Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications

The central problem in the treatment of cocaine and heroin addiction is high rates of relapse to drug use after periods of forced or self-imposed abstinence. Relapse can be modeled in laboratory animals a reinstatement procedure in which responding for drug is extinguished and then reinstated by acute exposure to the drug, drug cues, or stress. In this review, we first summarize data from recent (2003-2005) studies on the neural substrates involved in reinstatement of heroin and cocaine seeking. We also discuss the neural mechanisms underlying the progressive increase in cocaine seeking after withdrawal (incubation of cocaine craving). Finally, we provide an update on several novel candidate medications for relapse prevention suggested by recent preclinical studies, and we discuss the translation of findings from nonhuman laboratory studies to the clinical phenomenon of relapse.     

Carbamazepine-induced increases in total serum cholesterol: clinical and theoretical implications.

To assess the effect of carbamazepine (CBZ) upon total serum cholesterol, we examined 38 inpatients with affective illness and one with multiple personality disorder who received a course of CBZ monotherapy. CBZ therapy yielded significant increases in total serum cholesterol that became evident during the second week of therapy, persisted throughout therapy, and reversed in the first few weeks after discontinuation of therapy. CBZ-induced increases in total cholesterol appeared independent of initial mood state, diagnostic subtype, baseline cholesterol or thyroid indices; CBZ levels, doses, and level-to-dose ratios; and the degree of change in mood and thyroid indices. CBZ induction of enzymes mediating cholesterol synthesis is a possible mechanism of the increase in total cholesterol observed with CBZ therapy. Although preclinical studies suggest possible influence of cholesterol on neurotransmitter regulation and behavior, clinical studies have yielded conflicting data. There are insufficient data to support a role for cholesterol in the anticonvulsant and psychotropic mechanisms of CBZ. The increase in total serum cholesterol seen with CBZ therapy is likely due to an increase in the high density lipoprotein fraction and is thus not likely to be clinically problematic in relationship to atherosclerosis.     

Alcoholics' attributions of factors affecting their relapse to drinking and reasons for terminating relapse episodes

This study was designed to examine alcoholics' attributions about their relapses. The subjects were 36 male alcoholic participants in a study of the effectiveness of group behavioral marital therapy (BMT) for alcoholism. Subjects' treatment condition had been determined by random assignment to either the BMT, interactional marital therapy, or control group. At a two year posttreatment follow-up interview, subjects were asked what they thought the main reasons were for starting and stopping drinking in their two most recent relapses. Subjects' responses showed that both interpersonal and psychological factors were perceived to affect relapses, with some treatment group differences in how relapses were viewed. Subjects reported a variety of factors in their stopping drinking, with anticipation of negative consequences the most frequently reported reason. The treatment groups did not differ on their attributions for relapse termination. The results were interpreted as replicating and extending previous studies of relapse among alcoholics by showing the importance of spouse and other family members in subjects' attributions of relapse and their termination.     

Contributing factors to outpatient pharmacy near miss errors: a Malaysian prospective multi-center study

International Journal of Clinical Pharmacy - Background Detecting errors before medication dispensed or ‘near misses’ is a crucial step to combat the incidence of dispensing error....     

Abstinence and relapse in outpatient cocaine addicts

A discussion is provided of clinical techniques for establishing abstinence and preventing relapse in cocaine addicts within the context of an intensive outpatient treatment program. A basic tenet of this article is that to produce higher success rates in these and other drug-dependent patients more attention must be paid to some very fundamental treatment issues, such as program structure, counselor attitude, and patient motivation.     

Treating crack cocaine dependence: the critical role of relapse prevention.

In order to adequately address the treatment needs of crack cocaine dependent persons, a multidimensional approach to relapse prevention must be utilized. The value of a biopsychosocial model of crack addiction and the concept of phases of recovery in providing a rationale for the recommended approach to relapse prevention are emphasized. Research findings on the determinants of relapse for crack dependent patients and the psychosocial characteristics of the crack dependent individual justify the utility of certain relapse prevention strategies. Specifically, an approach to relapse is advocated that includes the provision of pharmacological adjuncts, psychoeducation on the multideterminants of relapse, and psychotherapy that attempts to remediate underlying psychological problems that are typically found in crack dependent patients.     

Metabolomics of cocaine: implications in toxicity

Abstract

Cocaine is the most commonly used illicit drug among those seeking care in Emergency Departments or drug detoxification centers. Cocaine, chemically known as benzoylmethylecgonine, is a naturally occurring substance found in the leaves of the Erythroxylum coca plant. The pharmacokinetics of cocaine is dependent on multiple factors, such as physical/chemical form, route of administration, genetics and concurrent consumption of alcohol. This review aims to discuss metabolomics of cocaine, namely by presenting all known metabolites of cocaine and their roles in the cocaine-mediated toxic effects.     

Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications

Stress- and drug-related cues are major factors contributing to high rates of relapse in addictive disorders. Brain imaging studies have begun to identify neural correlates of stress and drug cue-induced craving states. Findings indicate considerable overlap in neural circuits involved in processing stress and drug cues with activity in the corticostriatal limbic circuitry underlying both affective and reward processing. More recent efforts have begun to identify the relationships between neural activity during stress and drug cue exposure and drug relapse outcomes. Findings suggest medial prefrontal, anterior and posterior cingulate, striatal and posterior insula regions to be associated with relapse outcomes. Altered function in these brain regions is associated with stress-induced and drug cue-induced craving states and an increased susceptibility to relapse. Such alterations can serve as markers to identify relapse propensity and a more severe course of addiction. Efficacy of pharmacological and behavioral treatments that specifically target stress and cue-induced craving and arousal responses may also be assessed via alterations in these brain correlates. [Sinha R, Li C-SR. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev 2007;26:25 - 31]     

The HPA axis in cocaine use: implications for pharmacotherapy.

The role of the hypothalamic-pituitary-adrenal (HPA) axis in cocaine use is reviewed within the context of two approaches to developing pharmacological treatments in humans: (1) reducing the reinforcing effects of cocaine and (2) reducing cocaine addict's susceptibility to stress-induced relapse. This review suggests that HPA-axis-suppressing medications are unlikely to block cocaine's reinforcing effects completely but may be useful in decreasing the frequency of use by increasing the addicted individual's resistance to stress-induced relapse. Implications for designing inpatient studies to test the safety and efficacy of candidate pharmacological agents are discussed.     

Neurobiology of relapse to heroin and cocaine seeking: a review

The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.     

Variation in substance use relapse episodes among adolescents: a longitudinal investigation

Substance use disorders are chronically relapsing conditions, and there is a need to evaluate whether relapse precursors are consistent across multiple relapses. We identified latent groups of relapse characteristics over time in adolescents with alcohol and substance use disorders following an inpatient treatment episode. Youth (N = 124, mean age = 16 years, 56% male, 60% Caucasian) were interviewed while in treatment and biannually during the first year after treatment to gather contextual information about first and second relapse episodes. We identified two latent classes of relapse precursors labeled aversive-social (41% at initial relapse, 57% at subsequent relapse) and positive-social (59% at initial relapse, 43% at subsequent relapse). Classes were stable in structure over time; however, only 61% of those assigned to aversive-social and 39% assigned to positive-social classes at initial relapse remained there for the subsequent relapse. Findings highlight the dynamic nature of relapse for youth and have important clinical implications.     

Psychological and environmental determinants of relapse in crack cocaine smokers

The paper reviews approaches to relapse in the treatment of cocaine abusers. Approaches reveal a common mechanism underlying relapse that involves drug craving, recall of euphoria, environmental cues, denial, myths of being able to sell or use drugs, and painful affect states necessitating use of a multifaceted clinical technique. Empirical validation of a common mechanism underlying relapse establishes a typology of psychological and environmental determinants of relapse for crack cocaine smokers (N = 35) who relapse after hospital detoxification and return a second time. Major findings are that relapse follows a painful emotional state (40%), failure to enter arranged aftercare treatment (37%), or encounters with conditioned environmental stimuli (34%), and involves narcissistic psychopathology and denial (28.5%) and interpersonal stress (24%); 85.7% involve multideterminants. Case examples illustrate the role of multideterminants in relapse. The paper educates clinicians to the integrated theory and multifaceted clinical technique necessary for efficacious treatment of cocaine patients, while the typology predicts probable relapse situations.     

Predicting cocaine consumption in Spain: A mathematical modelling approach

In this article, we analyse the evolution of cocaine consumption in Spain and we predict consumption trends over the next few years. Additionally, we simulate some scenarios which aim to reduce cocaine consumption in the future (sensitivity analysis). Assuming cocaine dependency is a socially transmitted epidemic disease, this leads us to propose an epidemiological-type mathematical model to study consumption evolution. Model sensitivity analysis allows us to design strategies and analyse their effects on cocaine consumption. The model predicts that 3.5% of the Spanish population will be habitual cocaine consumers by 2015. The simulations carried out suggest that cocaine consumption prevention strategies are the best policy to reduce the habitual consumer population. In this article, we show that epidemiological-type mathematical models can be a useful tool in the analysis of the repercussion of health policy proposals in the short-time future.     

Predicting relapse to alcohol and drug abuse via quantitative electroencephalography.

A sensitive and specific screening test that would identify the subset of substance-abusing patients at highest risk for relapse would constitute an important advance for treatment planning. This study examined the relative value of quantitative electroencephalography as a rapid, inexpensive, and noninvasive measure of relapse potential. The subjects were 107 substance-dependent patients enrolled in residential treatment programs. All were unmedicated and free of the complicating effects of major medical and neurological disorders. Structured clinical interview data and a 5-minute recording of the resting, eyes-closed electroencephalogram were obtained after patients had verifiably maintained abstinence for 1-5 months. Patients were then monitored for relapse or successful abstinence by research staff for an ensuing 6-month period. ANCOVAs of EEG power spectral density within pre-defined frequency bands revealed an enhanced amount of high frequency (19.5-39.8 Hz) beta activity among the 48 patients who later relapsed compared to both 59 patients who maintained abstinence and 22 additional subjects with no history of substance dependence. Importantly, in subsequent logistic regression analyses, fast beta power was found to be superior to severity of illness, depression level, and childhood conduct problems in predicting relapse. With fast beta power as the sole predictor, the sensitivity, specificity, and positive and negative predictive value parameters for discriminating outcomes were 0.61, 0.85, 0.75, and 0.74, respectively. Additional ANCOVAs revealed that the EEG difference between relapse-prone and abstinence-prone groups was related to the interaction of two premorbid factors, viz., childhood Conduct Disorder and paternal alcoholism. The enhancement of fast beta electroencephalographic activity in patients who will later relapse most likely originates from a premorbid and subtle dysfunction involving frontal brain regions.     

Personality, stress, and social support in cocaine relapse prediction

This study identified prospective psychosocial predictors of relapse status and drug abuse severity in male subjects in the first year after residential treatment for cocaine dependence. Personality, stress, and social support measures from an intake assessment, and stress and support measures reflecting status during the three-month period prior to the one in which relapse was identified were used as predictors. A number of hypotheses were confirmed. Detached personality and stress predicted both cocaine relapse and outcome drug abuse severity. Perceived social support quality and social network size predicted cocaine relapse. Implications for relapse prevention are presented.     

A critical transition in cocaine self-administration: behavioral and neurobiological implications

Rationale It has long been hypothesized that human as well as animal cocaine users titrate their intake to maintain a specific level of cocaine reward. This hypothesis predicts that the dose–injection function of each subject individually should be a decreasing function, with no initial, gradual ascending limb. Objectives The present study was designed to test this specific prediction. Methods Rats were trained to self-administer cocaine under a continuous reinforcement schedule. After stabilization of cocaine self-administration, all rats were tested with a wide range of i.v. cocaine doses (0.0078–1 mg). To accurately measure the threshold dose of each individual, the pharmacological resolution was set at 0.0078 mg at the four lowest doses. Results As predicted, individual dose–behavior curves are discontinuous at a threshold dose, with a descending limb but no gradual, ascending limb. Below the threshold, there is no evidence for cocaine self-administration; at and above the threshold, the rate of injections spikes to its maximum and then decreases lawfully with the dose, a decrease that reflects cocaine titration. In all individuals, this critical transition occurred over a dose interval of less than 0.008 mg. Conclusions This study suggests that the cumulative effects of cocaine maintained during self-administration are all-or-nothing—a conclusion that confirms the regulation hypothesis of cocaine reward. The neurobehavioral consequences of this specific level of cocaine reward remain to be elucidated.     

Anticholinergics: theoretical and clinical overview

ABSTRACT

Introduction: Anticholinergics are a class of medicines that block the neurotransmitter, acetylcholine, in the brain and peripheral tissues. Medicines with anticholinergic activity are widely prescribed for and used by older people for various medical conditions. One-third to one-half of the medicines commonly prescribed for older people have anticholinergic activity. Several studies have reported anticholinergic burden to be a predictor of cognitive and functional impairments in older people.

Areas covered: This article exemplifies the theoretical and clinical aspects of medicines with anticholinergic activity, including pharmacology (definition of medicines that possess anticholinergic activity, antimuscarinic receptors, therapeutic and adverse effects), epidemiology, measures and effects of cumulative anticholinergic burden in older adults, and clinical recommendations. In addition, the gaps in the literature have been identified for future research.

Expert opinion: Many medicines that are commonly prescribed to older people have a degree of anticholinergic activity that can contribute to anticholinergic burden. Anticholinergic burden, measured in several ways that consider number, dose and/or degree of anticholinergic activity of medicines, has shown to be a predictor of adverse health and functional outcomes. The anticholinergic burden on older people should be minimised by avoiding, reducing dose and deprescribing medicines with anticholinergic activity where clinically possible.     

Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management.

Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.