recovery was significant in this group of patients during early inpatient treatment for opioid abuse. Although it has yielded significant effect in other patient populations, the BrainHQ program did not show a significant enhancement in cognitive recovery, compared to the active control group, in this pilot study of patients in treatment for opioid abuse. This study was limited by a small sample size and potential future variations should be considered, such as changes to intervention intensity and specific intervention exercises.

Exploring the link between ACEs and opioid use: A systematic review.

To review the current literature surrounding the relationship between adverse childhood experiences (ACEs) and opioid use disorder (OUD) to guide clinical identification of high-risk individuals and assess treatment implications. A PubMed search was conducted from the year 2000 to 2022 using a series of primary and secondary search terms. A total of 21,524 unique results were screened for relevancy to ACEs and OUDs. After excluding unrelated articles, a total of 48 articles were included in this systematic review. Increased frequency of ACEs was directly related to increased risk of OUD and lower onset age. ACEs were also associated with OUD severity. ACEs linked to OUD included childhood neglect, emotional abuse, physical abuse, and sexual abuse. Additionally, dysfunctional childhood home environment, female gender, and psychiatric/behavioral comorbidities increased the risk of OUD, while resilience was found to be a protective factor. Multiple biochemical markers were associated with both ACEs and OUD. Children experiencing multiple ACEs should be the target of preventative intervention by medical professionals. Clinicians should include ACEs in their opioid misuse risk assessment. High incidence of co-occurring psychiatric/behavioral disorders provides multiple treatment avenues for patients with OUD. Resilience, along with being therapy target, should be fostered early in the life course. Incorporation of family members may improve opioid abuse treatment outcomes. Future research should focus on interventions interrupting the progression of ACEs to OUD along with proposed biochemical pathways.

A Pathway to Treatment for Pregnant Women With Opioid Use Disorder.

Addiction to opioids, a well-known public health crisis, is now more prevalent in pregnant women as evidenced by the parallel rise with pregnant women in the epidemic with the general population. Evidence is now available that substantiates the need for global awareness to increase efforts in the treatment of pregnant women with opioid use disorder (OUD) as this vulnerable population lacks equal access to opioid abuse treatment across the United States. The overarching aim and purpose of this quality improvement project was to increase access to treatment for pregnant women with OUD who are currently underserved in a community located in Florida. Between January and April 2022, the 4Ps (parents, partners, past, and pregnancy), a validated screening tool, was implemented in an organization that accepts individuals with substance abuse. Each positive screen was referred for assessment for buprenorphine induction and medication-assisted treatment follow-up. Descriptive statistics were collected counting the number of screens completed, the number of positive screens, the number of referrals, and the number of patients remaining in treatment for 30 and 60 days. Twenty-two screens were completed. The results yielded an increase in referrals, a 75% increase in treatment of pregnant women, and an average of 83% of participants remained in treatment. The implementation of a validated screening tool assisted in increasing access to treatment for pregnant women with OUD. Once implemented, the screening tool forges a pathway for referrals and evidence-based treatment for pregnant women with OUD.

Potential therapeutic targets for the treatment of opioid abuse and pain.

Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.

Intervensi Farmakologi Sindrom Putus Obat pada Penyalahguna Opioid

Opioid withdrawal syndrome appears after abrupt discontinuation of opioids characterized by watery eyes, runny nose, muscle pain, anxiety, yawning, gooseflesh, mydriasis, gastrointestinal discomfort, and rapid heartbeat. Globally, opioid abuse remains a significant problem, necessitating adequate treatment of drug syndrome in opioid addicts, particularly pharmaceutical therapy. Therefore, this study aimed to identify, evaluate, and analyze pharmacological management in opioid abusers. The articles used were retrieved based on specific limitations using the main keywords "opioid withdrawal syndrome treatment" and additional keywords "heroin, fentanyl, morphine" that were published in PubMed, ScienceDirect, and SpringerLink. From the 21 articles included, heroin abuse was the most prevalent. The primary treatment for opioid abuse is substitution therapy of opioid or non-opioid such as lofexidine, naltrexone, buprenorphine, dronabinol, methadone, pregabalin, oxytocin, antagonist corticotropin-releasing factor type 1 (CRF1), tramadol, clonidine, and pioglitazone. Additionally, the patient received symptomatic therapy based on the condition. The drugs used for treatment and willingness to obtain therapy are the factors for the withdrawal completion rate. The results were evaluated using opioid withdrawal assessment, either from a subjective, objective, or clinical perspective.

28. The Paradox of an Integrated MAT OPAT Program

BackgroundPatients with substance use disorders (SUD), specifically opioid use disorder (OUD) and injection drug use (IDU) utilize healthcare resources for prolonged inpatient treatment of serious infections stemming from their addictions. For a variety of reasons, physicians treating these patients refuse to send these patients home to receive outpatient parenteral antimicrobial therapy (OPAT), and instead keep the patient in the hospital for several weeks or longer to complete treatment for the injection-related infections. Patients who do not have history of IDU are sent home with a PICC line to receive OPAT once they are no longer acutely ill and therefore no longer meet criteria to remain inpatient, which is the established standard of care. Patients with OUD and IDU are not allowed the same standard of care, and furthermore do not receive adequate, if any, therapy for their primary problem and reason for their serious infection – the addiction.Flow chart of the MAT-OPAT process MethodsMedication-assisted treatment (MAT) with buprenorphine-naloxone has been approved for treating adults with opioid use disorder as part of a comprehensive treatment program that also includes counseling and behavioral therapy. Until now in our healthcare system there has been no comprehensive and integrated program to safely discharge patients with OUD and IDU to receive OPAT via a PICC line, while simultaneously treating their addiction. We describe the implementation of a MAT-OPAT program. Please refer to the chart included.ResultsWe present a successful case of a 36-year-old male with a history of endocarditis associated with IV drug use and the intervention of the Healthcare System to link the patient to appropriate Infectious disease, behavioral health and medication adherence treatment for opioid abuse. The patient completed the IV antibiotic therapy and remained enrolled in the behavioral health program with a successful outcome.ConclusionMAT-OPAT implementation in large healthcare system with continuous outpatient support that includes Infectious Disease services, behavioral health and drug abuse rehabilitation therapy can be a successful strategy to minimize readmisión, cost and complications in patients with history of IV drug use and infections that require prolonged intravenous antibiotic therapy.Disclosures All Authors: No reported disclosures

A Review of DNA Risk Alleles to Determine Epigenetic Repair of mRNA Expression to Prove Therapeutic Effectiveness in Reward Deficiency Syndrome (RDS): Embracing "Precision Behavioral Management".

This is a review of research on “Precision Behavioral Management” of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system’s neurotransmitters. We are proposing a generalized approach called “Precision Behavioral Management”. This approach includes 1) using the Genetic Addiction Risk Severity (GARS, a 10 candidate polymorphic gene panel shown to predict ASI-alcohol and drug severity) to assess early pre-disposition to substance use disorder; 2) using a validated reward deficiency syndrome (RDS) questionnaire; 3) utilization of the Comprehensive Analysis of Reported Drugs (CARD™) to assess treatment compliance and abstinence from illicit drugs during treatment, and, importantly; 4) utilization of a “Pro-dopamine regulator (KB220)” (via IV or oral [KB220Z] delivery systems) to optimize gene expression, restore the balance of the Brain Reward Cascade’s neurotransmitter systems and prevent relapse by induction of dopamine homeostasis, and; 5) utilization of targeted DNA polymorphic reward genes to direct mRNA genetic expression profiling during the treatment process. Incorporation of these events can be applied to not only the under-considered African-American RDS community, but all victims of RDS, as a demonstration of a paradigm shift that uniquely provides a novel putative “standard of care” based on DNA guided precision nutrition therapy to induce “dopamine homeostasis” and rebalance neurotransmitters in the Brain Reward Cascade. We are also developing a Reward Deficiency Syndrome Diagnostic Criteria (RDSDC) to assist in potential tertiary treatment.

The utility of maraviroc, an antiretroviral agent used to treat HIV, as treatment for opioid abuse? Data from MRI and behavioural testing in rats.

Background:Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence.Methods:Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas.Results:Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment.Limitations:All experiments were performed in male rats only.Conclusion:Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.

Health(care) in the Crisis: Reflections in Science and Society on Opioid Addiction.

Opioid abuse and misuse have led to an epidemic which is currently spreading worldwide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current rather unsystematic approaches to tackle this health problem are not effective. This review suggests that fighting the opioid epidemic requires a structured public health approach. Therefore, it is important to consider not only scientific and biomedical perspectives, but societal implications and the lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context of chronic pain as well as post-surgery treatments, as the entrance of opioids in people’s lives. Linking pharmaceutical biology to narrative analysis is essential to understand the modulations of the usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient narratives can be an important resource in understanding the complexity of opioid abuse and addiction. In particular, the relationship between chronic pain and social inequality must be considered. The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched understanding can lead to more precise strategies of prevention or treatment of opioid abuse.

Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance.

Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

Opioid Modulation of the Gut-Brain Axis in Opioid-Associated Comorbidities.

Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.

Corydaline and l-tetrahydropalmatine attenuate morphine-induced conditioned place preference and the changes in dopamine D2 and GluA1 AMPA receptor expression in rats

Corydalis is a Chinese herb that has been used in China for hundreds of years for analgesic and other purposes. Corydaline and l-tetrahydropalmatine (l-THP) are the main active ingredients of Corydalis. This study was aimed to study the potential utility of corydaline and l-THP in the treatment of opioid abuse and addiction and explore the possible mechanisms underlying their pharmacological actions. Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine and Western-blot immunoreactive assays were used to evaluate morphine-induced changes in dopamine D2 receptor and GluA1 AMPA receptor and GluA2 AMPA receptor expression in the brain of rats. Systemic administration of corydaline (5 mg/kg, i.p.) or l-THP (1.25, 2.5,5 mg/kg) significantly inhibited the acquisition and expression of morphine-induced CPP in a dose-dependent manner. Corydaline or l-THP alone, at the same doses, failed to produce CPP or conditioned place aversion, and didn't affect locomotor activity. We then examined the expression of dopamine D2 receptor and GluA1 AMPA receptor and GluA2 AMPA receptor subunit expression in rats after acquisition of morphine-induced CPP. We found that repeated administration of morphine produced a significant reduction in dopamine D2 receptor expression in the prefrontal cortex, hippocamps, and striatum, while an increase in the striatal GluA1 AMPA receptor expression. Pretreatment with corydaline or l-THP blocked morphine-induced dopamine D2 receptor down-regulation and GluA1 AMPA receptor up-regulation in these brain regions. Corydaline and l-THP may have therapeutic potential in prevention and treatment of opioid abuse and addiction. The underlying mechanisms may be related to their antagonism on morphine-induced changes in dopamine and glutamate transmission in the brain.

Methocinnamox Produces Sustained Antagonism of the Antinociceptive Effects of Morphine and Persistent Decreases in [3H]DAMGO Binding to μ Opioid Receptors in Rat Cortex

The opioid crisis continues in the US despite the availability of pharmacotherapies that are effective in some patients. A novel μ opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action in blocking the effects of opioids, which could provide a substantial advantage over currently available medications, particularly for overdose. MCAM has been shown to attenuate the behavioral effects of μ, but not k, opioid receptor agonists, and this antagonism, which can last for several weeks, is thought to be due to pseudoirreversible binding of MCAM to μ opioid receptors. In the current study, a warm water tail withdrawal procedure was used to examine sustained antagonism by MCAM in one group of 8 rats. This study showed that 10 mg/kg MCAM attenuated the antinociceptive effects of morphine (1.78–17.8 mg/kg) 5 and 13 days after MCAM administration with antagonism beginning to wane 21 days after MCAM. In separate groups of 8 rats, that same dose of MCAM decreased [3H]DAMGO binding to μ opioid receptors in rat cortical homogenates measured 1, 5 and 21 days after MCAM injection, indicating that MCAM occupied μ opioid receptors at all time points tested. For example, maximal binding (Bmax) was 28.51 ± 3.33 and 30.96 ± 1.73 fmol/mg protein 5 and 21 days, respectively, after vehicle administration, and 16.03 ± 4.15 and 12.50 ± 1.27 fmol/mg protein 5 and 21 days, respectively, after administration of 10 mg/kg MCAM. Binding affinity (KD) was not markedly changed after MCAM administration. Thus, MCAM produces a sustained decrease in [3H]DAMGO binding to μ opioid receptors in rat cortex that parallels antagonism of the antinociceptive effects of μ opioid receptor agonists. This finding supports the notion that MCAM blocks the behavioral effects of μ opioid receptor agonists by binding pseudoirreversibly to these receptors. The unique binding profile of MCAM to μ opioid receptors could increase the usefulness of MCAM as a treatment for opioid abuse and overdose.Support or Funding InformationSupported by NIH (R01DA005018 and R01048417) and the Welch Foundation (AQ‐0039).

A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids.

The Toll-like receptor 4 (TLR4) antagonists, (+)-naloxone and (+)-naltrexone, have been reported to decrease self-administration of opioids in rats and to reduce other preclinical indicators of abuse potential. However, under the self-administration conditions studied, the effects of TLR4 antagonists were not reinforcer selective, questioning the involvement of those receptors and their mediated inflammatory response specifically in opioid abuse. The objectives of the current study were to further characterize the reinforcer specificity of TLR4 antagonism in opioid self-administration and to explore its effects in a preclinical model of craving/relapse. The TLR4 antagonist (+)-naltrexone decreased responding in rats trained to self-administer the µ-opioid receptor agonist remifentanil, but with a potency that was not significantly different from that observed in another group of subjects in which responding was maintained by food reinforcement. Responding reinstated by heroin injection was decreased by (+)-naltrexone; however, a similar reduction was not reproduced with the administration of another TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides, administered into the NAcc shell. Thus, TLR4 antagonists lacked reinforcer selectivity in reducing opioid self-administration and were not uniformly effective in a model of craving/relapse, suggesting limitations on the development of (+)-naltrexone or TLR4 antagonists as treatments for opioid abuse.

Effects of Acute and Repeated Methocinnamox Treatment on Fentanyl Self‐administration in Rhesus Monkeys

Opioid abuse remains a serious public health challenge despite the availability of effective medications. Recent studies showed that the pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) attenuates the reinforcing and respiratory‐depressant effects of heroin in rhesus monkeys, suggesting it could be an effective treatment for opioid abuse and overdose. The current study extends this work by evaluating MCAM for its capacity to attenuate the reinforcing effects of the potent, high‐efficacy opioid fentanyl. Because successful treatment of opioid use disorder requires long‐term and, usually, repeated treatment, the current study also evaluated effects of repeated MCAM administration.Four rhesus monkeys responded for i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion) under a fixed‐ratio 30 schedule. Once responding was stable, naltrexone (0.0032, 0.01, or 0.032 mg/kg) or MCAM (0.1 or 0.32 mg/kg) was administered s.c. prior to a session. On a separate occasion, 0.32 mg/kg of MCAM was injected every 12 days for a total of 5 administrations over 49 days. Cocaine was substituted for fentanyl every fourth session to examine the selectivity of effects of MCAM.When given acutely, both doses of MCAM decreased responding for fentanyl on the day of treatment, with the larger dose (0.32 mg/kg) decreasing the number of infusions from an average of 24 under baseline to 7. Responding remained significantly lower than baseline for 2 and 14 days following administration of 0.1 and 0.32 mg/kg of MCAM, respectively. Naltrexone also decreased fentanyl self‐administration, with the largest dose (0.032 mg/kg) decreasing the number of infusions from 26 under baseline to 3 after treatment; however, responding returned to baseline the next day. When given every 12 days, MCAM decreased responding for fentanyl for more than 70 days; the time for responding to recover after 5 injections of MCAM was not different from the time to recovery after 1 injection. MCAM did not alter responding for cocaine in either experiment.MCAM decreased self‐administration of the potent, high‐efficacy opioid fentanyl but not cocaine. Effects of a single injection of MCAM lasted much longer (> 2 weeks) than those of naltrexone (< 24 hr), and MCAM remained effective for over 2 months with repeated treatment. These results confirm and extend previous studies, demonstrating that MCAM produces longlasting and selective suppression of opioid self‐administration and that MCAM remains effective following repeated administration. Moreover, recovery of responding following discontinuation of repeated MCAM treatment indicates that the opioid system was not disrupted. The long duration of action of MCAM is likely due, at least in part, to pseudoirreversible binding to mu opioid receptors, suggesting it would insurmountably block the abuse‐related effects of opioids. Taken together, these data indicate that MCAM could be a safe, effective, and long‐acting treatment for opioid use disorder and overdose.Support or Funding InformationThis work was supported, in part, by the National Institutes of Health [R01DA005018, R01DA048417, and R01DA007315] and the Welch Foundation [AQ‐0039].

Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats.

Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD.

Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.

Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.