Prescription opioid dispensing patterns among patients with schizophrenia or bipolar disorder.

BACKGROUND: Patients with schizophrenia (SZ) or bipolar disorder (BD) may have increased risk of complications from prescribed opioids, including opioid-induced respiratory depression. We compared prescription opioid pain medication dispensing for patients with SZ or BD versus controls over 5 years to assess dispensing trends. METHODS: This retrospective, observational study analysed US claims data from the IBM® MarketScan® Commercial and Multi-State Medicaid databases for individuals aged 18-64 years with prevalent SZ or BD for years 2015-2019 compared with age- and sex-matched controls. Baseline characteristics, comorbidities, and medication use were assessed. Proportions of individuals dispensed prescription opioids chronically (ie, ≥70 days over a 90-day period or ≥ 6 prescriptions annually) or nonchronically (≥1 prescription, chronic definition not met) were assessed. RESULTS: In 2019, the Commercial and Medicaid databases contained records for 4773 and 30,179 patients with SZ and 52,780 and 63,455 patients with BD, respectively. Patients with SZ or BD had a higher prevalence of comorbidities, including pain, versus controls in each analysis year. From 2015 to 2019, among commercially insured patients with SZ, chronic opioid-dispensing proportions decreased from 6.1% (controls: 2.7%) to 2.3% (controls: 1.2%) and, for patients with BD, from 11.4% (controls: 2.7%) to 6.4% (controls: 1.6%). Chronic opioid dispensing declined in Medicaid-covered patients with SZ from 15.0% (controls: 14.7%) to 6.7% (controls: 6.0%) and, for patients with BD, from 27.4% (controls: 12.0%) to 12.4% (controls: 4.7%). Among commercially insured patients with SZ, nonchronic opioid dispensing decreased from 15.5% (controls: 16.4%) to 10.7% (controls: 11.0%) and, for patients with BD, from 26.1% (controls: 17.5%) to 20.0% (controls: 12.2%). In Medicaid-covered patients with SZ, nonchronic opioid dispensing declined from 22.5% (controls: 24.4%) to 15.1% (controls: 12.7%) and, for patients with BD, from 32.3% (controls: 25.9%) to 24.6% (controls: 13.6%). CONCLUSIONS: The proportions of individuals dispensed chronic or nonchronic opioid medications each year were similar between commercially and Medicaid-insured patients with SZ versus controls and were higher for patients with BD versus controls. From 2015 to 2019, the proportions of individuals who were dispensed prescription opioids chronically or nonchronically decreased for patients with SZ or BD and controls.

Characteristics and treatment preferences of individuals with opioid use disorder seeking to transition from buprenorphine to extended-release naltrexone in a residential setting.

BACKGROUND AND OBJECTIVES: Treatment for individuals receiving medication for opioid use disorder (MOUD) should follow an informed patient-centered approach. To better support patient autonomy in the decision-making process, clinicians should be aware of patient preferences and be prepared to educate and assist patients in transitioning from one MOUD to another, when clinically indicated. This posthoc analysis describes the characteristics of clinical trial participants (NCT02696434) with a history of opioid use disorder (OUD) seeking to transition from buprenorphine (BUP) to extended-release naltrexone (XR-NTX). METHODS: The posthoc analysis included adults with OUD currently receiving BUP (≤8 mg/day) and seeking transition to XR-NTX (N = 101) in a residential setting. Baseline participant characteristics and OUD treatment history were reviewed. All patients completed a screening questionnaire that asked about their reasons for seeking transition to XR-NTX and for choosing BUP. RESULTS: The most common reasons for initiating a transition to XR-NTX were "Seeking to be opioid-free" (63.4%) and "Tired of daily pill taking" (25.7%). Positive predictors of transition included a more extensive BUP treatment history and a history of prescription opioid abuse. Most participants stated they were not aware of XR-NTX as a treatment option when initiating BUP (78.2%). DISCUSSIONS AND CONCLUSIONS: Patients' reasons for seeking XR-NTX transition, more extensive BUP treatment history, and a history of prescription opioid abuse, may positively predict outcomes. SCIENTIFIC SIGNIFICANCE: These findings may assist clinicians in optimizing outcomes of the BUP to XR-NTX transition and supporting patients to make better informed MOUD decisions.

Patient characteristics associated with initiation of XR-naltrexone for opioid use disorder in clinical trials.

BACKGROUND: Extended-release injectable naltrexone (XR-naltrexone) is effective for treatment of patients with opioid use disorder (OUD), but initiation remains a barrier due to the challenge of tolerating opioid withdrawal prior to administration. Understanding factors associated with successful initiation of XR-naltrexone could facilitate its implementation through patient-treatment matching. METHODS: We combined data from five consecutive studies that sought to initiate patients with active opioid use onto XR-naltrexone using a rapid procedure consisting of minimal buprenorphine, non-opioid medications for treating opioid withdrawal, and ascending low doses of oral naltrexone. Associations between patient characteristics and initiating naltrexone were estimated with logistic regression models. To evaluate whether associations differed between inpatient and outpatient settings, patient characteristic-by-setting interactions were also estimated. RESULTS: 409 patients were included in the analyses and 228 (56%) received the first injection. A significantly greater percent of inpatients (62%) vs outpatients (48%) initiated XR-naltrexone. Initiation success was significantly more likely on an inpatient basis for heroin (60.9% inpatient vs 36.2% outpatient), intravenous (56.3% inpatient vs 22.5% outpatient), and speedball users (68.1% inpatient vs 32.3% outpatient). Prescription opioid users showed similar, higher initiation rates across settings (68.9% inpatient; 73.7% outpatient). CONCLUSIONS: An inpatient setting may be the preferred strategy for rapid initiation of XR-naltrexone for opioid users with greater severity, including heroin or speedball injection users or those who use opioids intravenously. Initiation on an outpatient basis may be more likely to succeed for prescription opioid users.

Evaluation of Opioid Overdose Reports in Patients Treated with Extended-Release Naltrexone: Postmarketing Data from 2006 to 2018.

INTRODUCTION: After treatment with naltrexone extended-release injectable suspension (XR-NTX), a µ-opioid receptor antagonist, opioid tolerance is reduced from pretreatment baseline. Patients may be vulnerable to opioid overdose if they attempt to override the blockade during treatment, at the end of a dosing interval, after missing a dose, or after discontinuing treatment. OBJECTIVE: We analyzed postmarketing data to characterize reporting rates of opioid overdose during treatment with and after discontinuation of XR-NTX. METHODS: Postmarketing adverse event reports within the XR-NTX safety database, received 2006-2018, for patients treated with XR-NTX for any indication were reviewed for opioid overdose cases. Assessable cases were categorized by timing of the event from the last dose of XR-NTX (latency): ≤28 days (on treatment), 29-56 days, and >56 days from last dose of XR-NTX. Within each latency group, cases were further classified as serious and, of those, cases that had a fatal outcome. RESULTS: During the 12-year period, an estimated 495,602 patients received XR-NTX. Opioid overdose was reported in 161 cases; of these, 66 contained sufficient information to determine latency. Reporting rates of opioid overdose per 10,000 patients treated were similar among latency groups: 0.54 for ≤28 days (0.24 fatal), 0.34 for 29-56 days (0.16 fatal), and 0.44 for >56 days (0.40 fatal) from the last dose of XR-NTX. CONCLUSIONS: Over the 12-year period, the reporting rates of opioid overdose were similar during treatment with or after discontinuation of XR-NTX and <10/10,000 patients exposed. Our findings are limited by the nature of spontaneously reported safety data.

The Molecular Neurobiology of Twelve Steps Program & Fellowship: Connecting the Dots for Recovery.

There are some who suggest that alcoholism and drug abuse are not diseases at all and that they are not consequences of a brain disorder as espoused recently by the American Society of Addiction Medicine (ASAM). Some would argue that addicts can quit on their own and moderate their alcohol and drug intake. When they present to a treatment program or enter the 12 Step Program & Fellowship, many addicts finally achieve complete abstinence. However, when controlled drinking fails, there may be successful alternatives that fit particular groups of individuals. In this expert opinion, we attempt to identify personal differences in recovery, by clarifying the molecular neurobiological basis of each step of the 12 Step Program. We explore the impact that the molecular neurobiological basis of the 12 steps can have on Reward Deficiency Syndrome (RDS) despite addiction risk gene polymorphisms. This exploration has already been accomplished in part by Blum and others in a 2013 Springer Neuroscience Brief. The purpose of this expert opinion is to briefly, outline the molecular neurobiological and genetic links, especially as they relate to the role of epigenetic changes that are possible in individuals who regularly attend AA meetings. It begs the question as to whether "12 steps programs and fellowship" does induce neuroplasticity and continued dopamine D2 receptor proliferation despite carrying hypodopaminergic type polymorphisms such as DRD2 A1 allele. "Like-minded" doctors of ASAM are cognizant that patients in treatment without the "psycho-social-spiritual trio," may not be obtaining the important benefits afforded by adopting 12-step doctrines. Are we better off with coupling medical assisted treatment (MAT) that favors combining dopamine agonist modalities (DAM) as possible histone-deacetylase activators with the 12 steps followed by a program that embraces either one or the other? While there are many unanswered questions, at least we have reached a time when "science meets recovery," and in doing so, can further redeem joy in recovery.

Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients: role of enhanced brain reward functional connectivity and homeostasis redeeming joy.

BACKGROUND: Lucid dreams are frequently pleasant and training techniques have been developed to teach dreamers to induce them. In addition, the induction of lucid dreams has also been used as a way to ameliorate nightmares. On the other hand, lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. In the latter conditions, lucid dreams can assume an unpleasant and frequently terrifying character. CASE PRESENTATIONS: We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. In the first case study, a 51-year-old, obese woman, diagnosed with PTSD and depression, had attempted suicide and experienced terrifying lucid nightmares linked to sexual/physical abuse from early childhood by family members including her alcoholic father. Her vivid "bad dreams" remained refractory in spite of 6 months of treatment with Dialectical Behavioral Therapy (DBT) and standard pharmaceutical agents which included prazosin, clonidie and Adderall. The second 39-year-old PTSD woman patient had also suffered from lucid nightmares. RESULTS: The medication visit notes reveal changes in the frequency, intensity and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient's regimen. The patient reported her first experience of an extended period of happy dreams. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter. CONCLUSIONS: These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies.

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

BACKGROUND: The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. METHODS: To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. RESULTS: While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. CONCLUSION: Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one's genetic risk for RDS.

Using the Neuroadaptagen KB200z™ to Ameliorate Terrifying, Lucid Nightmares in RDS Patients: the Role of Enhanced, Brain-Reward, Functional Connectivity and Dopaminergic Homeostasis.

BACKGROUND: Lucid Dreams are a form of dream life, during which the dreamer may be aware that he/she is dreaming, can stop/re-start the dreams, depending on the pleasantness or unpleasant nature of the dream, and experiences the dream as if he/she were fully awake. Depending on their content, they may be pleasant, un-pleasant or terrifying, at least in the context of patients, who also exhibit characteristics of Reward Deficiency Syndrome (RDS) and Posttraumatic Stress Disorder (PTSD). CASE SERIES: We present eight clinical cases, with known substance abuse, childhood abuse and diagnosed PTSD/RDS. The administration of a putative dopamine agonist, KB200Z™, was associated with the elimination of unpleasant and/or terrifying, lucid dreams in 87.5% of the cases presented, whereas one very heavy cocaine abuser showed a minimal response. These results required the continuous use of this nutraceutical. The lucid dreams themselves were distinguishable from typical, PTSD nightmares insofar as their content did not appear to reflect a symbolic rendition of an originally-experienced, historical trauma. Each of the cases was diagnosed with a form of RDS, i.e., ADHD, ADD, and/or Tourette's syndrome. They all also suffered from some form of Post-Traumatic-Stress-Disorder (PTSD) and other psychiatric diagnoses as well. CONCLUSION: The reduction or elimination of terrifying Lucid Dreams seemed to be dependent on KB220Z, whereby voluntary stopping of the agent results in reinstatement of the terrifying non-pleasant nature of the dreams. Following more required research on a much larger population we anticipate confirmation of these seemingly interesting observations. If these results in a small number of patients are indeed confirmed we may have found a frontline solution to a very perplexing and complicated symptom known as lucid dreams.

Neurogenetics and gene therapy for reward deficiency syndrome: are we going to the Promised Land?

INTRODUCTION: Addiction is a substantial health issue with limited treatment options approved by the FDA and as such currently available. The advent of neuroimaging techniques that link neurochemical and neurogenetic mechanisms to the reward circuitry brain function provides a framework for potential genomic-based therapies. AREAS COVERED: Through candidate and genome-wide association studies approaches, many gene polymorphisms and clusters have been implicated in drug, food and behavioral dependence linked by the common rubric reward deficiency syndrome (RDS). The results of selective studies that include the role of epigenetics, noncoding micro RNAs in RDS behaviors especially drug abuse involving alcohol, opioids, cocaine, nicotine, pain and feeding are reviewed in this article. New targets for addiction treatment and relapse prevention, treatment alternatives such as gene therapy in animal models, and pharmacogenomics and nutrigenomics methods to manipulate transcription and gene expression are explored. EXPERT OPINION: The recognition of the clinical benefit of early genetic testing to determine addiction risk stratification and dopaminergic agonistic, rather than antagonistic therapies are potentially the genomic-based wave of the future. In addition, further development, especially in gene transfer work and viral vector identification, could make gene therapy for RDS a possibility in the future.

Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation.

As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region-specific differential responses to drugs and food (including other non-substance-addictive behaviors) via either "surfeit" or "deficit." With this in mind, we hereby propose a "reward deficiency solution system" that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier.

Clinically Combating Reward Deficiency Syndrome (RDS) with Dopamine Agonist Therapy as a Paradigm Shift: Dopamine for Dinner?

Everyday, there are several millions of people that are increasingly unable to combat their frustrating and even fatal romance with getting high and/or experiencing "normal" feelings of well-being. In the USA, the FDA has approved pharmaceuticals for drug and alcohol abuse: tobacco and nicotine replacement therapy. The National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) remarkably continue to provide an increasing understanding of the intricate functions of brain reward circuitry through sophisticated neuroimaging and molecular genetic applied technology. Similar work is intensely investigated on a worldwide basis with enhanced clarity and increased interaction between not only individual scientists but across many disciplines. However, while it is universally agreed that dopamine is a major neurotransmitter in terms of reward dependence, there remains controversy regarding how to modulate its role clinically to treat and prevent relapse for both substance and non-substance-related addictive behaviors. While the existing FDA-approved medications promote blocking dopamine, we argue that a more prudent paradigm shift should be biphasic-short-term blockade and long-term upregulation, enhancing functional connectivity of brain reward circuits.

Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS): Targeting Polymorphic Reward Genes for Carbohydrate Addiction Algorithms.

Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of "Personalized Medicine" in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term "Reward Deficiency Syndrome (RDS)" to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as "Genetic Addiction Risk Score" (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. We propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx, allowing for customized nutrigenomic targeting of these risk alleles by altering KB220Z ingredients as an algorithmic function of carrying these polymorphic DNA-SNPS, potentially yielding the first ever nutrigenomic solution for addiction and pain.

Designer Drugs: A Synthetic Catastrophe.

Synthetic stimulants can cause hallucinations, aggressive behaviors, death and are sometimes legal. These substances are sold as plant food and bath salts that are "Not for Human Consumption", therefore skirting the 1986 Federal Analogue Act and giving a false pretense of safety. Studies have proved that these substances are toxic, have a high abuse potential, and are becoming extremely prevalent in the United States. This creates a dilemma for law enforcement agents, hospitals, and substance use disorder treatment centers. Urine Drug Testing is utilized as a clinical diagnostic tool in substance use disorder treatment centers, and the furious pace at which new synthetic stimulants are introduced to the black market are making the detection via urine increasingly difficult. This article will discuss the prevalence, pharmacology and difficulty developing laboratory assays to detect synthetic stimulants.

Molecular Genetic Testing in Pain and Addiction: Facts, Fiction and Clinical Utility.

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors as well as altered pain tolerance. While there are many studies claiming a genetic association with addiction and other behavioral infractions, defined as Reward Deficiency Syndrome (RDS), not all are scientifically accurate and in some case just wrong. Albeit our bias, we discuss herein the facts and fictions behind molecular genetic testing in RDS (including pain and addiction) and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDX™), the first test to accurately predict one's genetic risk for RDS.