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...on Medical Aspects
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www.ProjectCork.org
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Summer 2012
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Neonatal drug withdrawal. (review).
Hudak ML; Tan RC. Pediatrics 129(2): article E540-E560, 2012. (165 refs.)
Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives. Copyright 2012, American Academy of Pediatrics.
The impact of cannabis use on cognitive functioning in patients with schizophrenia: A meta-analysis of existing findings and new data in a first-episode sample.
Yucel M; Bora E; Lubman DI; Solowij N; Brewer WJ; Cotton SM et al. Schizophrenia Bulletin 38(2): 316-330, 2012. (79 refs.)
Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use. Copyright 2012, Oxford University Press.
Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection.
Leggio L; Ferrulli A; Zambon A; Caputo F; Kenna GA; Swift RM et al. Addictive Behaviors37(4): 561-564, 2012. (30 refs.)
Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10 mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p = 0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p = 0.0132) and a trend toward a significant reduction in INR levels from baseline (p = 0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients. Copyright 2012, Elsevier Science.
Cerebral effects of binge drinking: Respective influences of global alcohol intake and consumption pattern.
Maurage P; Joassin F; Speth A; Modave J; Philippot P; Campanella S. Clinical Neurophysiology 123(5): 892-901, 2012. (70 refs.)
Objective: Binge drinking is a major health concern, but its cerebral correlates are still largely unexplored. We aimed at exploring (1) the cognitive step at which these deficits appear and (2) the respective influence of global alcohol intake and specific binge-drinking consumption pattern on this deficit. Methods: On the basis of a screening phase (593 students), 80 participants were selected and distributed in four groups (control non-drinkers, daily drinkers, low and high binge drinkers). Event-related potentials (ERPs) were recorded while performing a simple visual oddball task. Results: Binge drinking was associated with massive ERP impairments, starting at the perceptive level (P100/N100 and N170/P2) and spreading through the attentional (N2b/P3a) and decisional (P3b) ones. Moreover, these deficits were linked with global alcohol intake and also with the specific binge-drinking consumption pattern. Conclusions: Binge drinkers presented early and global ERP deficits, affecting basic and high-level cognitive stages. Moreover, we showed that binge drinking is deleterious for the brain because of alcohol consumption per se, and also because of its specific consumption pattern. Significance: The present results show that binge-drinking habits lead to striking brain consequences, particularly because of the repeated alternation between intense intoxications and withdrawal episodes. Copyright 2012, Elsevier Science.
Chronic pain, addiction severity, and misuse of opioids in Cumberland County, Maine.
Heimer R; Dasgupta N; Irwin KS; Kinzly M; Harvey AP; Givens A et al. Addictive Behaviors 37(3): 346-349, 2012. (53 refs.)
Background: Few studies have examined the relationship between chronic pain and opioid abuse in non-clinical populations. We sought to investigate this in a street-recruited sample of active opioid abusers in Cumberland County, Maine. USA, a locale that had experienced substantial increases in opioid abuse. Methods: A community-based sample was recruited using respondent-driven sampling. Participants were screened to identify those who had consumed illicit opioids in the prior month and administered a structured survey that included the Addiction Severity Index (ASI) and Brief Pain Inventory (R) (BPI). Results: More than 40% of the 237 individuals reported recurring pain that interfered with daily living. For more than three-quarters of those reporting chronic pain, opioid misuse preceded the onset of chronic pain. The order of onset was not associated with differences in sociodemographic, current levels of drug misuse. or ASI and BPI scores. BPI scores were associated with medical and psychological ASI domains. Compared to those not reporting chronic pain, those doing so were more likely to have a regular physician but were more likely to report difficulty gaining admission to substance abuse treatment programs. Conclusion: Chronic pain was a common co-occurring condition among individuals misusing opioids. Better efforts are needed to integrate pain management and substance abuse treatment for this population. Copyright 2012, Elsevier Science.
Fatalities temporally associated with the ingestion of ibogaine. (review).
Alper KR; Stajic M; Gill JR. Journal of Forensic Sciences 57(2): 398-412, 2012. (161 refs.)
Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioid detoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.576 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine. Copyright 2012, Wiley-Blackwell.
Frontoparietal connectivity in substance-naive youth with and without a family history of alcoholism.
Wetherill RR; Bava S; Thompson WK; Boucquey V; Pulido C; Yang TT et al. Brain Research 1432: 66-73, 2012. (83 refs.)
Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naive youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naive youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps < .05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps > .34). Substance-naive youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders. Copyright 2012, Elsevier Science.
Growth hormone doping in sports: A critical review of use and detection strategies. (review).
Baumann GP. Endocrine Reviews 33(2): 155-186, 2012. (248 refs.)
GH is believed to be widely employed in sports as a performance-enhancing substance. Its use in athletic competition is banned by the World Anti-Doping Agency, and athletes are required to submit to testing for GH exposure. Detection of GH doping is challenging for several reasons including identity/similarity of exogenous to endogenous GH, short half-life, complex and fluctuating secretory dynamics of GH, and a very low urinary excretion rate. The detection test currently in use (GHisoform test) exploits the difference between recombinant GH (pure 22K-GH) and the heterogeneous nature of endogenousGH (several isoforms). Its main limitation is the short window of opportunity for detection (similar to 12-24 h after the last GH dose). A second test to be implemented soon (the biomarker test) is based on stimulation of IGF-I and collagen III synthesis by GH. It has a longer window of opportunity (1-2 wk) but is less specific and presents a variety of technical challenges. GH doping in a larger sense also includes doping with GH secretagogues and IGF-I and its analogs. The scientific evidence for the ergogenicity of GH is weak, a fact that is not widely appreciated in athletic circles or by the general public. Also insufficiently appreciated is the risk of serious health consequences associated with high-dose, prolonged GH use. This review discusses the GH biology relevant to GH doping; the virtues and limitations of detection tests in blood, urine, and saliva; secretagogue efficacy; IGF-I doping; and information about the effectiveness of GH as a performance-enhancing agent. Copyright 2012, Endocrine Society.
Nucleus accumbens response to incentive stimuli anticipation in children of alcoholics: Relationships with precursive behavioral risk and lifetime alcohol use.
Yau WYW; Zubieta JK; Weiland BJ; Samudra PG; Zucker RA; Heitzeg MM. Journal of Neuroscience 32(7): 2544-2551, 2012. (46 refs.)
Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond previous substance use confounds and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied 20 18- to 22-year-old COAs and 20 controls, developmentally well characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (ages 12-14 years) externalizing behavioral risk. None met criteria for Diagnostic and Statistical Manual of Mental Disorders IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared with controls. However, additional analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest that a close association between motivational responses, alcohol consumption, and behavioral risk may underlie addiction vulnerability in COAs. Copyright 2012, Society of Neuroscience.
Huffing air conditioner fluid: A cool way to die?
Phatak DR; Walterscheid J. American Journal of Forensic Medicine and Pathology 33(1): 64-67, 2012. (8 refs.)
"Huffing," the form of substance abuse involving inhalants, is growing in popularity because of the ease and availability of chemical inhalants in many household products. The purpose in huffing is to achieve euphoria when the chemicals in question interact with the central nervous system in combination with oxygen displacement. The abuser is lulled into a false sense of safety despite the well-documented potential for lethal cardiac arrhythmia and the effects of chronic inhalant abuse, including multisystem organ failure, and brain damage. Huffing air conditioner fluid is a growing problem given the accessibility to outdoor units and their fluid components, such as difluorochloromethane (chlorodifluoromethane, Freon), and we have classified multiple cases of accidental death due to the toxicity of difluorochloromethane. Given the ubiquity of these devices and the vast lack of gating or security devices, they make an inviting target for inhalant abusers. Acute huffing fatalities have distinct findings that are present at the scene, given the position of the decedent and proximity to the air conditioner unit. The purpose of the autopsy in these cases is to exclude other potential causes of death and to procure specimens for toxicological analysis. Copyright 2012, Lippincott, Williams & Wilkins.
Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate. (review).
Haile CN; Mahoney JJ; Newton TF; De La Garza R. Pharmacology & Therapeutics 134(2): 260-277, 2012. (378 refs.)
Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine. Copyright 2012, Elsevier Science.
Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: A prospective study.
Feldman HS; Jones KL; Lindsay S; Slymen D; Klonoff-Cohen H; Kao K et al. Alcoholism: Clinical and Experimental Research 36(4): 670-676, 2012. (26 refs.)
Background: The physical features of fetal alcohol syndrome include smooth philtrum, thin vermillion border, short palpebral fissures, microcephaly, and growth deficiencies on weight and height. However, little is known about the specific quantities of alcohol exposure, pattern of drinking, timing of exposure, and magnitude of risk for each of these features. Methods: Using data on 992 subjects collected prospectively in California between 1978 and 2005, we examined the patterns and timing of alcohol exposure in relation to these features. Structural features were assessed by a dysmorphologist who performed a blinded physical examination of all infants. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0 to 6 weeks postconception, 6 to 12 weeks postconception, first trimester, second trimester, and third trimester. Results: Higher prenatal alcohol exposure in every pattern was significantly associated with the incidence of smooth philtrum but not with short palpebral fissures. The strongest associations were with timing of exposure in the second half of the first trimester (RR 1.25, 95% CI 1.14 to 1.36 for average number of drinks per day; RR 1.17, 95% CI 1.09 to 1.26 for maximum number of drinks in 1 episode). Similarly, thin vermillion border was most strongly associated with exposure in the second half of the first trimester. Findings with respect to timing of exposure were similar for microcephaly and reduced birth weight. However, reduced birth length was increased with exposure in any trimester. These associations were linear, and there was no evidence of a threshold. Conclusions: Reduced birth length and weight, microcephaly, smooth philtrum, and thin vermillion border are associated with specific gestational timing of prenatal alcohol exposure and are dose-related without evidence of a threshold. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy. Copyright 2012, Research Society on Alcoholism.
QT Interval screening in methadone maintenance treatment: Report of a SAMHSA expert panel. (editorial).
Martin JA; Campbell A; Killip T; Kotz M; Krantz MJ; Kreek MJ et al. Journal of Addictive Diseases 30(4): 283-306, 2011. (108 refs.)
In an effort to enhance patient safety in opioid treatment programs, the Substance Abuse and Mental Health Services Administration convened a multi-disciplinary Expert Panel on the Cardiac Effects of Methadone. Panel members (Appendix A) reviewed the literature, regulatory actions, professional guidances, and opioid treatment program experiences regarding adverse cardiac events associated with methadone. The Panel concluded that, to the extent possible, every opioid treatment program should have a universal Cardiac Risk Management Plan (incorporating clinical assessment, electrocardiogram assessment, risk stratification, and prevention of drug interactions) for all patients and should strongly consider patient-specific risk minimization strategies (such as careful patient monitoring, obtaining electrocardiograms as indicated by a particular patient's risk profile, and adjusting the methadone dose as needed) for patients with identified risk factors for adverse cardiac events. The Panel also suggested specific modifications to informed consent documents, patient education, staff education, and methadone protocols. Copyright 2011, Taylor & Francis.
Sex hormone activity in alcohol addiction: Integrating organizational and activational effects. (review).
Lenz B; Muller CP; Stoessel C; Sperling W; Biermann T; Hillemacher T et al. Progress In Neurobiology 96(1): 136-163, 2012. (559 refs.)
There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brain's reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies. Copyright 2012, Elsevier Science.
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