N-Isopropylbenzylamine-induced conditioned place preference, sensitization behaviour and self-administration in rodents.

N-Isopropylbenzylamine (N-ipb), a chain isomer of methamphetamine (METH) with similar physical properties, has been used as a substitute for METH in seized drug samples. However, the abuse potential of N-ipb remains unclear. Therefore, this study aimed to evaluate the abuse potential of N-ipb in comparison to METH, by using conditioned place preference (CPP), locomotor sensitization and intravenous self-administration tests. The results showed that N-ipb at a dose of 3 mg·kg-1 significantly induced CPP in mice, which was comparable to the effect of METH at 1 mg·kg-1 . Either acute or repeated N-ipb injections (1 or 3 mg·kg-1 ) failed to raise the locomotor activity. However, acute treatment with 10 mg·kg-1 N-ipb elevated the locomotor activity compared with saline, while chronic injection of 10 mg·kg-1 N-ipb induced a delayed and attenuated sensitization compared with 1 mg·kg-1 METH. Rats could acquire N-ipb self-administration at a dose of 1 mg·kg-1 ·infusion-1 , and a typical inverted U-shaped dose-response curve was obtained for N-ipb. The mean dose of N-ipb that maintained the maximum response was greater than that of METH, indicating that N-ipb is less potent for reinforcement than METH. In the economic behavioural analysis, comparison of essential values derived from the demand elasticity revealed that N-ipb is less efficacy as a reinforcer than METH. The present data demonstrate that N-ipb functions as a reinforcer and has a potential for abuse. However, the potency of psychomotor stimulation and the reinforcing effectiveness of N-ipb are lower than those of METH.

Is schedule IV suvorexant an appropriate reference drug of abuse to use in preclinical abuse liability testing in the rat?

The abuse potential of novel CNS-active drug candidates with low specificity for known receptors involved in abuse might be complex to test preclinically relative to an appropriate reference drug of abuse. Suvorexant, a Schedule IV dual orexin receptor antagonist was investigated for its potential use as a reference drug in Drug Discrimination Learning (DDL) studies. Firstly, toxicokinetic properties of suvorexant were determined in male and female rats after single oral doses of 160 and 325 mg/kg in MC and PEG400. Thereafter the subjective effects of suvorexant at 325 mg/kg versus vehicle were evaluated in a DDL paradigm and plasma exposures were measured. Mean maximum plasma exposures in male rats after a single dose of 325 mg/kg suvorexant were 2.5- (MC) to 10.5-fold (PEG400) the human exposure at supratherapeutic doses of 40 mg q.d. (Cmax:1.1 µM), and 4.9- (MC) to 20.8-fold (PEG400) the approved maximum human efficacious dose (20 mg q.d.; 0.557 µM). Training male rats at 325 mg/kg in the DDL study however did not result in discriminative stimulus generalisation versus respective vehicles. Suvorexant, a Schedule IV dual orexin receptor antagonist failed to serve as a robust reference drug of abuse in the DDL paradigm in rats despite appropriate exposures.

Challenging the Sensitive Window Hypothesis: Timing Effects of Maternal Depressive Symptoms on the Intergenerational Transmission of Maltreatment and Psychopathology in the Next Generation.

OBJECTIVE: The current study explored the role of maternal depressive symptoms in the intergenerational transmission of childhood maltreatment and developmental psychopathology. Based on the sensitive window hypothesis, the effects of earlier versus later maternal depression symptoms on child development were analysed. METHOD: Ninety-nine mother-child dyads, 65% of which had high-risk teenage mothers, participated in a longitudinal study with three assessments in the first 18 months of the child's life (T1-T3) and a 4th reassessment (T4) at the child's preschool age. Using serial mediation analyses, we tested whether the relationship between the mother's own maltreatment history (Childhood Experience of Care and Abuse Questionnaire) and the child's psychopathological outcome at preschool age was mediated in a causal effect chain by maternal depression in the first 2 years of life, by current maternal depression (Beck Depression Inventory-II) and by current maternal child abuse potential (Child Abuse Potential Inventory). The children's emotional problems and externalizing symptoms were assessed at preschool age by parent or teacher Strengths and Difficulties Questionnaire ratings. RESULTS: The results indicated that especially later maternal depression mediated the relationship between maternal childhood maltreatment and negative developmental outcomes in the next generation. The effects of maltreatment type on maternal depression were rather nonspecific. However, mental abuse affected existing risk factors more directly over time compared to physical and sexual abuse. Additionally, the impact of early life maltreatment and maternal depression on child psychopathology varied by rater. The pathway to externalizing symptoms was significant only in teacher ratings and for the pathway to emotional problems only in maternal ratings. CONCLUSIONS: The present findings suggest that early maternal depression followed by ongoing maternal depression plays a mediating role in the intergenerational cycle of maltreatment. Therefore, in the future, interventions should be offered at an early stage, but also extend well beyond the first 2 years of a child's life, addressing maternal depression and trauma.

The use of BCAP in Finland: toward correct classification rate.

OBJECTIVE: Further validation of Brief Child Abuse Potential (BCAP) inventory, for setting the correct classification rate. METHODS: Data collection from potential abusers (n = 47), visiting in the hospital clinic meant for parents having special needs due to problems with alcohol and drugs connected to other evidence-based risk factors of child abuse. The risk level was compared between these 47 parents and previously collected data from 450 parents, representing general population. RESULTS: There were no differences between likely abusers and the general population. Among both groups, 6% had elevated abuse risk and there were no differences in appearance of dimensions including in the abuse scale. CONCLUSIONS: Assuming child abuse based on known risk factors is not enough, when setting the correct classification rate. We need more accurate knowledge about the abuse, and the family life situation in general. However, assessing risk factors of child maltreatment systematically with the BCAP, can still serve as a fruitful basis of assessing parents' needs and worries as the basis for providing support what they need.

Child Abuse Potential in Young German Parents: Predictors, Associations with Self-reported Maltreatment and Intervention Use.

Since child maltreatment has highly negative effects on child adjustment, early identification of at-risk families is important. This study focuses on longitudinal risk factors for child maltreatment and associations between abuse risk and occurrence. It also examines whether abuse risk and involvement in early childhood intervention are associated. The sample comprises 197 German caregivers with children under 3 years of age. Data was collected in two waves. The Brief Child Abuse Potential Inventory assessed abuse risk. Socio-demographic, parent, child and family-related risk factors were measured using screening tools. The analysis revealed that parental characteristics (psychopathology, own maltreatment experiences etc.) were associated with concurrent abuse risk. Longitudinal changes in abuse risk were linked to caregiver education and child-related factors. Cumulative risk did not explain more variance than specific risk factors. Significant associations with caregiver-reported abuse were found, and data suggest that some burdened families cannot be reached by early childhood intervention.

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial.

BACKGROUND: Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS: We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS: Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS: Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused.

New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: Implications for abuse.

Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4-F-PCP and 4-Keto-PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4-F-PCP and 4-Keto-PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self-administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA-related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein, deltaFosB (∆FosB), and brain-derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4-F-PCP and 4-Keto-PCP-induced CPP and self-administration; however, only 4-F-PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4-F- and 4-Keto-induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p-CREB, ∆FosB, and BDNF. The results suggest that 4-F-PCP and 4-Keto-PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.

Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant.

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans.

Pharmacokinetics and Abuse Potential of Asalhydromorphone, a Novel Prodrug of Hydromorphone, After Intranasal Administration in Recreational Drug Users.

OBJECTIVES: Hydromorphone (HM) is a potent µ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. DESIGN: Single-center, randomized, double-blind, crossover study. SETTING: Clinical research site. SUBJECTS: Healthy adult, nondependent recreational opioid users. METHODS: Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. RESULTS: Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on "at-the-moment" (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. CONCLUSIONS: The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study.

OBJECTIVE: To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone. DESIGN: This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non-physically dependent recreational opioid users. SETTING: Inpatient clinical research site. SUBJECTS: Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years). METHODS: The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking "at this moment" (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo. RESULTS: Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone. CONCLUSIONS: NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.

The potent psychomotor, rewarding and reinforcing properties of 3-fluoromethamphetamine in rodents.

3-fluoromethamphetamine (3-FMA), a derivative of methamphetamine (METH), produces behavioral impairment and deficits in dopaminergic transmission in the striatum of mice. The abuse potential of 3-FMA has not been fully characterized. The aim of this study was to evaluate the effects of 3-FMA on locomotor activity as well as its rewarding and reinforcing properties in the conditioned place preference (CPP) and self-administration procedures. Intravenous (i.v.) administration of 3-FMA (0.5 and 1.0 mg/kg) significantly increased locomotor activity in a dose-dependent manner in rats. In the CPP procedure, intraperitoneal administration of 3-FMA (10 and 30 mg/kg) produced a significant alteration in place preference in mice. In the self-administration paradigms, 3-FMA showed drug-taking behavior at the dose of 0.1 mg/kg/infusion (i.v.) during 2 hr sessions under fixed ratio schedules and high breakpoints at the dose of 0.3 and 1.0 mg/kg/infusion (i.v.) during 6 hr sessions under progressive ratio schedule of reinforcement in rats. A priming injection of 3-FMA (0.4 mg/kg, i.v.), METH (0.2 mg/kg, i.v.), or cocaine (2.0 mg/kg, i.v.) reinstated 3-FMA-seeking behavior after an extinction period in 3-FMA-trained rats during 2 hr session. Taken together, these findings demonstrate robust psychomotor, rewarding and reinforcing properties of 3-FMA, which may underlie its potential for compulsive use in humans.

25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential.

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1 ), dopamine D2 (DRD2 ), and serotonin 2A (5-HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD1 , DRD2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.

The Abuse Potential of Novel Synthetic Phencyclidine Derivative 1-(1-(4-Fluorophenyl)Cyclohexyl)Piperidine (4'-F-PCP) in Rodents.

The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

Cumulative socio-contextual risk and child abuse potential in parents of young children: Can social support buffer the impact?

Child abuse potential refers to characteristics and practices closely linked to child abuse. Past investigations document that the number of risk factors parents experience is a correlate of child abuse potential. The purpose of this investigation was to test a model with multiple domains of risk including cumulative socio-contextual risk, parenting locus of control, children's externalizing behavior problems, social support, and child abuse potential. Using self-report data from eighty-seven mothers of children between the ages of 1-5 years old, bivariate correlations and linear regression analyses revealed that cumulative socio-contextual risk was positively associated with child abuse potential and that this association remained statistically significant when controlling for parenting locus of control and child externalizing behavior problems. Additionally, social support moderated the association between cumulative risk and child abuse potential.

The nexus of opioids, pain, and addiction: Challenges and solutions.

Pain and addiction are complex disorders with many commonalities. Beneficial outcomes for both disorders can be achieved through similar principles such as individualized medication selection and dosing, comprehensive multi-modal therapies, and judicious modification of treatment as indicated by the patient's status. This is implicit in the term "medication assisted treatment" (MAT) for opioid use disorders (OUD), and is equally important in pain management; however, for many OUD and pain patients, medication is central to the treatment plan and should neither be denied nor withdrawn if critical to patient well-being. Most patients prescribed opioids for pain do not develop OUD, and most people with OUD do not develop it as a result of appropriately prescribed opioids. Nonetheless, concerns about undertreatment of pain in the late 20th century likely contributed to inappropriate prescribing of opioids. This, coupled with a shortfall in OUD treatment capacity and the unfettered flood of inexpensive heroin and fentanyl, behavioral economics and other factors facilitated the 21st century opioid epidemic. Presently, injudicious reductions in opioid prescriptions for pain are contributing to increased suffering and suicides by pain patients as well as worsening disparities in pain management for ethnic minority and low-income people. Many of these people are turning to illicit opioids, and no evidence shows that the reduction in opioid prescriptions is reducing OUD or overdose deaths. Comprehensive, science-based policies that increase access to addiction treatment for all in need and better serve people with pain are vital to addressing both pain and addiction.

Syringeability of morphine ARER, a novel, abuse-deterrent, extended-release morphine formulation.

Background: Extended-release (ER) morphine formulations are commonly manipulated for non-oral routes of administration, particularly via injection. Morphine ARER, an abuse-deterrent formulation of ER morphine, has both physical and chemical properties that deter abuse. Objectives: To assess the syringeability of morphine ARER using in vitro laboratory studies. Methods: Intact, cut, or crushed morphine ARER tablets were incubated in 1, 5, or 10 mL of room temperature or 90°C water for 1, 5, 10, or 30 min of agitation. Crushed ER morphine tablets were assessed in 10 mL room temperature water. The difficulty to draw the mixture into a syringe was assessed on a scale of 1 (very easy) to 10 (impossible). If the prepared mixture was syringeable, released morphine was measured analytically. Results: Crushed and cut morphine ARER tablets formed a viscous material when subjected to a liquid environment and were rated as "impossible to syringe" in ≤5 mL water and were slightly syringeable in 10 mL water. In contrast, all syringeability tests of crushed ER morphine were rated as "very easy to syringe". After 30 min in room temperature water, crushed ER morphine released 75% morphine whereas intact, cut, and crushed morphine ARER tablets released a maximum of 12%, 12%, and 5% of the total morphine content. Heating extractions resulted in increased morphine release. Conclusion: The difficulty to syringe morphine ARER when manipulated suggests that morphine ARER has abuse-deterrent properties that may deter intravenous abuse.

Associations between child physical abuse potential, observed maternal parenting, and young children's emotion regulation: Is participation in Early Head Start protective?

Clinicians working with Early Head Start (EHS) families consider family well-being and positive parent-child relationships as foundational to school readiness. Understanding the links between risk factors and these dimensions of family engagement can inform clinical decision-making, as risk assessments are used to tailoring program services. The current study examined the associations between high risk, or potential, for child physical abuse and both parenting quality and children's emotion regulation (ER) during toddlerhood; EHS participation was examined as a buffer. The sample included EHS-eligible mothers of infants (N = 80) drawn from one site of the EHS Research and Evaluation Project. Associations were tested between mothers' potential for child physical abuse, measured during infancy, and observed maternal sensitivity, positive regard, harshness, and children's ER skills at child ages 1 and 2 years. Results indicated that high potential for child physical abuse was associated with lower positive regard at age 1 and lower ER skills at age 2. EHS participation operated as a buffer on each of these associations. Implications for screening for child physical abuse potential and the constructs it represents in clinical settings as well as how EHS can promote family engagement are discussed.

Los clínicos que trabajan con familias del Programa de Comienzo Temprano (Early Head Start - EHS) consideran el bienestar familiar y las positivas relaciones entre progenitor y niño como aspectos fundamentales para estar listo para la escuela (US DHHS, 2011). El poder comprender las conexiones entre los factores de riesgo y estas dimensiones de la participación familiar puede servir de base para la toma de decisiones clínicas, ya que las evaluaciones de riesgo se usan para amoldar los servicios del programa. El presente estudio examinó las asociaciones entre el alto riesgo, o riesgo potencial, del abuso físico del niño y tanto la calidad de la crianza como la regulación de la emoción por parte del niño durante la primera etapa de la niñez; se examinó la participación en EHS como mediadora. El grupo muestra incluía madres de infantes elegibles para EHS (N = 80) quienes formaban parte de un mismo Proyecto de Investigación y Evaluación del Programa de Comienzo Temprano. Se pusieron a prueba las asociaciones entre el potencial de las madres de abuso físico del niño, medidas durante la infancia, y las observaciones de sensibilidad materna, consideraciones positivas, dureza, y las habilidades de regulación de la emoción del niño a la edad de 1 y 2 años del niño. Los resultados indicaron que el alto potencial de abuso físico del niño estaba asociado con más bajas consideraciones positivas a la edad de 1 año, así como con las más bajas habilidades de regulación de la emoción a la edad de 2 años. La participación en EHS funcionó como mediadora en cada una de estas asociaciones. Se discuten las implicaciones para detectar el potencial de abuso físico del niño y la estructura que representa en escenarios clínicos, y también cómo EHS puede promover la participación familiar.

Les cliniciens travaillant avec des familles du programme américain de Early Head Start (EHS) familles considèrent le bien-être familial et des relations parent-enfants positives comme étant les fondations de la préparation au cadre scolaire (US DHHS, 2011). Le fait de comprendre les liens entre les facteurs de risque et ces dimensions de l'engagement familial peut informer la prise de décision clinique, comme les évaluations de risque sont utilisées pour adapter les services de programmes. Cette étude s'est penchée sur les liens entre le risque élevé, ou potentiel, de maltraitance physique de l'enfant et à la fois la qualité du parentage et la régulation d'émotion des enfants durant la petite enfance; la participation à l'EHS étant examinée comme tampon. L'échantillon a inclus des mères de nourrissons étant admissible à l'EHS (N = 80), tiré d'un site du Projet de Recherche et d'Evaluation du EHS. Les associations ont été testées entre le potentiel de maltraitance physique de l'enfant par les mères, mesuré durant la très petite enfance, et la sensibilité maternelle observée, l'égard positif, la dureté, et les compétences de régulation de l'émotion des enfants aux âges de 1 et 2 ans. Les résultats indiquent qu'un fort potentiel de maltraitance de l'enfant était lié à un égard positif plus bas à l'âge de 1 ans, et à des compétences de régulation de l'émotion moins élevées à l'âge de 2 ans. La participation à l'EHS a servi de tampon dans chacune de ces associations. Les implications pour le dépistage de potentiel de maltraitance physique de l'enfant et pour les constructions qu'il représente dans les contextes cliniques, ainsi que la manière dont l'EHS peut promouvoir un engagement familial sont discutées.

Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies.

Providers who treat patients with chronic pain face a dual challenge: providing adequate access to opioid therapies for appropriate pain management while adopting strategies to minimize the risk for abuse. Commonly prescribed opioids have substantial abuse potential when administered intravenously, and extended-release (ER)/long-acting (LA) opioids may be targeted for IV abuse because of the higher per-dose medication level. The consequences of IV opioid abuse are severe and increase the risks for adverse outcomes, including mortality due to acute health events, serious infections, and deep vein thrombosis, to name a few. To reduce the potential for abuse of prescription opioids by both recreational and experienced drug abusers, abuse-deterrent formulations (ADFs) of opioid medications employ either physical/chemical barriers or agonist-antagonist combinations. Here we review the development and use of opioid ADFs as a harm-reduction strategy, and their potential for mitigating IV opioid abuse. The approved ER/LA opioids with ADF labeling in the United States include formulations of oxycodone, hydrocodone, and morphine. Findings from in vitro laboratory tests of abuse deterrence for opioid ADFs are described herein, as are data from human abuse potential studies for IV abuse of those ADF products, for which such studies are feasible (ie, abuse-deterrent agonist-antagonist formulations). The available ADF opioids may decrease both the attractiveness and the feasibility of IV abuse. The adoption of ADF opioids represents one tactic for providing access to needed medication for patients with chronic pain, while potentially reducing the risk for opioid abuse, in a comprehensive effort to combat the opioid epidemic.