Social and economic inequalities in fatal opioid and cocaine related overdoses in Luxembourg: A case–control study

BackgroundTo investigate social and economic inequalities in fatal overdose cases related to opioid and cocaine use, recorded in Luxembourg between 1994 and 2011.MethodsCross-examination of national data from law enforcement and drug use surveillance sources and of forensic evidence in a nested case–control study design. Overdose cases were individually matched with four controls, when available, according to sex, year of birth, drug administration route and duration of drug use. 272 cases vs 1056 controls were analysed. Conditional logistic regression analysis was performed to assess the respective impact of a series of socioeconomic variables.ResultsBeing professionally active [OR = 0.66 (95% CI 0.45–0.99)], reporting salary as main legal income source [OR = 0.42 (95% CI 0.26–0.67)] and education attainment higher than primary school [OR = 0.50 (95% CI 0.34–0.73)] revealed to be protective factors, whereas the professional status of the father or legal guardian of victims was not significantly associated to fatal overdoses.ConclusionsSocioeconomic inequalities in drug users impact on the occurrence of fatal overdoses. Compared to their peers, users of illicit drugs with lower socioeconomic profiles show increased odds of dying from overdose. However, actual and self-referred socioeconomic characteristics of drug users, such as educational attainment and employment, may have a greater predictive value of overdose mortality than the parental socioeconomic status. Education, vocational training and socio-professional reintegration should be part of drug-related mortality prevention policies.     

Changes in the prevalence and correlates of cocaine use and cocaine use disorder in the United States, 2001–2002 and 2012–2013

To present nationally representative data on changes in the prevalences of 12-month cocaine use, cocaine use disorder (CocUD) and 12-month CocUD among 12-month cocaine users between 2001 and 2002 and 2012–2013. Data were derived from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the 2012–2013 NESARC-III. Between 2001 and 2002 and 2012–2013, prevalences of 12-month cocaine use and DSM-IV CocUD significantly increased and 12-month CocUD among 12-month users significantly decreased. Increases in risk of cocaine use were seen across nearly all sociodemographic subgroups while increases in CocUD were observed among women, those in the oldest age group, Whites, individuals with the lowest incomes and highest education, and those residing in urban areas. Prevalence of CocUD among users significantly declined overall and among men, individuals aged 30–44 years old, the never-married, respondents with incomes between $20,000 and $34,000, and those residing in the Midwest. Increases in coca cultivation in Colombia in recent years together with increases in the purity of cocaine entering the U.S. portend more significant increases in the rates of cocaine use and CocUD in the U.S. along with increases in cocaine-related morbidity and mortality. The results of this study support the continued monitoring of cocaine use and CocUD in the U.S., especially in view of the narrowing of the gender gap and shifts in race-ethnic, age and socioeconomic differentials seen between 2001 and 2002 and 2012–2013.     

Patterns of cocaine and opioid co-use and polyroutes of administration among street-based cocaine users in Montréal,Canada

BackgroundEffective public health programs aimed at problematic cocaine users are challenged by the fact that they can have complex patterns of drug use with respect to polysubstance use and routes of drug administration. This study was carried out to explore the presence of subgroups of cocaine users on the basis of their concurrent use of opioids and their routes of cocaine and opioid administration, and to determine if subgroups could be differentiated in terms of sociodemographic factors and risk behaviours.MethodsRegular cocaine users (≥1 per week) were recruited in low-threshold services located in the Montréal downtown area. The following variables were examined: demographic characteristics, types of drug used, routes of drug administration, and condom use with occasional or commercial sexual partners. Latent class analysis and multinomial logistic regression modeling were carried out.Results886 cocaine users were recruited (83.5% male: mean age 35.38 years). A 5-class model was identified: (1) “cocaine smokers” (CSs) (n = 161; membership probability (MP) = 0.183); (2) “cocaine smokers/sniffers” (CSSs) (n = 201; MP = 0.218); (3) “cocaine injectors” (CIs) (n = 207; MP = 0.231); (4) “cocaine-opioid injectors” (COIs) (n = 277; MP = 0.291); (5) “cocaine-opioid polyroute users” (COPs) (n = 40; MP = 0.077). Compared with COIs, other subtypes were significantly different in terms of either age, duration of cocaine use, ethnic background, homelessness, polydrug use or condom use.ConclusionThe heterogeneity of consumption patterns supports the importance of offering an array of interventions aimed at problematic cocaine users. These should include the provision of clean injecting and smoking material, the promotion of safe sexual behaviours and the prevention of initiation to drug injection. In the absence of specific treatment, cocaine users should have access to primary health care services and addiction treatment based on innovative behavioural and pharmacological approaches.     

Rewarding effects of ethanol and cocaine in µ opioid receptor-deficient mice

To investigate the role of mu opioid receptors in the reinforcing effects of psychotropic drugs, the voluntary ethanol intake and ethanol- and cocaine-induced conditioned place preference in mu opioid receptor-deficient mice and their wild-type counterpartners was tested. Moreover, dopamine D1 and D2 receptor binding was measured. It was found that ethanol intake was significantly lower in deficient mice. Conditioned place preference in wild-type animals was induced with 5.0 mg/kg cocaine and this dose was ineffective in the knockouts. In this group conditioned place preference occurred after injection of 10.0 mg/kg cocaine. Cocaine induced a similar increase in locomotor activity in both groups of mice. There was no difference in dopamine D1 receptor binding, whereas dopamine D2 receptor binding was significantly lower in the hippocampus of deficient animals. This suggests that interaction between opioid systems and dopaminergic systems may account for the differences in responding to the drugs.     

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the μ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.     

The effects of dopamine D1 and D2 receptor antagonists on the rewarding effects of δ1 and δ2 opioid receptor agonists in mice

The effects of the dopamin D₁ antagonist SCH23390 and the D₂ antagonist sulpiride on the rewarding effects of opioid receptor agonists were examined in mice. Both [d-Pen², Pen⁵]enkephalin (DPDPE, 1–15 nmol, ICV), a selective ₁ opioid receptor agonist, and [d-Ala²]deltorphin II (DELT, 0.5–5 nmol, ICV), a selective ₂ opioid receptor agonist, produced a dose-dependent place preference in mice. The DPDPE (15 nmol, ICV)-induced place preference was abolished by BNTX (0.5 mg/kg, SC), a ₁ opioid receptor antagonist, but not by NTB (0.5 mg/kg, SC), a ₂ opioid receptor antagonist. In contrast, the DELT (5 nmol, ICV)-induced place preference was antagonized by NTB, but not BNTX. Pretreatment with SCH23390 (3 µg/kg, SC) abolished the DPDPE-induced place preference, but not affect the DELT-induced place preference. Moreover, pretreatment with sulpiride (40 mg/kg, SC) did not modify the place preference induced by DPDPE or DELT. In the present study, we found that the activation of both central ₁ and ₂ opioid receptors produced rewarding effects. Furthermore, these results suggest that the rewarding effects of ₁ opioid receptor agonist may be produced through activation of the central dopaminergic system, especially dopamine D₁ receptors, whereas the rewarding effects of ₂ opioid receptor agonists may be produced by some other mechanism(s).     

Chronic food restriction in rats augments the central rewarding effect of cocaine and the δ1 opioid agonist, DPDPE, but not the δ2 agonist, deltorphin-II

RATIONALE: There is some, albeit conflicting, evidence that 5-HT3 receptors might be involved in the actions of abused stimulants. Most studies have focussed on examinations of 5-HT3 antagonists; this might be due to a lack of high-affinity 5-HT3 agonists that readily penetrate the blood-brain barrier. OBJECTIVES: N-(3-Chlorophenyl) guanidine (MD-354) is a member of a novel class of 5-HT3 ligands developed in our laboratories. We have previously demonstrated that MD-354 can exert agonist effects and now further explore this action. METHODS: Rats (n=9) were trained to discriminate 2 mg/kg MD-354 from saline vehicle in a two-lever drug discrimination task (VI-15 s schedule of reinforcement). The actions of agents with 5-HT3 character were evaluated. The emetic and antiemetic actions of MD-354 were also examined using the shrew as test subject. RESULTS: Various agents with demonstrated 5-HT3 agonist properties substituted for the MD-354 stimulus (MD-354 ED50=0.5 mg/kg): quipazine (ED50=0.2 mg/kg), meta-chlorophenylbiguanide (mCPBG, ED50=1.4 mg/kg), 2-methyl 5-HT (ED50=4.5 mg/kg), 1-(2-naphthyl)biguanide (2-NBG, ED50=1.9 mg/kg), and N-(2-naphthyl)guanidine (2-NG, ED50=0.7 mg/kg). Administration of the training dose of MD-354 in combination with the 5-HT3 antagonists zacopride and tropisetron resulted in stimulus antagonism (AD50=0.02 mg/kg); administered alone, however, zacopride engendered 81% MD-354-appropriate responding (ED50=0.03 mg/kg). MD-354 was shown to produce an emetic effect in the shrew at very high doses (i.e., 40 mg/kg); however, when administered in combination with cisplatin, MD-354 behaved as an antiemetic agent at 10 mg/kg. CONCLUSION: Taken together, the results indicate that MD-354 is a 5-HT3 agonist and that it might be an agent with partial agonist activity.     

When does the cutting of cocaine and heroin occur? The first large-scale study based on the chemical analysis of cocaine and heroin seizures in Switzerland

BackgroundIllicit drug profiling can provide knowledge about illicit drug markets, informing on the level of distribution and its evolution in space and time. Illicit drug profiling is usually limited to impurities originally present in the illicit drug (e.g. alkaloids, co-extracted compounds or by-products). However, the benefit of a comprehensive analysis of cutting agents in drug seizures for law enforcement agencies, intelligence and health policy has not been thoroughly investigated in the literature and is the focus of this research.AimThis research aims at assessing when and how cutting (i.e. adulteration and dilution) occurs in the supply chain by analysing cocaine and heroin seizures made between 2006 and 2015 in Switzerland.MethodsCocaine and heroin seizures made along the supply chain by law enforcement agencies in the Western region of Switzerland were investigated for adulteration and dilution. A total number of 7841 cocaine and 3476 heroin specimens coming from 1341 and 721 seizures, respectively, were analysed.ResultsThe results show that, for both illicit drugs, adulteration and/or dilution occur before arrival into Switzerland as well as in Switzerland. While cocaine is adulterated and diluted, heroin is only adulterated. Interestingly, the same mixture of adulterants (i.e. caffeine-paracetamol) is used to cut heroin at each step in the supply chain.ConclusionGaining knowledge about adulteration and dilution at different stages in the supply chain enhances our understanding of drug markets. It also highlights differences along the supply chain and in the distribution of both drugs in Switzerland.     

Possible involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin

In the present study, we attempt to analyse the potential involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin. A trauma-pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. Antinociception was determined by tail-flick latency to hot waster at 50℃. Melatonin produced the antinociceptive effect in dose-dependent manner after i. p or i. c.v. administration Injected i. c. v. to rats, naloxone（10μg） obviously antagonized the antinociceptive effect induced by i.p. melatonin.     

The role of the dynorphin/κ opioid receptor system in anxiety

Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders.     

Comparison of the opioid receptor antagonist properties of naltrexone and 6 beta-naltrexol in morphine-naïve and morphine-dependent mice

It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In na?ve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.     

Importance of sex and relative efficacy at the µ opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids

RATIONALE: Recent studies indicate that mu opioids are generally more potent and effective as antinociceptive agents in male than female rodents. OBJECTIVES: To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower efficacy mu opioids buprenorphine and dezocine in F344 and Lewis rats. METHODS: Using a warm-water tail-withdrawal procedure, the antinociceptive effects of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administration. RESULTS: Under acute conditions, morphine was more potent in males and during chronic morphine administration tolerance development was generally greater in males. As males were more sensitive to the acute effects of morphine, the functional chronic morphine dose (i.e., chronic morphine dose/acute morphine ED50) administered to males was larger than in females. Analyses of the relationship between the functional chronic morphine dose and tolerance indicated that morphine tolerance development was comparable in males and females. Under acute conditions, buprenorphine and dezocine were more potent and effective in males. During chronic morphine administration, cross-tolerance was conferred to these opioids as evidenced by rightward, and in some cases downward, shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more frequently observed in females. CONCLUSIONS: That comparable levels of morphine tolerance were obtained in males and females when the functional chronic morphine dose was taken into consideration suggests that the mechanism underlying tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic morphine administration further suggest that these opioids have lower efficacy at the mu opioid receptor in females.     

Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor

RATIONALE: Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys. OBJECTIVES: To evaluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception. METHODS: Antinociceptive testing was conducted using a rat warm-water (50-56 degrees C) tail-withdrawal procedure. Dose-response and time-course determinations were performed with various opioids. RESULTS: Across the nociceptive stimulus intensities tested, the high-efficacy mu opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females. CONCLUSIONS: That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of mu opioids as antinociceptive agents is greater in male than female rats.     

Effectiveness of nalbuphine,a κ-opioid receptor agonist and μ-opioid receptor antagonist,in the inhibition of INa,IK(M), and IK(erg) unlinked to interaction with opioid receptors

Nalbuphine (NAL) is recognized as a mixer with the κ-opioid receptor agonist and the μ-opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE-14 hippocampal neurons were investigated. In the whole-cell current recordings, NAL suppressed the peak amplitude of voltage-gated Na⁺ current (I_Na) with an IC₅₀ value of 1.9 μM. It shifted the steady-state inactivation curve of peak I_Na to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL-mediated inhibition of peak I_Na. In continued presence of NAL, subsequent application of either dynorphin A_1-13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak I_Na. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate I_Na, increased peak I_Na with slowed current inactivation; however, further application of NAL suppressed Tef-mediated suppression of peak I_Na followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M-type K⁺ current [I_K(M)] with an IC₅₀ value of 5.7 μM, while it slightly suppressed erg-mediated and delayed-rectifier K⁺ currents. In the inside-out current recordings, NAL failed to modify the activity of large-conductance Ca²⁺-activated K⁺ channels. In differentiated NG108-15 neuronal cells, NAL also suppressed the peak I_Na, and subsequent addition of Tef reversed NAL-induced suppression of I_Na. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including I_Na and I_K(M), thereby influencing the functional activities of central neurons.     

Itai-itai disease is not associated with polymorphisms of the estrogen receptor α gene

Itai-itai (or ouch-ouch) disease is a syndrome accompanied by bone mineral disorders, and which may be related to oral cadmium exposure. Itai-itai predominantly affects postmenopausal women with a history of multiple childbirths. Recently, it has been reported that polymorphisms of the estrogen receptor α (ERα) gene are associated with postmenopausal reduction of bone mineral density in Japanese women. However, estrogen receptors have never been studied in itai-itai disease. In this study, we examined the genotypic distributions of PvuII and XbaI restriction fragment length polymorphisms (RFLPs) of the ERα gene in patients with itai-itai disease and compared them with those of control subjects. The RFLPs are represented here as Pp (PvuII) and Xx (XbaI); the capital and small letters signify the absence and presence of restriction sites, respectively. The genotypic distributions of the patient group were: PP, 14.8%; Pp, 55.6%; pp, 29.6%; XX, 7.4%; Xx, 29.6%; and xx, 63.0%. These distributions were similar to those observed for the control groups, hence no pattern of genotypic distribution was observed that could be related to itai-itai disease. We conclude that RFLPs of the ERα gene may not be associated with itai-itai disease. Received: 4 May 1999 / Accepted: 16 August 1999     

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

RATIONALE: We previously demonstrated that the prototypical kappa-opioid receptor agonist U-50,488H did not affect the discriminative stimulus effects of cocaine, and the dose of U-50,488H which significantly induced aversive effects attenuated the rewarding effects of cocaine. OBJECTIVES: In the present study, the effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine were examined in rats. METHODS: In the drug discrimination procedure, the effects of TRK-820 on the discriminative stimulus effects of cocaine were examined in rats that had been trained to discriminate between 10 mg/kg cocaine and saline. TRK-820-induced place preference or place aversion and the effects of TRK-820 on the cocaine (4 mg/kg)-induced place preference were examined using a conditioned place preference procedure in rats. RESULTS: TRK-820 did not engender cocaine-like responding in rats trained to discriminate between 10 mg/kg cocaine and saline. In combination tests, low doses of TRK-820, which did not affect the response rate, significantly attenuated the discriminative stimulus effects of cocaine, and these effects of TRK-820 were reversed by a kappa-opioid receptor antagonist, nor-BNI. In the conditioned place preference procedure, low doses of TRK-820, which did not affect the response rate in the drug discrimination, did not produce either place preference or place aversion, whereas, higher dose (80 microg/kg) of TRK-820 slightly but significantly induced a place aversion. Under these conditions, the cocaine-induced place preference was completely attenuated by low doses of TRK-820. These results may prompt further investigation of the effectiveness of the new kappa-opioid receptor agonist TRK-820 as a novel pharmacotherapeutic compound for the treatment of cocaine addiction.     

Antidepressants and psychostimulants in pediatric populations: is there an association with mania?

This article reviews the literature that examines whether exposure to psychostimulants or antidepressants precipitates or exacerbates manic symptoms, or decreases the age at onset of mania in pediatric populations. A PubMed search using relevant key words identified studies targeting five distinct clinical groups: (i) youth without a diagnosis of bipolar disorder (BD) at the time of exposure to psychostimulants; (ii) youth with a diagnosis of BD at the time of exposure to psychostimulants; (iii) youth without a diagnosis of BD at the time of exposure to antidepressants; (iv) youth with a diagnosis of BD at the time of exposure to antidepressants; and (v) youth who develop BD after exposure to these medications. In patients with attention-deficit hyperactivity disorder (ADHD), the risk for mania was found to be relatively low with the use of psychostimulants. For patients with BD and ADHD, effective mood stabilization is important prior to adding a stimulant. For children with depression and/or anxiety, the risk of antidepressant-induced mania (AIM) was generally low (<2%), but the risk of general 'activation' secondary to a selective serotonin reuptake inhibitor (SSRI) may be greater (2-10%). However, rates of AIM in specialty clinics appear to be much higher. SSRIs may be particularly problematic in specific populations, such as those with some symptoms of mania or a family history of BD, but the precise risk is unknown. There is no clear evidence that stimulants or SSRIs accelerate the natural course of BD development in overall samples, but in individual cases prescribers should proceed cautiously when using these agents in youth already at risk for developing BD, such as those with ADHD and mood dysregulation, a history of prior AIM, a history of psychosis, or a family history of BD.