The autoimmune nature of morphine addiction.

The onset of the disease as a morphine addiction is associated with the appearance in the patient's body of antibodies directed against opiate receptors (ORs). Once anti-opiate receptor antibodies (anti-OR antibodies) appear in the blood they will tend to bind to ORs. Such binding will cause blocking of physiological functions of OR. The blockage is felt by a morphine addict as withdrawal syndrome. To get rid of this harmful condition, the addict increases the dose of morphine taken. This is where tolerance manifests itself. The drug addict is forced to increase the dose of morphine from time to time because of the body responds by producing the more and more anti-OR antibodies. The immunological nature of morphine addiction is the reason for lifelong changes in the body's reactivity to the drug. An addict can be cured if he gets rid of B- and T-memory cells, which specifically react to ORs.

Neuroimaging of opioid effects in humans across conditions of acute administration, chronic pain therapy, and opioid use disorder.

Evidence of central nervous system (CNS) exogenous opioid effects in humans has been primarily gained through neuroimaging of three participant populations: individuals after acute opioid administration, those with opioid use disorder (OUD), and those with chronic pain receiving opioid therapy. In both the brain and spinal cord, opioids alter processes of pain, cognition, and reward. Opioid-related CNS effects may persist and accumulate with longer opioid use duration. Meanwhile, opioid-induced benefits versus risks to brain health remain unclear. This review article highlights recent accumulating evidence for how exogenous opioids impact the CNS in humans. While investigation of CNS opioid effects has remained largely disparate across contexts of opioid acute administration, OUD, and chronic pain opioid therapy, integration across these contexts may enable advancement toward effective interventions.

Brain-derived neurotrophic factor serum levels as a candidate biomarker for withdrawal in crack heroin dependence.

BACKGROUND: Crack heroin is a novel opiate derivative with highly addictive properties and unfamiliar health consequences. It causes a variety of brain dysfunctions that are mediated by neurochemical alterations and abnormal neuroplasticity. Brain-derived neurotrophic factor (BDNF) is a widely recognized biological marker implicated in the neuropathology of substance use during substance use disorder and withdrawal. Its involvement can significantly contribute to the severity of withdrawal symptoms. Hence, this study aimed to evaluate BDNF levels in crack heroin users before and after withdrawal. METHODS: In this cross-sectional study, 148 male participants were recruited and divided into two groups: persons with crack heroin use disorder (n = 74) and the controls (n = 74). The BDNF serum levels were measured in both crack heroin users and control groups upon hospitalization and again after twenty-one days of withdrawal using the enzyme-linked immunosorbent assay. RESULTS: The results demonstrated that BDNF levels in persons with crack heroin use disorder upon admission were significantly lower than the levels observed upon discharge and in the control group (p < 0.05). Additionally, a significant difference in BDNF levels was found between persons with crack heroin use disorder at admission and discharge (p = 0.038). Furthermore, BDNF levels showed an inverse correlation with the daily dose of substance use (r= -0.420, p = 0.03) and the duration of crack heroin use (r= -0.235, p = 0.001). CONCLUSIONS: A progressive increment in BDNF levels during early detoxification is associated with the daily amount of substance use and the duration of substance use. Our findings suggest that changes in BDNF serum levels during crack heroin use disorder and withdrawal could serve as potential biomarkers for assessing the intensity of withdrawal symptoms and substance use-related behaviors.

Male and female rats show opiate withdrawal-induced place aversion and extinction in a Y-maze paradigm.

Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.

Involvement of the transient receptor potential A1 in morphine-induced conditioned place preference and physical dependence in mice.

The main side effects of opioid use are physiological and psychological dependence. The transient receptor potential channels, including transient receptor potential ankyrin 1 (TRPA1), are involved in various neurological disorders. We aimed to evaluate the effect of TRPA1 inhibition on morphine-induced conditioned place preference (CPP) and physical dependence. For induction of CPP, morphine (10 and 20 mg/kg) was administrated for four consecutive days to male BALB/c mice. The effects of HC030031 (TRPA1 antagonist, 10, 25, and 50 mg/kg) on the expression and reinstatement of morphine-induced CPP were evaluated. For induction of physical dependence, morphine was injected three times a day for 3 days. Withdrawal-related behaviors such as jumping and defecation were precipitated by the administration of naloxone to morphine-dependent mice. The effect of HC030031 on jumping and defecation was assessed. The results showed that 20 mg/kg of morphine elicited a significant CPP. HC030031 reduced the expression of morphine CPP without any change in the locomotor activity. It also decreased the reinstatement of morphine CPP. HC030031 mitigated morphine withdrawal via reducing jumping and defecation. The present study demonstrated that HC030031 decreased morphine-associated CPP and physical dependence. It is presumed that TRPA1 has interaction with the main pharmacological effects of morphine.

A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients.

PURPOSE: The full potential of methadone maintenance treatment (MMT) is often limited by the large inter-individual variability in both pharmacokinetics (PK) and pharmacodynamics (PD), and by the risk of torsade de pointes, a severe adverse effect caused by QTc prolongation. The current study aims to quantitate the contribution of genetic polymorphisms and other variables in PK/PD variability, and their contribution to the QTc interval prolongation in Chinese MMT patients. METHODS: Population PK models were developed to fit (R)- and (S)-methadone PK data. Hierarchical models were tested to characterize the PK profile, the concentration-QTc relationship, and concentration-urinalysis illicit drug testing relationship, with demographics and genetic variants being included as covariates. Simulation based on the developed PK/PD models was performed to assess the effect of methadone dose and genetic variants on QTc interval prolongation. RESULTS: The PK data were best-fit by a one-compartment, first-order absorption model. Clearance of (R)- and (S)-methadone was both affected by the weighted activity score derived from genetic variants. A linear model was used to describe both the methadone concentration-urinalysis illicit drug testing relationship and the methadone concentration-QTc relationship. Concentration of (R)- and (S)-methadone exhibits a comparable effect on QTc prolongation. Simulation showed that the percentage of QTc higher than 450 ms was almost doubled in the lowest clearance group as compared the highest when methadone dose was greater than 120 mg. CONCLUSIONS: The large variability in PK/PD profiles can be partially explained by the genetic variants in an extent different from other population, which confirmed the necessity to conduct such a study in the specific Chinese patients.

Prospective Study on Factors Associated with Referral of Patients with Opioid Maintenance Therapy from Specialized Addictive Disorders Centers to Primary Care.

Background: One of the most important issues for opiate maintenance therapy efficacy is the involvement of primary care physicians (PCPs) in opiate use disorder treatment, especially after referral from specialized units. This study aimed to analyze the progress of subjects in a specialized center and after referral to PCPs. Methods: This study was an observational prospective study. Recruitment took place in a specialized addictive disorder center in western France. All patients were evaluated (sociodemographical data, severity of substance use disorders through the TMSP scale, the quality of life through the TEAQV scale) by physicians during the 5-year-follow up of the study. Analysis focused on four main times during follow-up: entry/last visit into specialized care and into primary care. Results: 113 patients were included in this study; 93% were receiving methadone and 7% buprenorphine. Ninety (90) were referred to primary care. In primary care follow-up, the probability of the lowest severity score for substance use disorders remained stable over time. Conclusions: In daily practice, a center specialized in addictive disorders referred OMT management to PCPs for a majority of patients, and benefits regarding substance use disorders severity and quality of life remained stable after referral. Our results need to be confirmed.

Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; An fMRI study.

BACKGROUND: Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. METHODS: This study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.

Tobacco use disorder: Prevalence, associated factors and its influence on quality of life among patients on methadone assisted treatment.

Background and Objectives: Smoking is the primary cause of preventable death and is highly prevalent among patients on methadone assisted treatment (MAT). This study aims to assess the prevalence of tobacco use disorder (TUD) among patients on MAT, the factors associated with TUD, and to examine the association between TUD and quality of life.Methods: A total of 171 male patients receiving MAT in two Malaysian government hospitals were assessed for TUD, levels of nicotine dependence, relevant associated factors and quality of life using DSM-5 criteria, Fagerström Test for Nicotine Dependence (FTND), Opiate Treatment Index (OTI), Mini-International Neuropsychiatric Interview (M.I.N.I.) and World Health Organization Quality of Life (WHOQOL)-BREF.Results: The prevalence of TUD was 81.3%. Being employed was significantly associated with having a TUD. Among the patients with TUD, the mean FTND score was 3.8 (SD ± 2.0). Being younger, having poorer social function, and presence of current opioid dependence were significantly correlated with higher FTND scores. There was no significant difference in the quality of life between patients with and without TUD. Following multiple linear regression analysis, being unmarried and poor health status were the two factors that significantly predicted a lower quality of life in all four domains of WHOQOL-BREF.Conclusions: Given the high prevalence of TUD among methadone-assisted patients, smoking cessation treatment should be integrated into the MAT program in Malaysia. Also, addressing patients' marital and health issues during MAT can be instrumental in improving their quality of life.

Negative Mood Induction Increases Choice of Heroin Versus Food Pictures in Opiate-Dependent Individuals: Correlation With Self-Medication Coping Motives and Subjective Reactivity.

Acute growth in negative affect is thought to play a major role in triggering relapse in opiate-dependent individuals. Consistent with this view, three lab studies have demonstrated that negative mood induction increases opiate craving in opiate-dependent individuals. The current study sought to confirm these effects with a behavioral measure of heroin seeking, and test whether the effect is associated with self-reported opiate use to cope with negative affect and subjective reactivity to mood induction. Participants were heroin-dependent individuals engaged with treatment services (n = 47) and control participants (n = 25). Heroin users completed a questionnaire assessing reasons for using heroin: negative affect, social pressure, and cued craving. Baseline heroin choice was measured by preference to enlarge heroin versus food thumbnail pictures in two-alternative forced-choice trials. Negative mood was then induced by depressive statements and music before heroin choice was tested again. Subjective reactivity was indexed by negative and positive mood reported at the pre-induction to post-test timepoints. Heroin users chose heroin images more frequently than controls overall ( p = .001) and showed a negative mood-induced increase in heroin choice compared to control participants (interaction p < .05). Mood-induced heroin choice was associated with self-reported heroin use to cope with negative affect ( p < .05), but not social pressure ( p = .39) or cued craving ( p = .52), and with subjective mood reactivity ( p = .007). These data suggest that acute negative mood is a trigger for heroin seeking in heroin-dependent individuals, and this effect is pronounced in those who report using heroin to cope with negative affect, and those who show greater subjective reactivity to negative triggers. Interventions should seek to target negative coping motives to build resilience to affective triggers for relapse.

Detection of Spatiotemporal Prescription Opioid Hot Spots With Network Scan Statistics: Multistate Analysis.

BACKGROUND: Overuse and misuse of prescription opioids have become significant public health burdens in the United States. About 11.5 million people are estimated to have misused prescription opioids for nonmedical purposes in 2016. This has led to a significant number of drug overdose deaths in the United States. Previous studies have examined spatiotemporal clusters of opioid misuse, but they have been restricted to circular shaped regions. OBJECTIVE: The goal of this study was to identify spatiotemporal hot spots of opioid users and opioid prescription claims using Medicare data. METHODS: We examined spatiotemporal clusters with significantly higher number of beneficiaries and rate of prescriptions for opioids using Medicare payment data from the Centers for Medicare & Medicaid Services. We used network scan statistics to detect significant clusters with arbitrary shapes, the Kulldorff scan statistic to examine the significant clusters for each year (2013, 2014, and 2015) and an expectation-based version to examine the significant clusters relative to past years. Regression analysis was used to characterize the demographics of the counties that are a part of any significant cluster, and data mining techniques were used to discover the specialties of the anomalous providers. RESULTS: We examined anomalous spatial clusters with respect to opioid prescription claims and beneficiary counts and found some common patterns across states: the counties in the most anomalous clusters were fairly stable in 2014 and 2015, but they have shrunk from 2013. In Virginia, a higher percentage of African Americans in a county lower the odds of the county being anomalous in terms of opioid beneficiary counts to about 0.96 in 2015. For opioid prescription claim counts, the odds were 0.92. This pattern was consistent across the 3 states and across the 3 years. A higher number of people in the county with access to Medicaid increased the odds of the county being in the anomalous cluster to 1.16 in both types of counts in Virginia. A higher number of people with access to direct purchase of insurance plans decreased the odds of a county being in an anomalous cluster to 0.85. The expectation-based scan statistic, which captures change over time, revealed different clusters than the Kulldorff statistic. Providers with an unusually high number of opioid beneficiaries and opioid claims include specialties such as physician's assistant, nurse practitioner, and family practice. CONCLUSIONS: Our analysis of the Medicare claims data provides characteristics of the counties and provider specialties that have higher odds of being anomalous. The empirical analysis identifies highly refined spatial hot spots that are likely to encounter prescription opioid misuse and overdose. The methodology is generic and can be applied to monitor providers and their prescription behaviors in regions that are at a high risk of abuse.

Mindfulness-based therapy modulates default-mode network connectivity in patients with opioid dependence.

Recently, mindfulness-based programs have shown promising clinical effects in the treatment of substance-use disorders (SUD). While several studies linked mindfulness to decreased default mode network (DMN) connectivity in meditators, only a few studies investigated its effects in patients with SUD. This study aimed to detect changes in DMN connectivity in opiate dependent patients receiving mindfulness based therapy (MBT) during their first month of treatment. Data from 32 patients that were assigned to MBT or treatment as usual (TAU) groups was investigated using resting-state functional MRI at 1.5 T before and after four weeks of treatment. Independent Component Analysis was used to investigate distinct (anterior vs. posterior) DMN subsystems. Connectivity changes after treatment were related to measures of impulsivity, distress tolerance and mindfulness. Increased mindfulness scores after treatment were found in patients receiving MBT compared to TAU. Within the anterior DMN, decreased right inferior frontal cortical connectivity was detected in patients who received MBT compared to TAU. In addition, within the MBT-group decreased right superior frontal cortex connectivity was detected after treatment. Inferior frontal cortex function was significantly associated with mindfulness measures. The data suggest that MBT can be useful during abstinence from opiates. In opiate-dependent patients distinct functional connectivity changes within the DMN are associated with MBT.

Treatment of opioid dependence with buprenorphine/naloxone sublingual tablets: A phase 3 randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. METHODS: This multicenter, double-blind, placebo-controlled study included four periods: induction (3-5 days), stabilization (7-21 days), randomization/treatment (6 weeks), and postmedication follow-up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self-reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. RESULTS: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26-38) versus 6 days (5-8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21-0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26-38); placebo, 5 days (5-8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25-0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. DISCUSSION: Efficacy and safety results from this clinical trial support a positive benefit-risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid-dependent Chinese population.

Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.

PURPOSE: An oral formulation of methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia. METHODS: This Phase III, randomized, double-blind, placebo-controlled trial, evaluated changes in pain intensity scores (0= no pain to 10= worst possible pain) and opioid use in adults with chronic noncancer pain. Patients taking ≥50 mg/day oral morphine equivalent dose (MED) for ≥14 days before screening with less than three rescue-free bowel movements/week received oral methylnaltrexone 150 mg/day (n=201), 300 mg/day (n=201), 450 mg/day (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed. RESULTS: The primary condition requiring opioid use was back pain (68.2% of 803 patients). Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week as needed (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral methylnaltrexone 150 mg (200.0 mg/day), methylnaltrexone 450 mg (218.0 mg/day), and placebo (209.7 mg/day), but was slightly higher in the oral methylnaltrexone 300-mg group (252.6 mg/day). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of treatment (214.5-235.6 mg/day) and at the end of the as needed phase (202.3-234.9 mg/day). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral methylnaltrexone combined, 10.1%; placebo, 7.0%). CONCLUSION: Oral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

Factors underlying risk taking in heroin-dependent individuals: Feedback processing and environmental contingencies.

Evidence suggests that factors influencing risk-taking include whether decisions are made based on emotions (affective systems) or cognitions (deliberative systems), the processing of feedback (e.g., deciding to attend a rehabilitation facility for opioid addiction treatment after an intervention held by a family member), and attention to environmental contingencies (e.g., considering the probability of an outcome such as the likelihood of contracting tetanus from a shared needle; or the gains and losses associated with a decision, such as the benefits and costs of taking drugs). Although drug-dependent individuals tend to take more risks than non-drug users, the factors underlying risk-taking are unknown. The current study tested, for the first time, the influences of performance feedback (i.e., whether feedback about performance is integrated into decision-making in heroin-dependent individuals) and attention to environmental contingencies (i.e., the influence of the probability of a loss, the gain amount, and the loss amount associated with a scenario) on risk-taking in heroin-dependent individuals. Heroin-dependent patients undergoing maintenance therapy for opioid addiction (n = 25) and healthy controls (n = 27) completed the feedback and no-feedback conditions of the Columbia Card Task (CCT). Analyses of covariance, controlling for education and task design (the order in which the CCT conditions were completed) as covariates revealed a significant interaction between (a) probability, gain and loss amount, and group, and (b) group and probability. Our findings suggest that heroin-dependent patients pay less attention to environmental contingencies during risk-taking than controls. Addressing these factors may facilitate greater adherence to treatment programs and lower rates of relapse.

Mind reading abilities in opiate-dependent patients: An exploratory study.

OBJECTIVES: Impairments in social cognition have been described as playing a major role in the maintenance of addictive behavior in substance abusers. This study aimed to investigate the Theory of Mind (ToM) ability of opiate-dependent (OD) patients and to explore whether TOM ability was correlated with length of substance abuse, age at onset of substance abuse and length of abstinence. METHODS: OD patients (N = 29) and non-dependent individuals (NDI) (N = 29) were submitted to the Theory of Mind Assessment Scale (Th.o.m.a.s.), a semi-structured interview, and to the Versailles-Lecture Intentionnelle en Situation (V-LIS), a movie paradigm in which participants have to infer the characters' intentions. RESULTS: The results confirmed a deficit in ToM ability in OD patients, with OD patients demonstrating poorer performance than NDI on both the V-LIS and the Th.o.m.a.s. The combination of perspective taking and reflecting on others' mental states was particularly difficult for OD patients. Furthermore, impairments in ToM abilities were not correlated with the age at onset of substance abuse or to the duration of substance abuse or abstinence. CONCLUSIONS: The results suggest OD patients may have impaired social cognition, demonstrating deficits in even basic social interaction skills, which may constitute a risk factor for addiction. These findings underline the importance of developing interventions to improve social cognition ability during the rehabilitation of OD patients.

CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward.

The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2-64 mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (∼3.5-fold) morphine-conditioned place preference and maraviroc further potentiated these effects (∼5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24 h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids.

Reward and punishment-based compound cue learning and generalization in opiate dependency.

Substance dependence is thought to be mediated by abnormalities in cognitive abilities, but how this impacts decision-making remains unclear. This study aimed to test whether people who are opiate dependent differed from never-dependent controls in learning from reward and punishment or in the generalization of learning to novel conditions. Participants with opiate dependency consisted of 21 people who were outpatients in a methadone maintenance program; the control group consisted of 21 healthy participants with no histories of substance abuse. Subjects completed a computer-based task that involved two phases: the training phase involved participants being presented with compound stimulus (a shape and color) in each trial, with the goal of learning which compounds to 'pick' for rewards or 'skip' to avoid punishment. The test phase involved a transfer test, where stimuli from the first phase were combined together to form novel compounds without feedback. The control group demonstrated fewer errors compared to opiate-dependent individuals during the training phase. In the test phase, controls used prior knowledge of both shapes and colors in responding; however, opiate-dependent individuals used shapes but did not use their knowledge of color to modulate responding. When performance during training was equated in the groups using a learning threshold, this difference between groups on the generalization test remained. A deficit in learning generalization might be indicative of group differences in learning strategies in operation during training; however, future work is necessary to uncover the specific neural substrates in action during transfer tasks, and to determine the effects of acute methadone dosage on decision-making.

Evaluation of Antioxidant Status, High Sensitivity C-reactive Protein, and Insulin Resistance in Male Chronic Opiate Users Without Comorbidities.

BACKGROUND: There is a paucity of data on frequency of metabolic syndrome (MS), insulin resistance (IR), and oxidative stress in Indian opiate users without comorbidities. OBJECTIVES: To determine the influence of opiate use on frequency of MS, homeostasis model assessment for IR (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), and oxidative stress in opiate-dependent male patients without comorbidities. METHODS: Participants (n = 120) were grouped as controls (Group I), pure opiate dependents (Group II), opiate + tobacco dependents (Group III), and tobacco dependents (Group IV) with a minimum of 1-year dependence participated in the study. Participants were evaluated for anthropometric parameters, blood pressure (BP), fasting blood sugar, insulin, HOMA-IR, lipid profile, hs-CRP, and total antioxidant status (TAS). Frequency of MS was determined based on modified Adult Treatment Panel-III. The data were analyzed using one-way ANOVA, multiple regression by SPSS 21. RESULTS: Frequency of MS in opiate dependents was higher than control. There was a significant difference in serum insulin, HOMA-IR, and TAS levels of the study groups. Multiple regression analysis showed dependence years, body mass index, waist-hip ratio, systolic blood pressure, diastolic blood pressure (DBP), HOMA-IR, and hs-CRP to be significant independent predictors of TAS in Group II and III patients with MS after adjusting for age and education years. TAS and DBP significantly predicted hs-CRP after adjusting for age and education years in Group II and III patients with MS. No such relation was seen in Group I and IV. CONCLUSIONS: Chronic opiate-dependent males without comorbidity are a unique group that shows low-grade inflammation, oxidative stress, and prevalence of MS predisposing them to future risk of cardiovascular diseases.