Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice

Opioid use disorder (OUD) is a major public health issue that has reached epidemic levels in some parts of the world. It is a chronic and complex neurobiological disease associated with frequent relapse to drug taking. Craving, defined as an overwhelmingly strong desire or need to use a drug, is a central component of OUD and other substance use disorders. In this review, we describe the neurobiological and neuroendocrine pathways that underpin craving in OUD and also focus on the importance of assessing and treating craving in clinical practice. Craving is strongly associated with patients returning to opioid misuse and is therefore an important treatment target to reduce the risk of relapse and improve patients’ quality of life. Opioid agonist therapies (OAT), such as buprenorphine and methadone, can significantly reduce craving and relapse risk, and it is essential that patients are treated optimally with these therapies. There is also evidence to support the benefits of non-pharmacological approaches, such as cognitive behavioral therapy and mindfulness-based interventions, as supplementary treatments to opioid agonist therapies. However, despite the positive impact of these treatments on craving, many OUD patients continue to suffer with negative affect and dysphoria. There is a clear need for further studies to progress our understanding of the neurobiological basis of craving and addiction and to identify novel therapeutic strategies as well as to optimize the use of existing treatments to improve outcomes for the growing numbers of patients affected by OUD.

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title: Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016
abstract: Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends.  We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016.  The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2–73·2) of deaths in 2016 with 19·3% (18·5–20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00–8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006–16—age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176–181) increase in deaths in ages 90–94 years and a 210% (208–212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe.  The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. 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title: The Neurobiology of Opioid Dependence: Implications for Treatment
abstract: Opioid tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic opioid abuse. The opioid abuser’s struggle for recovery is in great part a struggle to overcome the effects of these changes. Medications such as methadone, LAAM, buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. Despite the effectiveness of medications, they must be used in conjunction with appropriate psychosocial treatments.

title: Treatment of Opioid-Use Disorders.
abstract: This article provides an overview of the current treatment of opioid-related conditions, including treatments provided by general practitioners and by specialists in substance-use disorders. The recent dramatic increase in misuse of prescription analgesics, the easy accessibility of opioids such as heroin on the streets, and the epidemic of opioid overdoses underscore how important it is for physicians to understand more about these drugs and to be able to tell patients about available treatments for substance-use disorders. Opioids include most prescription analgesics as well as products of the poppy plant (e.g., opium, morphine, and codeine).1 Although opioids usually are prescribed to control pain, diminish cough, or relieve diarrhea, they also produce feelings of euphoria, tranquility, and sedation that may lead the patient to continue to take these drugs despite the development of serious related problems. These problems include the need to escalate doses in order to achieve these desired effects; such levels of opioids can overwhelm respiratory drive and lead to death.1,2 Opioid-use disorders are seen in persons from all educational and socioeconomic backgrounds. Recognition of such disorders has contributed to efforts to change physicians’ prescribing practices and to train first responders regarding the parenteral administration of naloxone (Narcan or Evzio), a mu-opioid receptor antagonist.2 In the United States, an estimated 400,000 persons have used heroin in the past month and 4 million have reported nonmedical use of prescription pain relievers.3-5 By some estimates, almost 17,000 deaths per year are related to opioids; drug poisoning is one of the leading causes of accidental death in the United States. Approximately 3 million persons in the United States and almost 16 million worldwide have a current or past opioid-use disorder.6 The global burden of disease from opioid-related conditions approaches 11 million life-years lost from health problems, disabilities, and early death.7 In the 2013 Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (Table 1), an opioid-use disorder is defined as the repeated occurrence within a 12-month period of 2 or more of 11 problems, including withdrawal, giving up important life events in order to use opioids, and excessive time spent using opioids. A cluster of 6 or more items indicates a severe con dition.4,8 The clinical course of opioid-use disorders involves periods of exacerbation and remission, but the underlying vulnerability never  This pattern is similar to that of other chronic relapsing conditions (e.g., diabetes and hypertension) in which perfect control of symptoms is difficult and patient adherence to treatment is often incomplete. Although persons with opioid problems are likely to have extended periods of abstinence from opioids and often do well,9 the risk of early death, primarily from an accidental overdose, trauma, suicide, or an infectious disease (e.g., human immunodeficiency virus [HIV] infection), is increased by a factor of 20.10-15 Legal problems are especially likely in persons with criminal records and high impulsivity.13 The risk of adverse outcomes decreases markedly with abstinence from opioids.9,16 Dan L. Longo, M.D.,

title: Addiction and the brain antireward system.
abstract: A neurobiological model of the brain emotional systems has been proposed to explain the persistent changes in motivation that are associated with vulnerability to relapse in addiction, and this model may generalize to other psychopathology associated with dysregulated motivational systems. In this framework, addiction is conceptualized as a cycle of decreased function of brain reward systems and recruitment of antireward systems that progressively worsen, resulting in the compulsive use of drugs. Counteradaptive processes, such as opponent process, that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to repeatedly drive the allostatic state. Excessive drug taking thus results in not only the short-term amelioration of the reward deficit but also suppression of the antireward system. However, in the long term, there is worsening of the underlying neurochemical dysregulations that ultimately form an allostatic state (decreased dopamine and opioid peptide function, increased corticotropin-releasing factor activity). This allostatic state is hypothesized to be reflected in a chronic deviation of reward set point that is fueled not only by dysregulation of reward circuits per se but also by recruitment of brain and hormonal stress responses. Vulnerability to addiction may involve genetic comorbidity and developmental factors at the molecular, cellular, or neurocircuitry levels that sensitize the brain antireward systems.

title: Recommendations for buprenorphine and methadone therapy in opioid use disorder: a European consensus
abstract: Management of patients with opioid use disorder (OUD) commonly includes opioid agonist therapy (OAT) as a part of an integrated treatment plan. These interventions are associated with proven benefits to the individual and society.  The use of methadone and buprenorphine within an integrated treatment plan in the management of patients with OUD: this work provides consensus recommendation on pharmacotherapy in OUD to assist clinicians with practical decision making in this field.  Pharmacotherapy is recommended as part of an integrated OUD treatment approach with psychosocial interventions, with the goal of reducing risks of illicit opioid use, overdose mortality, infection with HIV or HCV, improving health, psychological and social outcomes. Access to OAT should be prioritised in the treatment of OUD. Treatment choices in OUD pharmacotherapy should be based on the needs of the individual and characteristics of medications. Recommendations for choices of OAT are based on clinical efficacy, safety, patient preference, side effects, pharmacological interactions, quality of life, dose titration potential and outcomes (control craving, ongoing opioids consumption or other drugs, and potentially psychiatric comorbidities). Special groups, pregnant women, prisoners, patients with mental health problems have specific needs which must be addressed with expert input.

title: The clinical significance of drug craving
abstract: Although drug craving has received considerable research attention over the past several decades, to date there has been no systematic review of the general clinical significance of craving. This paper presents an overview of measurement issues of particular relevance to a consideration of use of craving in clinical settings. The paper then considers the relevance of craving across a broad array of clinical domains, including diagnosis, prognostic utility, craving as an outcome measure, and the potential value of craving as a direct target of intervention. The paper is both descriptive and prescriptive, informed by the current state of the science on craving with recommendations for the definition of craving, assessment practices, future research, and clinical applications. We conclude that craving has considerable utility for diagnosis and as a clinical outcome, and that findings from future research will likely expand the clinical potential of the craving construct in the domains of prognosis and craving as a treatment target.

title: DSM-5 criteria for substance use disorders: recommendations and rationale.
abstract: Since DSM-IV was published in 1994, its approach to substance use disorders has come under scrutiny. Strengths were identified (notably, reliability and validity of dependence), but concerns have also arisen. The DSM-5 Substance-Related Disorders Work Group considered these issues and recommended revisions for DSM-5. General concerns included whether to retain the division into two main disorders (dependence and abuse), whether substance use disorder criteria should be added or removed, and whether an appropriate substance use disorder severity indicator could be identified. Specific issues included possible addition of withdrawal syndromes for several substances, alignment of nicotine criteria with those for other substances, addition of biomarkers, and inclusion of nonsubstance, behavioral addictions.This article presents the major issues and evidence considered by the work group, which included literature reviews and extensive new data analyses. The work group recommendations for DSM-5 revisions included combining abuse and dependence criteria into a single substance use disorder based on consistent findings from over 200,000 study participants, dropping legal problems and adding craving as criteria, adding cannabis and caffeine withdrawal syndromes, aligning tobacco use disorder criteria with other substance use disorders, and moving gambling disorders to the chapter formerly reserved for substance-related disorders. The proposed changes overcome many problems, while further studies will be needed to address issues for which less data were available.

title: The Role of Craving in Substance Use Disorders: Theoretical and Methodological Issues.
abstract: Craving is a central feature of addiction. Its recent inclusion as a diagnostic criterion for substance use disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders appears at a time when craving research is at an all-time high. Craving is thought to predict relapse and may deter individuals from even trying to quit. Researchers have developed experimental craving-induction paradigms to identify factors contributing to craving and to test interventions to alleviate craving. This review offers a critique of laboratory craving studies, with particular emphasis on cigarette craving. It raises questions concerning several conceptual and methodological assumptions underlying this research, identifies processes that may explain why cravings are linked to drug use and relapse, addresses contextual factors that may influence various experiences of craving, and considers recent interventions targeting craving. The relation between craving and both emotion and coping is discussed, as well as the level of insight that individuals have about their own future cravings.

title: Definitions related to the medical use of opioids: evolution towards universal agreement.
abstract: Misunderstandings regarding the nature and occurrence of addiction have historically been barriers to the appropriate treatment of pain and have stigmatized the medical use of opioids. This article reviews the evolution of nomenclature related to addiction, presents current scientific understanding of addiction that may help shape universally acceptable terminology, and discusses an integrated effort of pain and addiction professionals to reach consensus on addiction-related terms. The article suggests key principles that may clarify terminology including: clear differentiation of the concepts of addiction and physical dependence, conceptualization of addiction as a multidimensional disease, and use of a label for the phenomenon of addiction that does not include the ambiguous term "dependence." More universal agreement on terminology related to addiction is expected to improve the treatment of both pain and addictive disorders; improve communication between health care providers, regulators, and enforcement agencies; and reduce health care and other societal costs.

title: Plasticity of reward neurocircuitry and the 'dark side' of drug addiction
abstract: Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a 'dark side'—a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.

title: The clinical neurobiology of drug craving
abstract: Drug craving has re-emerged as a relevant and important construct in the pathophysiology of addiction with its inclusion in DSM-V as a key clinical symptom of addictive disorders. This renewed focus has been due in part to the recent neurobiological evidence on craving-related neural activation and clinical evidence supporting its association with drug use, relapse, and recovery processes. This review covers the neurobiology of drug craving and relapse risk with a primary focus on cocaine addiction and a secondary emphasis on alcohol addiction. A conceptualization of drug craving on the continuum of healthy desire and compulsive seeking, and the associated neurobiological adaptations associated with the development of an increased craving/wanting state is presented. Altered dopamine neurochemistry as well as disrupted prefrontal control and hyperactive striatal-limbic responses in experiencing drug cues, stress, drug intake and in basal relaxed states are identified as neurobiological signatures that predict drug craving and drug use. Thus, the clinical and neurobiological features of the craving/wanting state are presented with specific attention to alterations in these cortico-limbic-striatal and prefrontal self-control circuits that predict drug craving and relapse risk. The methodological challenges that need to be addressed to further develop the evolving conceptual approach to the neuroscience of drug craving is presented, with a focus on identification and validation of biomarkers associated with the craving state and treatment approaches that may be of benefit in reversing the neurobiological adaptations associated with drug craving to improve treatment outcomes in addiction.

title: Common Brain Mechanisms of Chronic Pain and Addiction
abstract: While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients.

title: Drug Addiction, Dysregulation of Reward, and Allostasis
abstract: This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.

title: The incentive sensitization theory of addiction: some current issues
abstract: We present a brief overview of the incentive sensitization theory of addiction. This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these systems cause pathological incentive motivation (‘wanting’) for drugs. We address some current questions including: what is the role of learning in incentive sensitization and addiction? Does incentive sensitization occur in human addicts? Is the development of addiction-like behaviour in animals associated with sensitization? What is the best way to model addiction symptoms using animal models? And, finally, what are the roles of affective pleasure or withdrawal in addiction?

title: A Triadic Neurocognitive Approach to Addiction for Clinical Interventions
abstract: According to the triadic neurocognitive model of addiction to drugs (e.g., cocaine) and non-drugs (e.g., gambling), weakened “willpower” associated with these behaviors is the product of an abnormal functioning in one or more of three key neural and cognitive systems: (1) an amygdala-striatum dependent system mediating automatic, habitual, and salient behaviors; (2) a prefrontal cortex dependent system important for self-regulation and forecasting the future consequences of a behavior; and (3) an insula dependent system for the reception of interoceptive signals and their translation into feeling states (such as urge and craving), which in turn plays a strong influential role in decision-making and impulse control processes related to uncertainty, risk, and reward. The described three-systems account for poor decision-making (i.e., prioritizing short-term consequences of a decisional option) and stimulus-driven actions, thus leading to a more elevated risk for relapse. Finally, this article elaborates on the need for “personalized” clinical model-based interventions targeting interactions between implicit processes, interoceptive signaling, and supervisory function aimed at helping individuals become less governed by immediate situations and automatic pre-potent responses, and more influenced by systems involved in the pursuit of future valued goals.

title: The Human BNST: Functional Role in Anxiety and Addiction
abstract: The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region—the bed nucleus of the stria terminalis (BNST)—in the body’s stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stress-related disorders and identify novel neural targets for treatment.

title: Neurobiologic Advances from the Brain Disease Model of Addiction.
abstract: This article reviews scientific advances in the prevention and treatment of substance-use disorder and related developments in public policy. In the past two decades, research has increasingly supported the view that addiction is a disease of the brain. Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned, perhaps because the aberrant, impulsive, and compulsive behaviors that are characteristic of addiction have not been clearly tied to neurobiology. Here we review recent advances in the neurobiology of addiction to clarify the link between addiction and brain function and to broaden the understanding of addiction as a brain disease. We review findings on the desensitization of reward circuits, which dampens the ability to feel pleasure and the motivation to pursue everyday activities; the increasing strength of conditioned responses and stress reactivity, which results in increased cravings for alcohol and other drugs and negative emotions when these cravings are not sated; and the weakening of the brain regions involved in executive functions such as decision making, inhibitory control, and self-regulation that leads to repeated relapse. We also review the ways in which social environments, developmental stages, and genetics are intimately linked to and influence vulnerability and recovery. We conclude that neuroscience continues to support the brain disease model of addiction. Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance addictions and related behavioral addictions (e.g., to food, sex, and gambling) but may also improve our understanding of the fundamental biologic processes involved in voluntary behavioral control. In the United States, 8 to 10% of people 12 years of age or older, or 20 to 22 million people, are addicted to alcohol or other drugs. 1 The abuse of tobacco, alcohol, and illicit drugs in the United States exacts more than $700 billion annually in costs related to crime, lost work productivity, and health care. 2-4 After centuries of efforts to reduce addiction and its related costs by punishing addictive behaviors failed to produce adequate results, recent basic and clinical research has provided clear evidence that addiction might be better considered and treated as an acquired disease of the brain (see Box 1 for definitions of substance-use disorder and addiction). Research guided by the brain disease model of addiction has led to the development of more effective methods of prevention and treatment and to more informed public health policies. Notable examples include the Mental Health Parity and Addiction Equity Act of 2008, which requires medical insurance plans to provide the same coverage for substance-use disorders and other mental illnesses that is provided for other illnesses, 5 and the proposed bipartisan Senate legislation that From the National Institute on Drug Abuse (N.D.V.) and the National Institute of Alcohol Abuse and Alcoholism (G.F.K.) — both in Bethesda, MD; and the Treatment Research Institute, Philadelphia (A.T.M.). Address reprint requests to Dr. Volkow at the National Institute on Drug Abuse, 6001 Executive Bld., Rm. 5274, Bethesda, MD 20892, or at nvolkow@ nida . nih . gov.

title: Neurocircuitry of Addiction
abstract: Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: ‘binge/intoxication’, ‘withdrawal/negative affect’, and ‘preoccupation/anticipation’ (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex–dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

title: Hedonic Homeostatic Dysregulation as a Driver of Drug-Seeking Behavior.
abstract: Drug addiction can be defined by a compulsion to seek and take drug and loss of control in limiting intake, and the excessive drug taking derives from multiple motivational mechanisms. One such mechanism is the emergence of a negative emotional state when access to the drug is prevented, reflecting hedonic homeostatic dysregulation. Excessive drug taking then results in part via the construct of negative reinforcement. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within basal forebrain structures, including the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Chronic exposure or extended access to self-administration of all major drugs of abuse produces during abstinence increases in reward thresholds, increases in aversive anxiety-like responses, increases in extracellular levels of CRF in the central nucleus of the amygdala, and increases in drug self-administration. CRF receptor antagonists block excessive drug intake produced by dependence. A combination of decreased reward system function and increased brain stress response system function is hypothesized to be responsible for hedonic homeostatic dysregulation that drives drug seeking behavior in dependence. Such hedonic dysregulation is hypothesized to extend into protracted abstinence to provide a residual negative emotional state that enhances the salience of cues eliciting drug seeking and relapse.

title: Neurobiologic Processes in Drug Reward and Addiction
abstract: &NA; Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These “hard‐wired” changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

title: Addiction as a stress surfeit disorder
abstract: Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

title: κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction
abstract: Addictions to cocaine or heroin/prescription opioids [short-acting μ-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. κ-Opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN), have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive-like states. KOPr/dynorphin activation is implicated in depression/anxiety, often comorbid with addictions. In this opinion article we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric comorbidity.

title: Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems.
abstract: Anhedonia is a condition that leads to the loss of feelings pleasure in response to natural reinforcers like food, sex, exercise, and social activities. This disorder occurs in addiction, and an array of related neuropsychiatric syndromes, including schizophrenia, depression, and Post Traumatic Stress Disorder (PTSD). Anhedonia may by due to derangements in mesolimbic dopaminergic pathways and their terminal fields (e.g., striatum, amygdala, and prefrontal cortex) that persist long after the traces of the causative drugs are eliminated (pharmacokinetically). Here we postulate that anhedonia is not a distinct entity but is rather an epiphenomenon of hypodopaminergic states and traits arising from the interaction of genetic traits and epigenetic neurobiological alterations in response to environmental influences. Moreover, dopaminergic activity is rather complex, and so it may give rise to differential pathophysiological processes such as incentive sensitization, aberrant learning and stress-like "anti-reward" phenomena. These processes may have additive, synergistic or antagonistic interactions with the concurrent reward deficiency states leading in some instances to more severe and long-lasting symptoms. Operant understanding of the neurogenetic antecedents to reward deficiency syndrome (RDS) and the elucidation of reward gene polymorphisms may provide a map for accessing an individual's genetic risk for developing Anhedonia. Prevention techniques that can restore homeostatic balance via physiological activation of dopaminergic receptors (D2/D3) may be instrumental for targeting not only anhedonia per se but also drug craving and relapse.

title: The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors
abstract: Stress is a complex experience that carries both aversive and motivating properties. Chronic stress causes an increase in the risk of depression, is well known to increase relapse of drug seeking behavior, and can adversely impact health. Several brain systems have been demonstrated to be critical in mediating the negative affect associated with stress, and recent evidence directly links the actions of the endogenous opioid neuropeptide dynorphin in modulating mood and increasing the rewarding effects of abused drugs. These results suggest that activation of the dynorphin/kappa opioid receptor (KOR) system is likely to play a major role in the pro-addictive effects of stress. This review explores the relationship between dynorphin and corticotropin-releasing factor (CRF) in the induction of dysphoria, the potentiation of drug seeking, and stress-induced reinstatement. We also provide an overview of the signal transduction events responsible for CRF and dynorphin/KOR-dependent behaviors. Understanding the recent work linking activation of CRF and dynorphin/KOR systems and their specific roles in brain stress systems and behavioral models of addiction provides novel insight to neuropeptide systems that regulate affective state.

title: κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms
abstract: κ Opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that κ agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the κ agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the α2-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of κ opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by κ agonists.

title: The effects of spiradoline (U‐62066E), a κ‐opioid receptor agonist, on neuroendocrine function in man
abstract: Opioid drugs act on specific receptors which are principally classified into μ, δ and κ subtypes. Spiradoline (U‐62066E) is a κ‐selective agent which has been shown to possess potent anti‐nociceptive effects but does not show cross tolerance with morphine. We have assessed the neuroendocrine effects of spiradoline in healthy volunteers with two doses (1.6 and 4.0 μg kg−1, i.m.) of the compound. Six male non‐smokers aged 19–27 years were studied by use of a randomized, double‐blind three‐limb placebo‐controlled cross‐over design. Blood was taken from an  venous cannula basally and at 15 min intervals for 2 h for determination of serum cortisol, prolactin, growth hormone (GH) and catecholamines. Psychological function was assessed by the Stanford Sleepiness Scale (SSS) and the Addiction Research Centre Inventory (ARCI) administered before the medication and at 35 min, 1 h 25 min and 2 h afterwards. Cardiovascular variables were recorded at 10 min intervals. Results were analysed by analysis of variance. Spiradoline showed a significant (P<0.05) dose‐dependent increase in free water clearance, as predicted for a κ‐opioid agonist. It also caused a dose‐dependent stimulation of prolactin, (increment over baseline for higher dose 214%), GH (433%) and cortisol (215%) release (P<0.05). There were no significant drug‐related changes in plasma catecholamines, blood pressure, pulse or psychological variables. We have therefore confirmed that κ‐opioids increase free‐water clearance and may participate in the stimulation of prolactin and GH release. In contrast to μ and δ‐opioid agonists, this novel κ‐agonist stimulates cortisol release in man.

title: Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic–pituitary–adrenal axis in monkeys
abstract: Opioids can modulate neuroendocrine function. Less is known about the involvement of opioid receptor subtypes in the stimulatory effects of opioids on the primate hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the stimulatory effects of opioids selective for each receptor subtype on plasma adrenocorticotropic hormone (ACTH) and cortisol levels in both male and female monkeys. The blood collection procedure was conducted in home-caged and unanesthetized rhesus monkeys that showed low and stable basal ACTH and cortisol levels. Three opioid receptor agonists, fentanyl, U-50488H, and SNC80, were used in behaviorally active doses; they are highly selective for mu, kappa, and delta opioid receptors, respectively. Plasma samples were collected at multiple time points before and after IV administration of each compound and were quantified by radioimmunoassay. Neither fentanyl (0.0003-0.02mg/kg) nor SNC80 (0.03-0.3mg/kg) changed either ACTH or cortisol basal levels. In contrast, U-50488H (0.01-1mg/kg) dose-dependently stimulated ACTH and cortisol release in both male and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were blocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine. The antagonist effect of nor-binaltorphimine lasted up to 20 weeks. These results indicate that only synthetic kappa, but not mu or delta opioid receptor agonists stimulate HPA axis activity after acute administration in primates.

title: Urinary 17-ketosteroid excretion during a cycle of addiction to morphine.
abstract: Single doses of 45 or more mg of morphine sulfate administered to human male subjects were followed by decreased excretion of 17-KS. Addiction to morphine, lasting from 35 to 144 days, caused a significant fall in the excretion of 17-KS. Evidence of partial tolerance to the depressant effect of morphine on urinary 17-KS appeared during periods of addiction lasting 143 days. A striking rise in urinary 17-KS, with levels usually exceeding those of the predrug period, occurred on the second to fourth day of withdrawal. The maximal increase coincided with the most severe symptoms of abstinence and the greatest drop in eosinophil counts. During recovery, urinary 17-KS returned to preaddiction levels. Administration of ACTH (10 IU) resulted in a striking rise in 17-KS excretion and a fall in cosinophil counts during control, addiction, and recovery periods. Similar responses to 5 and 2½ units occurred. Administration of 5000 units of chorionic gonadotropin over a 5-day period caused enhanced excretion of 17-KS which was greater during addiction than during control and recovery periods. During addiction there was some evidence of delay in the response to hormonal stimulation. The maximal fall in eosinophil counts was sometimes retarded for about 2 hours after ACTH infusion. The maximal response to gonadotropin was usually postponed for 2 or more days. ACTH and gonadotropin administered in combination did not have additive effects on excretion of urinary 17-KS. A cycle of morphine addiction did not affect the content of butanol-extractable iodine in blood serum.

title: Hypothalamus-pituitary-adrenal axis of heroin addicts.
abstract: The hypothalamus-pituitary-adrenal axis of heroin addicts was investigated by evaluating plasma cortisol levels throughout the day in 37 heroin abusers (HA), 17 of whom showed detectable morphine levels, indicating heroin administration in the previous hours and in 12 controls. All HA showed lower cortisol levels in basal condition (100.7 +/- 61.7 ng/ml, M +/- S.D.) compared to the control group (159.7 +/- 40.6, P less than 0.05). Moreover all HA (65.1 +/- 28.9%), and in particular those taking heroin during the study (39.1 +/- 41.4%), show a reduced cortisol decrease in the evening, which was significantly lower than in controls (85.3 +/- 10.1%; P less than 0.01). As far as the acute effects of opiates are concerned morphine (0.1 mg/kg) significantly reduced plasma cortisol levels within 60 min in a group of 8 healthy subjects. The same pattern was displayed by only 3/8 HA whose morphine levels were higher than 1 ng/ml, i.e. in those reaching the highest plasma morphine concentrations. These data indicate that chronic opiate abuse leads to a hypoadrenalism which could be the result of morphine-induced changes at the hypothalamic level.

title: Drug dependence: stress and dysregulation of brain reward pathways.
abstract: The motivating factors for the development, maintenance and persistence of drug addiction can be distilled to four major sources of reinforcement in drug dependence: positive reinforcement and negative reinforcement, conditioned positive reinforceŽ ment and conditioned negative reinforcement Wikler, . 1973 . In addition to the major sources of reinforcement in drug dependence, both the persistence of ongoing addiction, as well as the relapse to drug addiction, days, months or years after the last use of the drug may be due, in part, not only to the conditioned positive and negative reinforcement, and also to the negative reinforcement of protracted abstiŽ nence when that exists as, for instance, has been well . documented in the case of opiate addiction but also to much more subtle factors which result from chronic changes or abnormalities in the brain following chronic exposure to a drug of abuse due to the Ž intrinsic neuroplasticity of the brain Dole et al., . 1966; Kreek, 1987, 1992 . These changes may contribute to a general, ill-defined feeling of dysphoria, anxiety or abnormality and also could be considered a Ž form of protracted abstinence Koob and LeMoal, . 1997 . In addition, genetic factors and early environmental factors may contribute to variations or abnormalities in neurobiologic function which may yield some individuals more vulnerable, both to the initial acquisition of drug addiction, as well as relapse to drug use once achieving the abstinent state. Extensive studies both in animal models of a variety of types, as well as basic clinical research in humans, using neu-

title: Serum Cortisol Secretion During Heroin Abstinence Is Elevated Only Nocturnally
abstract: Several studies indicate abnormalities in the hypothalamic-pituitary-adrenal axis (HPA) during acute opiate withdrawal, but protracted withdrawal has gotten less study. The current study further characterized the 24-hour time course of plasma cortisol levels in heroin-dependent individuals who were abstinent for 10–15 days, which is beyond the 5 days of acute withdrawal, compared to demographically matched healthy controls using samples collected every 3 hours over 24 hours and assessed with radioimmunoassay (RIA). The abstinent heroin-dependent participants had significantly higher plasma cortisol levels nocturnally suggesting a loss of diurnal variation in these heroin subjects.

title: Hypercortisolism after opioid discontinuation in rapid detoxification of heroin addicts.
abstract: Long-term opioid consumption can induce hypoadrenalism through impairment of the hypothalamic-pituitary-adrenal axis. Results of the present study showed that, in heroin addicts, saliva cortisol concentrations varied according to the amount of recently consumed heroin and the time elapsed since the last self-administration. Hypercortisolism was observed either after abrupt withdrawal of heroin or the last dose of methadone. Post-detoxification hypercortisolism was still present on day 16 after the last opioid consumption, whereas it was not observed in abstinent addicts for a mean period of 4 months. During detoxification treatment, mean AUC8-24 cortisol in saliva of clonidine or guanfacine-treated patients was significantly higher than that in methadone-treated patients. It may be hypothesized that elevated cortisol levels may account for untoward effects of adrenergic agonist therapy which, in turn, may represent an added risk factor for relapse during detoxification. Further studies are necessary to correlate the severity of withdrawal symptoms to cortisol levels in opioid addicts detoxified with alpha 2-adrenergic agonist substitution.

title: Salivary cortisol during opiate dependence and withdrawal
abstract: Seventeen inpatients (14 men, three women) with opiate dependence and polysubstance misuse participated in a longitudinal study of salivary cortisol secretion during and after lofexidine detoxification treatment. Both opiate withdrawal symptoms and salivary cortisol were measured every morning for up to 25 days. Results were compared with a control group of 10 normal volunteers. There was an 80% reduction in withdrawal symptom severity between the first 12 days and the subsequent 12 days of treatment. Salivary cortisol fell from a mean of 22.3 nm/l over days 1–12 to 18.5 nm/l during days 13–25, a reduction of 17%. Salivary cortisol concentration correlated significantly with withdrawal symptom severity. Salivary cortisol levels remained significantly higher than controls for the duration of the study. The study supports a role for hypothalamo–pituitary–adrenal (HPA) activation in opiate withdrawal. The contribution of persistant dysregulation of the HPA, found in this study, to the vulnerability for relapse after abstinence has been achieved, is discussed.

title: Craving by imagery cue reactivity in opiate dependence following detoxification
abstract: Frequent relapses in opioid addiction may be a result of abstinentemergent craving. Exposure to various stimuli associated with drug use (drug cues) may trigger craving as a conditioned response to ′drug cues′.  The present study explored the effects of imagery cue exposure on psychophysiological mechanisms of craving, viz. autonomic arousal, in detoxified opiate addicts.  Opiate dependent subjects (N=38) following detoxification underwent imagery cue reactivity trials.The subjects were asked to describe verbally and then imagine their craving experiences.  Craving was measured subjectively by using Visual Analogue Scale and autonomic parameters of galvanic skin resistance (GSR), pulse rate (PR), and skin temperature (ST) was taken during cue imagery. Spearman′s r and Wilcoxon signed ranks test were employed in analysis. Multivariate repeated measurement analysis (wilk′s Lambda) was employed wherever appropriate. Subjective measures of craving, GSR and PR increased significantly whereas ST decreased significantly during drug related cue imagery as compared to neutral cues.  The results support that cue imagery is a powerful tool in eliciting craving. Hence, it can be used as a screening manoeuvre for detecting individuals with high cue reactivity, as well as for extinction of craving.

title: Laboratory-induced cue reactivity among individuals with prescription opioid dependence.
abstract: Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n = 20) as compared to controls (n = 17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence.

title: Cue-induced craving to paraphernalia and drug images in opioid dependence.
abstract: Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence.



Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N = 50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving.



Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group.



These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type.



Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further clarify cue-induced craving in this population.

title: Drug-related cues exacerbate decision making and increase craving in heroin addicts at different abstinence times
abstract: RationaleRelapse is a persistent problem in the management of addiction. Drug-related cues are powerful instigators of relapse. Impulsive decision making may contribute to relapse through a poorly considered assessment of the consequences of drug use. Drug cues robustly increase subjective craving, which is frequently associated with relapse. present study explored the effects of drug-related cues on decision making and craving in heroin addicts at different abstinence times: 1, 3, 12, and 24 months.MethodsThe 75 male participants were given 5 min exposure to neutral and drug-associated cues while decision making performance, craving, blood pressure, heart rate, and emotional state pre- and post-exposure were assessed. The Iowa Gambling Task was used to evaluate decision making ability in heroin addicts.ResultsDrug-related cues exacerbated impulsive decision making and increased craving, heart rate, and systolic pressure in heroin addicts at all abstinence times.ConclusionsDrug-related cues aggravated decision making and increased craving in former heroin addicts who had been drug-free for 1–24 months, which might have significant clinical implications for the prevention of relapse.

title: Cue-induced craving and physiological reactions in recently and long-abstinent heroin-dependent patients.
abstract: To understand the different patterns of cue-induced craving and physiological reactions among recently abstinent and long-abstinent heroin-dependent patients.



26 healthy adult controls (HC), 29 long-abstinent (more than 1 year, LA), and 26 recently abstinent (less than 1 month, RA) heroin-dependent individuals were exposed to heroin-related and neutral video cues, one video per session, on different days in random order. Self-reported heroin craving by a 10-point visual analog scale (VAS), physiological reactions [skin conductance (SC), muscle electromyography (MEG), skin temperature (TEMP)] and cardiovascular arousal [heart rates (HR), systolic blood pressure (HBP) and diastolic blood pressure (LBP)] were assessed at baseline and after exposure.



Both heroin-abstinent groups showed increased heroin craving, SC, MEG, HR, SBP and LBP after exposure to heroin-related video, compared to the control group and compared to exposure to the neutral video. Except the RA group showed more HR changes, changes of heroin craving, SC, MEG, HR, SBP and LBP after exposure to the heroin cue video were not different between the LA and RA groups.



Abstinent heroin-dependent patients had elevated craving and physiological reactions after exposure to videos containing heroin-related cues and the cue induced responses still occurred in long-abstinent patients. This phenomenon should be addressed in treatment and recovery services for heroin dependence.

title: Exacerbated Craving in the Presence of Stress and Drug Cues in Drug-Dependent Patients
abstract: In addiction, risk factors for craving and use include stress and drug-related cues. Stress and cues have additive or more-than-additive effects on drug seeking in laboratory animals, but, surprisingly, seem to compete with one another (ie, exert less-than-additive effects) in human laboratory studies of craving. We sought heretofore elusive evidence that human drug users could show additive (or more-than-additive) effects of stress and cues on craving, using ecological momentary assessment (EMA). Outpatients (N=182) maintained on daily buprenorphine or methadone provided self-reports of stress, craving, mood, and behavior on electronic diaries for up to 16 weeks. In three randomly prompted entries (RPs) per day, participants reported the severity of stress and craving and whether they had seen or been offered opioids, cocaine, cannabis, methamphetamine, alcohol, or tobacco. In random-effects models controlling for between-person differences, we tested effects of momentary drug-cue exposure and stress (and their interaction) on momentary ratings of cocaine and heroin craving. For cocaine craving, the Stress × Cue interaction term had a positive mean effect across participants (M=0.019; CL95 0.001–0.036), denoting a more-than-additive effect. For heroin, the mean was not significantly greater than 0, but the confidence interval was predominantly positive (M=0.019; CL95 −0.007–0.044), suggesting at least an additive effect. Heterogeneity was substantial; qualitatively, the Stress × Cue effect appeared additive for most participants, more than additive for a sizeable minority, and competitive in very few. In the field, unlike in human laboratory studies to date, craving for cocaine and heroin is greater with the combination of drug cues and stress than with either alone. For a substantial minority of users, the combined effect may be more than additive.

title: Neurobiology of addiction: a neurocircuitry analysis.
abstract: Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.

title: Mood and Neuroendocrine Response to a Chemical Stressor, Metyrapone, in Buprenorphine-Maintained Heroin Dependence
abstract: Heroin dependence is associated with a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, proposed as a biological correlate of craving. Maintenance treatment with methadone normalizes HPA axis activity. Here, we examined HPA axis activity under maintenance treatment with the increasingly utilized partial opiate agonist buprenorphine.



Responses to a metyrapone challenge were compared in 20 buprenorphine-maintained heroin addicts and 20 healthy volunteers (10 received a single 50 mg naltrexone dose [NTX+] and 10 received no naltrexone [NTX-]). Patients were 16 male subjects and 4 female subjects, aged 30 to 38 years, heroin-dependent and relapse-free under buprenorphine maintenance (BUP) for a minimum of 6 months. Healthy volunteers were 9 male subjects and 11 female subjects, aged 36 to 49 years, with no history of dependence. Serial measures were obtained of plasma adrenocorticotropic hormone (ACTH) and cortisol and Profile of Mood States (POMS) ratings over time. Subjects were genotyped for the OPRM1 118A/G polymorphism.



Buprenorphine maintenance showed a dampened HPA axis response to metyrapone, with OPRM1 118G carriers showing a significantly attenuated response compared with 118A carriers. The response of the NTX+ group was markedly increased. In contrast, negative affect was elevated in the BUP group but did not differ between NTX- and NTX+. Buprenorphine maintenance and NTX- groups did not differ in positive affect, whereas the NTX+ group was lower.



In contrast to exaggerated HPA axis responsiveness reported in untreated heroin dependence, response to metyrapone was subnormal in heroin addicts maintained on buprenorphine. Despite this, increased measures of negative affect were seen in this group. This implies a dissociation of HPA axis responsiveness and affect in heroin dependence.

title: PRECLINICAL STUDY: Corticotropin‐releasing factor‐1 receptor antagonists decrease heroin self‐administration in long‐ but not short‐access rats
abstract: Dysregulation of the stress‐related corticotropin‐releasing factor (CRF) system has been implicated in the development of drug dependence. The present study examined the effects of administering CRF type 1 (CRF1) receptor antagonists on heroin self‐administration in animals allowed short (1 hour) or long (8–12 hours) access to intravenous heroin self‐administration sessions. The nonpeptide CRF1 antagonists MJL‐1‐109‐2 (1 hour versus 8 hours access) or R121919 (1 hour versus 12 hours access) were systemically injected in both short‐ and long‐access rats.  reduced heroin self‐administration in long‐access animals without altering heroin intake in short‐access animals. Both MJL‐1‐109‐2 and R121919 decreased first‐hour intravenous heroin self‐administration selectively in long‐access rats, with R121919 decreasing cumulative heroin intake across the 12‐hour session. The results demonstrate that blockade of the CRF–CRF1 receptor system attenuates the increased heroin intake of rats with extended access to the drug.

title: Don’t stress about CRF: assessing the translational failures of CRF1antagonists
abstract: BackgroundDr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts.MethodsWe explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology.ResultsPotential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, (5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF2 receptor or CRF-binding protein molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation.ConclusionThe therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF’s role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

title: Pexacerfont as a CRF1 antagonist for the treatment of withdrawal symptoms in men with heroin/methamphetamine dependence: a randomized, double-blind, placebo-controlled clinical trial
abstract: We assessed the efficacy of pexacerfont, a CRF1 antagonist, for the treatment of withdrawal symptoms. In this randomized, double-blind, placebo-controlled clinical trial, male patients with amphetamine or opioid dependence, on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR), in the age range 18–55 years, received either pexacerfont or placebo (300, 200, and 100 mg/day in the first, second, and third week, respectively). No antidepressants, behavioral interventions, or substitution therapy were administered. Candidates were excluded if they had DSM-IV-TR axis I or II disorders (other than depressive/anxiety disorders). The primary outcomes were difference in the distribution of positive urine test results for heroin and methamphetamine at the end of the trial, and the mean difference in the change in the Visual Analog Scale (VAS) score for craving from the baseline to the endpoint between the two groups. No significant difference was detected for urine test results, but a significant difference was observed for craving scores. Also, significant time×treatment interactions were found for all the scales including VAS craving, VAS temptation severity, frequency of temptation, Clinical Opiate Withdrawal Scale, Amphetamine Withdrawal Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory II. Our findings favor pexacerfont as a potential treatment for withdrawal from drug dependence; however, further comprehensive studies are warranted.

title: Selective kappa opioid antagonists for treatment of addiction, are we there yet?
abstract: Kappa opioid receptor (KOP) is a G-protein coupled receptor mainly expressed in the cerebral cortex and hypothalamus. It is implicated in nociception, diuresis, emotion, cognition, and immune system functions. KOP agonists possess a strong analgesic effect accompanied by a feeling of dysphoria. On the other hand, antagonists of this receptor were found to block depression, anxiety, and drug-seeking behaviors in animal models. Recently, great interest has been given to the development of selective KOP antagonists as an addiction treatment that does not cause dependence itself or show high relapse rates like the currently used agents. This review provides a comprehensive survey of the KOP antagonists developed for this purpose together with their in vivo studies and clinical trials. In addition, a future perspective and recommendations for the work needed to develop clinically relevant KOP antagonists are presented.

title: Kappa‐Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials
abstract: Kappa‐opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive‐ and anxiety‐related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant‐ and anxiolytic‐like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress‐related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.

title: Craving correlates with mesolimbic responses to heroin-related cues in short-term abstinence from heroin: An event-related fMRI study
abstract: Craving is an important factor in relapse to drug abuse, and cue-induced craving is an especially powerful form of this construct. Neuroimaging methods have been utilized to study drug cue-induced craving and neural correlates in the human brain. However, very few studies have focused on characterizing craving and the neural responses to heroin-related cues in short-term abstinent heroin-dependent patients. Twenty-four heroin-dependent subjects and 20 demographically matched drug-naïve subjects participated in this study. An event-related cue-reactivity paradigm was employed, while changes in blood oxygen level-dependent (BOLD) signals were acquired by functional magnetic resonance imaging (fMRI). The heroin-dependent group reported significantly increased craving following exposure to heroin-related cues. Direct comparison between the two groups showed that brain activation to heroin-related minus neutral cues was significantly greater for the heroin-dependent group in the bilateral nucleus accumbens (NAc), caudate, putamen, amygdala, hippocampus/parahippocampus, midcingulate cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), medial frontal gyrus (MeFG), midbrain, thalamus, left anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and subcallosal gyrus. Changes in craving in the heroin-dependent group correlated positively with brain activation in the bilateral NAc, caudate, right putamen, and left ACC. The abstinence duration correlated positively with brain activation in the left caudate and right parahippocampal gyrus. In conclusion, the cue-reactivity paradigm significantly activated neural responses in the mesolimbic dopamine (DA) system and prefrontal cortex (PFC) and induced increased craving in short-term abstinent heroin-dependent patients. We suggest that these response patterns characterize the high vulnerability of relapse in short-term abstinent heroin-dependent subjects.

title: The measurement of drug craving.
abstract: This paper reviews theoretical and methodological issues in the measurement of drug craving, with an emphasis on self-report assessment. Despite the important role that craving plays in many research and clinical settings, the way in which the construct is conceptualized and measured rarely receives sufficient attention. Issues pertinent to conceptualizing craving are identified. Because there is no single perfect measure of craving, it is essential that researchers understand the limitations of each measure. Measurement performance concerns that affect the validity of different measures are reviewed. Non-verbal assessment methods are also reviewed. Research factors that may help determine the optimal measures for a given study are highlighted. It is concluded that advances in assessment will proceed only when combined with additional research and a better theoretical understanding of craving.

title: Assessing craving and its relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients.
abstract: Craving is viewed as a core feature of substance use disorders and has been shown to predict future drug use, particularly over the short term. Accordingly, craving is often assessed in treatment settings as a marker of risk for subsequent drug use. The identification of the briefest measure that maintains predictive validity is of particular value for both clinical and research settings to minimize assessment burden while maintaining utility for the prediction of use.



Data from a multi-site clinical trial of treatment for prescription opioid dependence were examined to evaluate whether a brief, 3-item craving scale administered each week predicted urine-confirmed self report of prescription opioid use in the subsequent week. Logistic regression models examining the association between craving and presence or absence of opioid use in the following week were conducted, controlling for opioid use in the previous week, treatment condition, and lifetime history of heroin use.



Greater craving was associated with a higher odds of prescription opioid use in the following week. For each one-unit increase on this 10-point scale, the odds of using opioids in the subsequent week was 17% higher. In addition to an item assessing urges, items assessing cue-induced craving and perceived likelihood of relapse in an environment where drugs were previously used contributed uniquely to this association.



A brief measure of prescription opioid craving predicted prescription opioid use among individuals in treatment. This measure offers an efficient strategy to inform the assessment of risk for use in this population.

title: Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).
abstract: The original Screener and Opioid Assessment for Patients with Pain (SOAPP) is a conceptually derived self-report questionnaire designed to predict aberrant medication-related behaviors among chronic pain patients considered for long-term opioid therapy. The purpose of this study was to develop and validate an empirically derived version of the SOAPP (SOAPP-R) that addresses some limitations of the original SOAPP. In successive steps, items were reduced from an initial pool of 142 to a 97-item beta version. The beta version was administered to 283 chronic pain patients receiving long-term opioid therapy. Items were evaluated based on data collected at follow-up, including correlation with the Aberrant Drug Behavior Index (ADBI), derived from interview data, physician ratings, and urine toxicology screens. Twenty-four items were retained and comprise the final SOAPP-R. Coefficient alpha was .88, and receiver operating characteristics curve analysis yielded an area under the curve of .81 (P < .001). A cutoff score of 18 showed adequate sensitivity (.81) and specificity (.68). The obtained psychometrics, along with the use of a predictive criterion that goes beyond self-report, suggest that the SOAPP-R is an improvement over the original version in screening risk potential for aberrant medication-related behavior among persons with chronic pain.



There is a need for a screener for abuse risk in patients prescribed opioids for pain. This study presents a revised version of the SOAPP-R that is empirically derived with good reliability and validity but is less susceptible to overt deception than the original SOAPP version 1.

title: Ecological momentary assessment in the investigation of craving and substance use in daily life: a systematic review.
abstract: Craving is viewed as a major determinant of relapse in persons with substance addiction, but this association remains poorly understood due to its time-limited nature and the biases associated with retrospective reporting. Ecological momentary assessment (EMA) offers new opportunities to examine both craving and substance use with strong ecological validity by collecting real-time data in daily life. This review examined all published studies using EMA to: (1) assess the link between craving and substance use; and (2) identify relevant moderators of craving among substance users.



We searched PubMed and PsycInfo databases up to October 31, 2013.



Ninety-one studies were selected, involving mostly tobacco smokers (73%). A majority of studies (92%) reported a positive relationship between craving and substance use, concurrently and prospectively, and among users with different levels of use for both legal and illegal substances. Results suggest that craving is a stronger predictor of relapse episodes when assessed in close temporal proximity to substance use. EMA data also confirmed the influence of diverse within-person and between-person sources of variation in daily life craving reports.



This review provides strong support for the link between craving and substance use, and underscores the importance of the timing of assessments.

title: Ecological momentary assessment of affect and craving in patients in treatment for prescription opioid dependence
abstract: Low positive affect (PA) is likely to contribute to risk of relapse; however, it has received relatively little attention in clinical research. This study examined the associations among positive affect, negative affect (NA), and craving in medically withdrawn patients using ecological momentary assessment (EMA). Participants (n=73) provided reports of their PA, NA, and craving 4 times a day for an average of 10.47 (SD=3.80) days. Person- and day-level associations between PA, NA, and craving were examined using multilevel models. A significant interaction emerged between person- and day-level PA such that PA on the day level was negatively associated with craving for individuals experiencing low mean PA throughout the study. No significant interaction emerged between person- and day-level NA. The main effects for both person- and day-level NA were significant. Individuals experiencing high NA throughout the study experienced higher craving overall and on days when NA was higher than usual, craving was also higher. Results suggest that high person- and day-level NA may directly contribute to the risk for relapse via increased craving, whereas low day- level PA may contribute to risk for relapse among individuals exhibiting low person-level PA via increased craving on days with lower than average levels of PA for those individuals. Given that there is a paucity of research relating low PA to craving, continued investigation into how and when low PA creates risk for relapse is warranted.

title: Ecological momentary assessment: what it is and why it is a method of the future in clinical psychopharmacology.
abstract: Current methods of assessment in clinical psychopharmacology have several serious disadvantages, particularly for the study of social functioning. We aimed to review the strengths and weaknesses of current methods used in clinical psychopharmacology and to compare them with a group of methods, developed by personality/social psychologists, termed ecological momentary assessment (EMA), which permit the research participant to report on symptoms, affect and behaviour close in time to experience and which sample many events or time periods. EMA has a number of advantages over more traditional methods for the assessment of patients in clinical psychopharmacological studies. It can both complement and, in part, replace existing methods. EMA methods will permit more sensitive assessments and will enable more wide-ranging and detailed measurements of mood and behaviour. These types of methods should be adopted more widely by clinical psychopharmacology researchers.

title: Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users
abstract: We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2–5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use.

title: Polydrug abuse among opioid maintenance treatment patients is related to inadequate dose of maintenance treatment medicine
abstract: BackgroundPolydrug abuse is a known problem among opioid-dependent patients receiving opioid maintenance treatment (OMT). However, improved laboratory diagnostics is required to reveal polydrug abuse in its current scope. Furthermore, there are few studies focusing on the relationship between polydrug abuse and adequacy of the dose of OMT medicine. This study aimed to evaluate the polydrug abuse among opioid-dependent patients receiving OMT with inadequate (Group IA) and adequate (Group A) doses of OMT medicine as experienced by the patients. Craving for opioids and withdrawal symptoms were evaluated as indicators of the adequacy rating.MethodsThis is a retrospective register-based study of 60 OMT patients on either methadone or sublingual buprenorphine/naloxone medication, whose polydrug abuse was studied from urine samples by means of a comprehensive high-resolution mass spectrometry method.ResultsInadequate doses of the OMT medicines were associated with higher subjective withdrawal scores and craving for opioids. Six groups of abused substances (benzodiazepines, amphetamines, opioids, cannabis, new psychoactive substances, and non-prescribed psychotropic medicines) were found among OMT patients. Group IA patients showed significantly more abuse of benzodiazepines and amphetamines than the Group A patients. All the new psychoactive substances and most of the non-prescribed psychotropic medicines were detected from the Group IA patients. There was no difference in the doses of the OMT medicine between Groups IA and A patients.ConclusionsPolydrug abuse, detected by definitive laboratory methods, was widespread and more common among Group IA than Group A patients, emphasizing the requirement for individual OMT medicine dose adjustment.

title: Alcohol Use Disorders in Opioid Maintenance Therapy: Prevalence, Clinical Correlates and Treatment
abstract: Maintenance therapy with methadone or buprenorphine is an established and first-line treatment for opioid dependence. Clinical studies indicate that about a third of patients in opioid maintenance therapy show increased alcohol consumption and alcohol use disorders. Comorbid alcohol use disorders have been identified as a risk factor for clinical outcome and can cause poor physical and mental health, including liver disorders, noncompliance, social deterioration and increased mortality risk. The effects of opioid maintenance therapy on alcohol consumption are controversial and no clear pattern has emerged. Most studies have not found a change in alcohol use after initiation of maintenance therapy. Methadone and buprenorphine appear to carry little risk of liver toxicity, but further research on this topic is required. Recent data indicate that brief intervention strategies may help reduce alcohol intake, but the existing evidence is still limited. This review discusses further clinical implications of alcohol use disorders in opioid dependence.

title: Suicidal ideation is associated with individual differences in prescription opioid craving and cue-reactivity among chronic pain patients
abstract: Given that chronic pain patients experience significant rates of suicidal ideation and suicide attempts, access to prescription opioids compounds the risk of death by suicide. These patients may experience heightened opioid craving and exhibit increased cue-reactivity to stimuli associated with past opioid use when suicidal ideation produces negative affective states. Because both opioids and suicidal behavior are used to alleviate emotional and physical pain through a process of negative reinforcement, elucidating factors that mediate this association may yield insight into suicide risk among chronic pain patients. This study examined the relationship between suicidal ideation and opioid craving and cue-reactivity, and tested opioid self-medication as a mediator of associations between those factors after controlling for the impact of pain severity. A sample of 115 chronic pain patients provided demographic and clinical information on the Obsessive Compulsive Drug Use Scale, the Current Opioid Misuse Measure, and the Brief Pain Inventory before completing an opioid dot probe task in which heart rate variability was recorded. As hypothesized, suicidal ideation was positively correlated with subjective opioid craving and physiological cue-reactivity. Self-medication significantly mediated the association between suicidal ideation, craving, and cue-reactivity. As opioids relieve the emotional pain linked with suicidal thoughts, chronic pain patients with higher levels of suicidal ideation may experience more intense opioid craving and exhibit heightened physiological cue-reactivity when compared to patients with low levels of suicidal ideation.

title: Thought suppression as a mediator of the association between depressed mood and prescription opioid craving among chronic pain patients
abstract: Emerging research suggests that prescription opioid craving is associated with negative mood and depression, but less is known about cognitive factors linking depressive symptoms to opioid craving among adults with chronic pain. The present cross-sectional study examined thought suppression as a mediator of the relation between depression and prescription opioid craving in a sample of chronic pain patients receiving long-term opioid pharmacotherapy. Data were obtained from 115 chronic pain patients recruited from primary care, pain, and neurology clinics who had taken prescription opioids daily or nearly every day for ≥90 days prior to assessment. In this sample, 60 % of participants met DSM-IV criteria for current major depressive disorder. Depressed mood (r = .36, p < .001) and thought suppression (r = .33, p < .001) were significantly correlated with opioid craving. Multivariate path analyses with bootstrapping indicated the presence of a significant indirect effect of thought suppression on the association between depressed mood and opioid craving (indirect effect = .09, 95 % CI .01, .20). Sensitivity analyses showed a similar indirect effect of suppression linking major depressive disorder diagnosis and opioid craving. Attempts to suppress distressing and intrusive thoughts may result in increased craving to use opioids among chronic pain patients with depressive symptoms. Results highlight the need for interventions that mitigate thought suppression among adults with pain and mood disorders.

title: Situational and psycho-social factors associated with relapse following residential detoxification in a population of Irish opioid dependent patients
abstract: To identify and describe the context and factors involved in the opioid lapse process following discharge from an Irish inpatient opioid detoxification treatment programme.  Prospective follow-up study of consecutive detoxified opioid dependent patients treated in a specialist inpatient drug dependency unit.  The Maudsley Addiction Profile and a structured interview were administered to 109 patients, 18–36 months after discharge.  Of 109 people interviewed at follow-up, 102 (94%) reported at least one episode of opioid use after leaving the residential treatment programme. Eighty eight patients (86% of the lapsers) identified more than one major factor contributing to their recidivism. The median number of factors identified as having a major role in the lapse was four. The most frequently reported major contributors to lapse were low mood (62%), difficulties with craving (62%), ease of access to heroin (48%) and missing the support of the treatment centre (43%).  Early lapse was common following inpatient treatment of opioid dependence. Lapse tended to result from a number of common, identifiable, high-risk situations, feelings and cognitions which may assist clinicians and patients develop lapse prevention strategies to anticipate and interrupt this process.

title: Mindfulness-based relapse prevention for substance craving.
abstract: Craving, defined as the subjective experience of an urge or desire to use substances, has been identified in clinical, laboratory, and preclinical studies as a significant predictor of substance use, substance use disorder, and relapse following treatment for a substance use disorder. Various models of craving have been proposed from biological, cognitive, and/or affective perspectives, and, collectively, these models of craving have informed the research and treatment of addictive behaviors. In this article we discuss craving from a mindfulness perspective, and specifically how mindfulness-based relapse prevention (MBRP) may be effective in reducing substance craving. We present secondary analyses of data from a randomized controlled trial that examined MBRP as an aftercare treatment for substance use disorders. In the primary analyses of the data from this trial, Bowen and colleagues (2009) found that individuals who received MBRP reported significantly lower levels of craving following treatment, in comparison to a treatment-as-usual control group, which mediated subsequent substance use outcomes. In the current study, we extend these findings to examine potential mechanisms by which MBRP might be associated with lower levels of craving. Results indicated that a latent factor representing scores on measures of acceptance, awareness, and nonjudgment significantly mediated the relation between receiving MBRP and self-reported levels of craving immediately following treatment. The mediation findings are consistent with the goals of MBRP and highlight the importance of interventions that increase acceptance and awareness, and help clients foster a nonjudgmental attitude toward their experience. Attending to these processes may target both the experience of and response to craving.

title: Before and after: craving, mood, and background stress in the hours surrounding drug use and stressful events in patients with opioid-use disorder
abstract: RationaleEcological momentary assessment (EMA) of specific events usually focuses more on antecedents and concomitants than on aftermaths.ObjectivesTo examine mental state both before and after discrete episodes of stress and drug use.MethodsFor up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated entries for stressful events (SEs) or lapses to drug use (DUs), and thrice daily when randomly prompted (RPs). Participants rated their stress, opioid craving, cocaine craving, and moods. RP entries within 5 h of an event were analyzed and compared to other RPs.ResultsStress, negative mood, and craving were generally higher before and after DUs and SEs compared to background levels in participants with at least one DU (n = 149) or SE (n = 158). Before DUs, there were increases in negative mood, opioid craving, and cocaine craving, but not background stress. Before SEs, there were increases in background stress, opioid craving, and cocaine craving, but not negative mood. These changes were more variable after events than before. Neither DUs nor SEs were significantly related to positive mood.ConclusionsStress increased before stressful-event entries, but was less evident before drug use. Craving increased in the hours before drug use and stressful events—and remained elevated in the hours after either event. These results suggest a stronger link between drug use and craving than between drug use and stress. Lapses to drug use did not improve mood or reduce stress, at least not at our 1-h-bin time resolution, suggesting that if such benefits exist, they are brief.

title: Feasibility and validity of computerized ambulatory monitoring in drug-dependent women.
abstract: To examine the feasibility and validity of computerized ambulatory monitoring in drug-dependent women.



61 women recruited from public substance abuse treatment centers in Montreal, Canada participated in the current study, 84% of whom reported past 30-day polysubstance use. Mood states, craving, and drug use were assessed by standard clinical instruments and by electronic interviews during 7-days of computerized ambulatory monitoring. Feasibility was assessed by examining compliance with intensive monitoring and equipment loss. Concurrent validity was assessed by examining the degree of correspondence of ambulatory data on craving, mood, and substance use with clinic-based assessments of similar constructs.



Participants completed an average 80% of all electronic assessments and no data collection devices were lost or stolen. Relationships among mood, stress, consumption, and craving assessed in the electronic interviews conformed to well-established patterns, and evidence of concurrent validity were found between scores from standard clinical instruments and similar constructs in daily life. Center for Epidemiological Studies-Depression Scale (CESD) scores were positively related to sad mood reported during the electronic interviews (p=0.001) and negatively related to happy mood states (p<0.001), explaining approximately 20% of the variance in each mood state. ASI drug use severity scores were positively associated with craving (p<0.001) and substance use (p<0.001), and explained 46% and 30% of these outcomes, respectively.



Computerized ambulatory monitoring is a feasible and valid data collection strategy in drug-dependent individuals.

title: Craving and substance use among patients with alcohol, tobacco, cannabis or heroin addiction: a comparison of substance- and person-specific cues.
abstract: It is well established that craving increases following exposure to substance-related 'cues', but the role of life-styles or substance use habits that are unique to each person remains poorly understood. This study examines the association of substance-specific and personal cues with craving and substance use in daily life.



Ecological momentary assessment was used during a 2-week period.



Data were collected in a French out-patient addiction treatment centre.



A total of 132 out-patients beginning treatment for alcohol, tobacco, cannabis or opiate addiction were included.



Using mobile technologies, participants were questioned four times per day relative to craving, substance use and exposure to either substance-specific cues (e.g. seeing a syringe) or personal cues unique to that individual (e.g. seeing the specific person with whom the substance is used).



Craving intensity was associated with the number of concurrently assessed substance-specific cues (t = 4.418, P < 0.001) and person-specific cues (t = 4.006, P < 0.001) when analysed jointly within the same model. However, only person-specific cues were associated with increases in craving over subsequent hours of the day (t = 2.598, P < 0.05). Craving intensity, in turn, predicted increases in later substance use (t = 4.076, P < 0.001). Causal mediation analyses demonstrated that the association of cues with later substance use was mediated by craving intensity (mediated effect = 0.007, 95% confidence interval = 0.004-0.011).



Unique person-specific cues appear to have a robust effect on craving addictive substances, and the duration of this association may persist longer than for more general substance-specific cues. Mobile technologies provide new opportunities for understanding these person-specific risk factors and for providing individually tailored interventions.

title: Effects of anxiety and mood disorders on craving and substance use among patients with substance use disorder: An ecological momentary assessment study.
abstract: Despite recognition of the negative impact of psychiatric comorbidity on addictive disorders, the mechanisms underlying this association remain poorly understood. The present investigation applied mobile technologies to examine the effect of comorbid mood or anxiety disorders on craving intensity and substance use within the natural conditions of daily life.



A total of 159 participants were recruited from a French outpatient addiction clinic and completed two weeks of computerized ambulatory monitoring of daily life experiences using Ecological Momentary Assessment (EMA). Patients described in real-time their emotional states, craving intensity, and substance use. Current mood and/or anxiety disorders were diagnosed according to DSM-IV criteria. The main substances of dependence were alcohol (n = 48), tobacco (n = 43), cannabis (n = 35), or opiates (n = 33).



Craving intensity strongly predicted substance use reported over subsequent hours of the day both in groups with (OR = 1.13, p = .009, n = 95) and without (OR = 1.20, p = .002, n = 64) current comorbid psychiatric disorders. Current comorbid mood and/or anxiety disorders were associated with higher craving intensity (γ coef = 0.632, SE = 0.254, p = .014) and consequently more frequent substance use (γ coef = 0.162, SE = 0.052, p = .003). A portion of increased substance use associated with current mood and/or anxiety disorders was independent of increases in craving intensity.



Attention to craving management is particularly important for patients with substance use disorders and comorbid mood and/or anxiety disorders, but additional interventions are also needed that address other mechanisms through which these disorders lead to an increase in substance use frequency, independently from craving.

title: Heroin craving and its correlations with clinical outcome indicators in people with heroin dependence receiving methadone maintenance treatment.
abstract: Craving for substance use has been added as one of the diagnostic criteria of substance use disorders in DSM-5. However, further research is necessary to examine and expand the clinical potential of craving in the assessment and treatment for heroin users. This study aimed to examine the psychometrics of the Desire for Drug Questionnaire-Chinese Mandarin version (DDQ-CM) and its clinical utility of assessing craving for heroin measured among heroin users with methadone maintenance treatment (MMT).



Self-reported craving for heroin use was measured on the DDQ-CM and visual analog scale among 314 intravenous heroin users receiving MMT. Self-reported heroin dependence, attitude toward heroin use, readiness to change heroin use, and depression were collected.



The results found that although the original three-factor model was acceptable for applying the DDQ-CM for heroin users with MMT, only the concurrent validity of the subscales of Desire and Intention and Negative Reinforcement was supported but not that of Control. Meanwhile, the levels of craving on the subscales of Desire and Intention and of Negative Reinforcement on the DDQ-CM were positively associated with the levels of heroin dependence, positive and negative attitudes toward heroin use, and depression, but negatively associated with readiness to change heroin use.



This study supported the application of the subscales of Desire and Intention and Negative Reinforcement on the DDQ-CM to measure heroin craving in Taiwanese-Chinese heroin users and supported the clinical implication of craving in heroin users with MMT.

title: Beyond drug use: a systematic consideration of other outcomes in evaluations of treatments for substance use disorders.
abstract: Across the addictions field, the primary outcome in treatment research has been reduction in drug consumption. A comprehensive view of the impact of substance use disorders on human functioning suggests that effective treatments should address the many consequences and features of addiction beyond drug use, a recommendation forwarded by multiple expert panels and review papers. Despite recurring proposals, and a compelling general rationale for moving beyond drug use as the sole standard for evaluating addiction treatment, the field has yet to adopt any core set of 'other' measures that are routinely incorporated into treatment research. Among the many reasons for the limited impact of previous proposals has been the absence of a clear set of guidelines for selecting candidate outcomes. This paper is the result of the deliberations of a panel of substance abuse treatment and research experts convened by the National Institute on Drug Abuse to discuss appropriate outcome measures for clinical trials of substance abuse treatments. This paper provides an overview of previous recommendations and outlines specific guidelines for consideration of candidate outcomes. A list of outcomes meeting those guidelines is described and illustrated in detail with two outcomes: craving and quality of life. The paper concludes with specific recommendations for moving beyond the outcome listing offered in this paper to promote the programmatic incorporation of these outcomes into treatment research.

title: The relationship between craving, anxiety, and other symptoms in opioid withdrawal.
abstract: Craving and anxiety share many similar attributes including comparable responses to pharmacological agents. To better characterize the relationship among craving, anxiety, and other opioid withdrawal signs and symptoms, we examined 32 opioid-dependent subjects undergoing clonidine-assisted opioid withdrawal. A 13-item analog scale measured subjective withdrawal symptoms. Statistical analyses of separate subscale items, using craving as the dependent variable, showed that the highest positive correlations occur for craving and anxiety. The high correlation between craving and anxiety suggests common mechanisms underlying both.

title: Context and craving during stressful events in the daily lives of drug-dependent patients
abstract: RationaleKnowing how stress manifests in the lives of people with substance-use disorders could help inform mobile “just in time” treatment.ObjectivesThe purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies.MethodsFor up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within-person from between-person effects; reffect sizes below are within-person.ResultsParticipants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity (reffect = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, −0.14; child, −0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (−0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data.ConclusionsThe contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving.

title: Sex differences in daily life stress and craving in opioid-dependent patients
abstract: Responses to stress and drug craving differ between men and women. Differences in the momentary experience of stress in relation to craving are less well-understood.  Using ecological momentary assessment (EMA), we examined sex differences in real-time in two areas: (1) causes and contexts associated with stress, and (2) the extent to which stress and drug cues are associated with craving.  Outpatients on opioid-agonist treatment (135 males, 47 females) reported stress, craving, and behavior on smartphones for 16 weeks. They initiated an entry each time they felt more stressed than usual (stress event) and made randomly prompted entries 3 times/day. In stress-event entries, they identified the causes and context (location, activity, companions), and rated stress and craving severity.  The causes reported for stress events did not differ significantly by sex. Women reported arguing and being in a store more often during stress events, and men reported working more often during stress events, compared to base rates (assessed via random prompts). Women showed a greater increase in opioid craving as a function of stress (p < 0.0001) and had higher stress ratings in the presence of both stress and drug cues relative to men (p < 0.01). Similar effects were found for cocaine craving in men (p < 0.0001).  EMA methods provide evidence based on real-time activities and moods that opioid-dependent men and women experience similar contexts and causes for stress but differ in stress- and cue-induced craving. These findings support sex-based tailoring of treatment, but because not all participants conformed to the overall pattern of sex differences, any such tailoring should also consider person-level differences.

title: Chronic pain, craving, and illicit opioid use among patients receiving opioid agonist therapy.
abstract: In a sample of patients receiving opioid agonist therapy, we evaluated whether having chronic pain was associated with (a) craving for opioids and (b) illicit opioid use.



In a cross-sectional study of adults on buprenorphine or methadone maintenance recruited from an urban medical center, we examined any craving for opioids (primary dependent variable) in the past week and recent illicit opioid use (secondary dependent variable). Illicit opioid use was defined as a positive urine drug test (UDT) for opiates and chronic pain was defined as bodily pain that had been present for at least 3 months. Multivariable logistic regression models were fit for each outcome, adjusting for age, sex, and non-white race. Additional models adjusted for depression (PHQ-9) and anxiety (STAI).



The sample included 105 adults on methadone or buprenorphine maintenance. Mean age was 43.8 (SD ±9.4)years; 48% were female and 32% non-white; 19% were on methadone. Chronic pain was present in 68% of the sample, 51% reported craving opioids in the past week, and 16% had a positive UDT. Chronic pain was associated with 3-fold higher odds of reporting craving in the past week (aOR=3.10; 95% CI: 1.28-7.50, p-value=0.01). The relative odds for having a positive UDT were not statistically significant (aOR=2.52; 95% CI: 0.64-9.90, p=0.18).



In this sample of patients treated with opioid agonist therapy, those with chronic pain had higher odds of reporting craving for opioids. Chronic pain with associated opioid craving potentially places this population at risk for relapse.

title: Day-to-day pain symptoms are only weakly associated with opioid craving among patients with chronic pain prescribed opioid therapy.
abstract: Over the past decade, there has been a substantial rise in the use of opioids for the treatment of chronic noncancer pain. Despite the potential benefits of opioid therapy, the rise in the use of opioids has been accompanied by escalating rates of prescription opioid misuse and addiction. There is now a growing body of evidence indicating that opioid craving (i.e., the subjective desire to consume opioids) is one of the strongest determinants of opioid misuse among patients with chronic pain prescribed opioids. Although research has elucidated some of the factors associated with opioid craving, the contribution of patients' levels of pain to opioid craving remains unclear.



The main objective of this study was to examine the day-to-day association between pain and opioid craving.



In this longitudinal cohort study, patients with chronic pain prescribed opioid therapy completed baseline measures and were then asked to provide daily reports of pain intensity and opioid craving for a period of 14 days.



Multilevel analyses indicated that day-to-day elevations in patients' levels of pain were associated with heightened opioid craving. That is, on more painful days, patients reported higher levels of craving. Within-person changes in pain intensity, however, explained less than 5% of the variance in patients' reports of craving.



Findings from this study suggest that patients with chronic pain do not crave their opioid medications simply because they experience high levels of pain. The theoretical and clinical implications of our findings are discussed.

title: The association between negative affect and prescription opioid misuse in patients with chronic pain: the mediating role of opioid craving.
abstract: Over the past decade, considerable research has accumulated showing that chronic pain patients experiencing high levels of negative affect (NA) are at increased risk for prescription opioid misuse. The primary objective of the present study was to examine the factors that underlie the association between NA and prescription opioid misuse among patients with chronic pain. In this study, 82 patients with chronic musculoskeletal pain being prescribed opioid medication completed the Current Opioid Misuse Measure, a well-validated self-report questionnaire designed to assess prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, NA, and opioid craving. A bootstrapped multiple mediation analysis was used to examine the mediating role of patients' pain intensity and opioid craving in the association between NA and prescription opioid misuse. Consistent with previous research, we found a significant association between NA and prescription opioid misuse. Interestingly, results revealed that opioid craving, but not pain intensity, mediated the association between NA and opioid misuse. The Discussion addresses the potential psychological and neurobiological factors that might contribute to the interrelationships among NA, opioid craving, and prescription opioid misuse in patients with pain. The clinical implications of our findings are also discussed.



Our study provides new insights into the factors that underlie the association between negative affect and prescription opioid misuse in patients with chronic pain. Our findings could have important clinical implications, particularly for patients being prescribed opioid medication, and for reducing rates of opioid misuse in patients with pain.

title: The association between catastrophizing and craving in patients with chronic pain prescribed opioid therapy: a preliminary analysis.
abstract: A growing number of studies have shown that opioid craving (i.e., the perceived need or desire to consume opioids) is one of the strongest determinants of prescription opioid misuse in patients with chronic pain prescribed opioid therapy. To date, however, the factors that are associated with craving in patients with pain remain largely unexplored. Based on previous research, there is reason to believe that catastrophizing might be associated with heightened opioid craving.



To test the hypothesis that catastrophizing would be associated with heightened craving in patients with chronic pain prescribed long-term opioid therapy.



In this cross-sectional study, 109 patients with chronic pain were asked to provide self-reports of catastrophizing and craving. Patients also provided self-reports of pain intensity and depressive symptoms.



We found that higher levels of catastrophizing were associated with higher levels of craving. Importantly, results of a regression analysis revealed that the association between catastrophizing and craving remained significant even after controlling for a host of demographic (i.e., age, sex), psychological (i.e., depressive symptoms), medical (i.e., pain intensity, pain duration), and medication regimen (i.e., opioid doses) variables.



Our preliminary findings provide valuable new insights into the determinants of craving in patients with pain. The finding that catastrophizing was associated with craving even after controlling for a host of demographic, psychological, medical, and medication regimen variables is particularly striking, and raises questions concerning the factors that underlie the association between catastrophizing and craving in patients prescribed opioid therapy.

title: Opioid attentional bias and cue-elicited craving predict future risk of prescription opioid misuse among chronic pain patients.
abstract: Some chronic pain patients receiving long-term opioid analgesic pharmacotherapy are at risk for misusing opioids. Like other addictive behaviors, risk of opioid misuse may be signaled by an attentional bias (AB) towards drug-related cues. The purpose of this study was to examine opioid AB as a potential predictor of opioid misuse among chronic pain patients following behavioral treatment.



Chronic pain patients taking long-term opioid analgesics (n=47) completed a dot probe task designed to assess opioid AB, as well as self-report measures of opioid misuse and pain severity, and then participated in behavioral treatment. Regression analyses examined opioid AB and cue-elicited craving as predictors of opioid misuse at 3-month posttreatment follow-up.



Patients who scored high on a measure of opioid misuse risk following treatment exhibited significantly greater opioid AB scores than patients at low risk for opioid misuse. Opioid AB for 200 ms cues and cue-elicited craving significantly predicted opioid misuse risk 20 weeks later, even after controlling for pre-treatment opioid dependence diagnosis, opioid misuse, and pain severity (Model R(2)=.50).



Biased initial attentional orienting to prescription opioid cues and cue-elicited craving may reliably signal future opioid misuse risk following treatment. These measures may therefore provide potential prognostic indicators of treatment outcome.

title: Does Report of Craving Opioid Medication Predict Aberrant Drug Behavior Among Chronic Pain Patients?
abstract: ObjectiveTo examine the relationship between the self-report of craving prescription medication and subsequent opioid misuse among chronic pain patients prescribed opioids for pain. MethodsSix hundred thirteen patients taking opioid medication for chronic noncancer pain were asked how often they have felt a craving for their medication on a scale from 0=never to 4=very often. All participants completed a series of baseline questionnaires. After 6 months the participants were administered a structured prescription drug use interview (Prescription Drug Use Questionnaire), and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist (Prescription Opioid Therapy Questionnaire). ResultsThree hundred thirty-seven participants (55.0%) reported that they never felt a craving for their medication, whereas 276 (45.0%) reported some degree of craving their medication (seldom to very often). Those who reported craving their medication were significantly more often male (P<0.01), unmarried (P<0.05), had lower scores on social desirability (P<0.001), and had been prescribed opioids for a longer time (P<0.05) than those who did not report craving medication. At 6-month follow-up, those who reported craving their medication showed higher scores on the Prescription Drug Use Questionnaire (P<0.001), had a higher incidence of physician-rated aberrant drug behavior on the Prescription Opioid Therapy Questionnaire (P<0.05), showed a higher frequency of abnormal urine toxicology screens (P<0.001), and more often had a positive Aberrant Drug Behavior Index (P<0.001). DiscussionThese results suggest that self-reported craving is a potential marker for identification of those at risk for opioid medication misuse.

title: Principles for managing OUD related to chronic pain in the Nordic countries based on a structured assessment of current practice
abstract: BackgroundLong-term use of opioid analgesics (OA) for chronic pain may result in opioid use disorder (OUD). This is associated with adverse outcomes for individuals, families and society. Treatment needs of people with OUD related to chronic pain are different compared to dependence related to use, and also injection, of illicit opioids. In Nordic countries, day-to-day practical advice to assist clinical decision-making is insufficient.AimTo develop principles based on expert clinical insights for treatment of OUD related to the long-term use of OA in the context of chronic pain.MethodsCurrent status including an assessment of barriers to effective treatment in Finland, Denmark, Iceland, Norway, Sweden was defined using a patient pathway model. Evidence to describe best practice was identified from published literature, clinical guidelines and expert recommendations from practice experience.ResultsAvailability of national treatment guidelines for OUD related to chronic pain is limited across the Nordics. Important barriers to effective care identified: patients unlikely to present for help, healthcare system set up limits success, diagnosis tools not used, referral pathways unclear and treatment choices not elucidated. Principles include the development of a specific treatment pathway, awareness/ education programs for teams in primary care, guidance on use of diagnostic tools and a flexible treatment plan to encourage best practice in referral, treatment assessment, choice and ongoing management via an integrated care pathway. Healthcare systems and registries in Nordic countries offer an opportunity to further research and identify population risks and solutions.ConclusionsThere is an opportunity to improve outcomes for patients with OUD related to chronic pain by developing and introducing care pathways tailored to specific needs of the population.

title: CONDITIONED INHIBITION OF CRAVING IN DRUG ADDICTION: A PILOT EXPERIMENT.
abstract: It seems likely that an important reason for the limited success of aversion treatment of drug addiction has been that the aversion is applied only to extrinsic stimuli associated with the drug. No attempt is ordinarily made to combat the endogenous habit. In the present experiment a subject with a Demerol (Pethidine) addiction of 3 years' standing was instructed to give himself a severe shock from a portable apparatus whenever he felt a desire for the drug arise endogenously. On three occasions he gave himself 4, 3 and 2 shocks respectively, dispelling the craving. After this the apparatus broke down, but for a period of 12 weeks the patient remained free from any but minor cravings that he could easily control.

title: Management of Opioid Addiction With Opioid Substitution Treatments: Beyond Methadone and Buprenorphine
abstract: With the opioid crisis in North America, opioid addiction has come in the spotlight and reveals the weakness of the current treatments. Two main opioid substitution therapies (OST) exist: buprenorphine and methadone. These two molecules are mu opioid receptor agonists but with different pharmacodynamic and pharmacokinetic properties. In this review, we will go through these properties and see how they could explain why these medications are recognized for their efficacy in treating opioid addiction but also if they could account for the side effects especially for a long-term use. From this critical analysis, we will try to delineate some guidelines for the design of future OST.

title: Effect of Methadone Maintenance Treatment on Heroin Craving, a Literature Review
abstract: Despite agreement that methadone maintenance treatment (MMT) is an effective and safe option for treatment of heroin dependence, there have been controversies about its effect on heroin craving. A systematic literature review of the PubMed database was used to find studies eligible for inclusion in the study. The authors present the results of 16 articles that met all inclusion criteria. Overall, 7 studies reported that methadone could reduce heroin craving, 4 studies reported that patients in MMT are still at risk of having heroin craving, 1 study reported that methadone could increase heroin craving, and 4 studies reported that methadone has a neutral effect on heroin craving. One may speculate from these data that methadone may help with heroin craving, but patients in MMT may still be at risk of cue-induced heroin cravings. Methadone provides a helpful tool for reducing some components of craving and risk of relapse for patient receiving MMT.

title: Heroin anticraving medications: A systematic review
abstract: Heroin craving is a trigger for relapse and dropping out of treatment. Methadone has been the standard medication for the management of heroin craving.  We explored the medication options other than methadone which may have heroin anticraving properties.  To be selected for the review, articles had to include outcome measures of the effect of the studied medication on subjective and/or objective opiate craving and be of the following two types: (1) randomized, controlled, and/or double-blind clinical trials (RCTs) examining the relationship between the studied medication and heroin craving; (2) nonrandomized and observational studies (NRSs) examining the relationship between the studied medication and heroin craving. Thirty-three articles were initially included in the review. Twenty-one were excluded because they did not meet the inclusion criteria. We present the results of 12 articles that met all the inclusion criteria.  Some new medications have been under investigation and seem promising for the treatment of opiate craving. Buprenorphine is the second most studied medication after methadone for its effect on opiate craving. At doses above 8 mg daily, it seems very promising and practical for managing opiate craving in patients receiving long-term opioid maintenance treatment.  In doses higher than 8 mg daily, buprenorphine is an appropriate treatment for opiate craving. More research with rigorous methodology is needed to study the effect of buprenorphine on heroin craving. Also more studies are needed to directly compare buprenorphine and methadone with regard to their effects on heroin craving.

title: Maintenance Medication for Opiate Addiction: The Foundation of Recovery
abstract: Illicit use of opiates is the fastest growing substance use problem in the United States, and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to human immunodeficiency virus, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication-assisted detoxification. This article provides a topical review of the three medications approved by the Food and Drug Administration for long-term treatment of opiate dependence: the opioid-agonist methadone, the partial opioid-agonist buprenorphine, and the opioid-antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction, but recent studies using extended-release naltrexone injections have shown promise. Although no direct comparisons between extended-release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared with methadone and buprenorphine. Further work is needed to directly compare each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication.

title: Long-term methadone maintenance reduces protracted symptoms of heroin abstinence and cue-induced craving in Chinese heroin abusers
abstract: Cession of heroin use may be followed by a protracted-abstinence (PA) syndrome consisting of craving, negative mood, and physiological changes. PA symptoms have rarely been compared between drug-free and methadone-maintained former heroin users after similar lengths of heroin abstinence.



Seventy former heroin users were included in one of four groups: in day 15-45 of methadone maintenance therapy (short-term MMT), in month 5-6 of MMT (long-term MMT), opiate-free for 15-45 days after methadone-assisted heroin detoxification (short-term post-methadone), and opiate-free for 5-6 months after methadone-assisted heroin detoxification (long-term post-methadone). PA symptoms (negative mood, dyssomnia, somatization, and craving), and blood pressure and pulse were assessed pre- and post-neutral videotape and pre- and post-heroin videotape.



Dyssomnia and the total PA score were worst in short-term post-methadone participants, mood was best in long-term MMT participants, and cue-induced craving was least severe in long-term MMT participants. Blood pressure and pulse did not differ across groups.



Even after acute withdrawal, the first months of heroin abstinence after methadone-assisted detoxification may be more difficult in terms of cue-induced craving and other PA symptoms than the first months of heroin abstinence during MMT. Our findings add to the literature supporting MMT for prevention of cue-induced heroin craving.

title: Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.
abstract: Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions.



Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis).



Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving.



In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

title: Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.
abstract: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels.



Patients were randomized to four dosage groups and treated double-blind.



Twelve outpatient opiate maintenance treatment centers throughout the United States.



Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment.



Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session.



Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events.



Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids.



The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

title: Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy.
abstract: Sublingual formulations of buprenorphine (BUP) and BUP/naloxone have well-established pharmacokinetic and pharmacodynamic profiles, and are safe and effective for treating opioid use disorder. Since approvals of these formulations, their clinical use has increased. Yet, questions have arisen as to how BUP binding to mu-opioid receptors (μORs), the neurobiological target for this medication, relate to its clinical application. BUP produces dose- and time-related alterations of μOR availability but some clinicians express concern about whether doses higher than those needed to prevent opioid withdrawal symptoms are warranted, and policymakers consider limiting reimbursement for certain BUP dosing regimens.



We review scientific data concerning BUP-induced changes in μOR availability and their relationship to clinical efficacy.



Withdrawal suppression appears to require ≤50% μOR availability, associated with BUP trough plasma concentrations ≥1 ng/mL; for most patients, this may require single daily BUP doses of 4 mg to defend against trough levels, or lower divided doses. Blockade of the reinforcing and subjective effects of typical doses of abused opioids require <20% μOR availability, associated with BUP trough plasma concentrations ≥3 ng/mL; for most individuals, this may require single daily BUP doses >16 mg, or lower divided doses. For individuals attempting to surmount this blockade with higher-than-usual doses of abused opioids, even larger BUP doses and <10% μOR availability would be required.



For these reasons, and given the complexities of studies on this issue and comorbid problems, we conclude that fixed, arbitrary limits on BUP doses in clinical care or limits on reimbursement for this care are unwarranted.

title: Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers: A Preliminary Study
abstract: A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally more opioid receptors that mediate heroin effects. In this preliminary study we examined in vivo μ opioid receptor (μOR) binding in three healthy opioid-dependent volunteers during maintenance on 2 and 16 mg sublingual buprenorphine (BUP) liquid, and after detoxification (0 mg) under double-blind, placebo-controlled conditions, and once in matched controls. Binding measures were obtained with the μOR-selective radioligand [11C]carfentanil (CFN) and PET 4 hrs after BUP administration. BUP induced dose-dependent reductions in μOR availability, 36–50% at 2 mg and 79–95% at 16 mg relative to placebo. Heroin abusers also had greater μOR binding potential in the inferofrontal cortex and anterior cingulate regions during placebo, compared to matched controls. Further studies are warranted to examine the relationship of μOR availability with BUP therapeutic actions, and the clinical implications of increased μOR binding during withdrawal.

title: Buprenorphine Pharmacokinetics: Relative Bioavailability of Sublingual Tablet and Liquid Formulations
abstract: Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM‐III‐R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration‐time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.

title: Effects of Buprenorphine Maintenance Dose on μ-Opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers
abstract: The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medication's ability to decrease μ-opioid receptor (μOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. We empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. We predicted and confirmed that higher BUP doses would decrease in vivo μOR availability (measured with PET and [11C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (±SEM) whole-brain μOR availability 41±8, 80±2, and 84±2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in μOR availability varied across ROIs (prefrontal cortex, 47% vs amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94–98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5–1, 5–6, and 13–14 ng/ml at 2, 16, and 32 mg, respectively). μOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal μOR occupation, μOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration–effect relationships.

title: Buprenorphine Duration of Action: Mu-opioid Receptor Availability and Pharmacokinetic and Behavioral Indices
abstract: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of micro opioid receptors (microORs). This study examined the duration of action of BUP at microORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers.



Availability of microOR (measured with positron emission tomography and [(11)C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere.



Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain microOR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of microOR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade.



Together with our previous findings, it appears that microOR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.

title: Naltrexone and buprenorphine combination in the treatment of opioid dependence
abstract: Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50mg oral dose) plus buprenorphine (4mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone+ buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p= 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p< 0.05; p< 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.

title: The Brain on Drugs: From Reward to Addiction
abstract: Advances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain's reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction.

title: Acute HPA axis response to naltrexone differs in female vs. male smokers
abstract: Both opioid antagonist administration and cigarette smoking acutely increase hypothalamic-pituitary-adrenal (HPA) axis activity as measured by adrenocorticotropic hormone (ACTH) and cortisol levels. However, male and female smokers may differ in their response to the opioid antagonist naltrexone, which may be partially mediated by sex differences in HPA axis function. Smokers, as a group, have frequently been shown to have HPA axis dysfunction, which may have relevance to the course and maintenance of nicotine dependence. The purpose of this study was to examine possible sex differences in HPA axis function by comparing stress-hormone response to naltrexone within healthy male and female smokers. Additionally, exploratory analyses compared the combined effects of naltrexone and cigarette smoking on hormonal responsivity between the sexes.



Thirty-eight healthy smokers (22 men) were tested in two separate morning sessions after 12h of smoking abstinence. For women, self-reports of menstrual cycle information were obtained prior to each session (date of last menstruation, cycle length, reproductive phase, etc.). Each participant received 50mg naltrexone or placebo capsule (in random order) and plasma levels of ACTH and cortisol were assessed at regular intervals for several hours. A subgroup of 12 participants underwent a similar, additional session in which they smoked a single cigarette three hours after naltrexone administration.



Naltrexone significantly increased ACTH and cortisol levels in women, but not men (DrugxSexxTime, p<0.05). A post hoc analysis suggested that women at an estimated 'high estrogen' phase had a greater cortisol response (DrugxEstrogen level, p<0.05) than those at an estimated 'low estrogen' phase. Exploratory analyses showed that smoking a single cigarette potentiated naltrexone-induced increases in ACTH (p<0.05) and cortisol (p<0.01) in all participants.



The findings support the hypothesis that women are more sensitive to opioid antagonism at the level of the HPA axis. Although further studies are needed to examine mechanisms underlying these responses, both results may have clinical implications for the use of naltrexone as a treatment for nicotine dependence.

title: Risk Factors for Craving and Relapse in Heroin Users Treated with Oral or Implant Naltrexone
abstract: Oral naltrexone effectively antagonizes heroin, but patient noncompliance limits its utility; sustained-release preparations may overcome this. Few data are available on optimal blood naltrexone levels for preventing craving and/or return to heroin use. This study assesses various risk factors, including blood naltrexone level, for heroin craving and relapse to illicit opioids.



Heroin-dependent persons from a randomized controlled trial of oral versus implant naltrexone were followed up for 6 months. Thirty-four participants received 50 mg oral naltrexone daily, plus placebo implant; thirty-five participants received a single dose of 2.3 g naltrexone implant, plus daily oral placebo tablets.



Compared to oral naltrexone patients, implant naltrexone patients were significantly less likely to use any opioids and had one-fifth the risk of using heroin > or = weekly. Risk of > or = weekly heroin use increased by 2.5 times at blood naltrexone concentration < .5 ng/mL compared with > or = .5 ng/mL, with 3 ng/mL associated with very low risk of use. Craving remained near "floor" levels for implant patients but rebounded to higher levels among oral patients. Lower craving scores (< or = 20/70) predicted lower relapse risk. Noncompliance with daily oral formula, higher baseline craving, longer history of use, and being younger predicted higher craving at follow-up.



Implant naltrexone was better associated with reduced heroin craving and relapse than oral naltrexone. Effective treatment was achieved at blood naltrexone levels of 1 ng/mL to 3 ng/mL, with higher levels associated with greater efficacy. Craving assessment may be valuable in predicting relapse risk allowing timely intervention.

title: Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant
abstract: Naltrexone is a μ-opioid receptor antagonist that blocks opioid effects. Craving, depression, anxiety, and anhedonia are common among opioid dependent individuals and concerns have been raised that naltrexone increases them due to blocking endogenous opioids. Here, we present data that address these concerns.  Assess the relationship between affective responses and naltrexone treatment.  Opioid dependent patients (N = 306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Test, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the Tukey test for those who remained and treatment and did not relapse, and between the last measure before dropout with the same measure for those remaining in treatment.  Depression, anxiety, and anhedonia were elevated at baseline but reduced to normal within the first 1–2 months for patients who remained in treatment and did not relapse. Other than a slight increase in two anxiety measures at week two, there were no significant between-group differences prior to treatment dropout.  These data do not support concerns that naltrexone treatment of opioid dependence increases craving, depression, anxiety or anhedonia.

title: Cognitive behavioral therapy for substance use disorders.
abstract: Cognitive behavioral therapy (CBT) for substance use disorders has shown efficacy as a monotherapy and as part of combination treatment strategies. This article provides a review of the evidence supporting the use of CBT, clinical elements of its application, novel treatment strategies for improving treatment response, and dissemination efforts. Although CBT for substance abuse is characterized by heterogeneous treatment elements such as operant learning strategies, cognitive and motivational elements, and skills-building interventions, across protocols several core elements emerge that focus on overcoming the powerfully reinforcing effects of psychoactive substances. These elements, and support for their efficacy, are discussed.

title: Motivational interviewing for substance abuse.
abstract: There are 76.3 million people with alcohol use disorders worldwide and 15.3 million with drug use disorders. Motivational interviewing (MI) is a client-centred, semi-directive method for enhancing intrinsic motivation to change by exploring and resolving ambivalence. The intervention is used widely, and therefore it is important to find out whether it helps, harms or is ineffective.



To assess the effectiveness of motivational interviewing for substance abuse on drug use, retention in treatment, readiness to change, and number of repeat convictions.


SEARCH STRATEGY
We searched 18 electronic databases, 5 web sites, 4 mailing lists, and reference lists from included studies and reviews. Search dates were November 30, 2010 for Cochrane Library, Medline, Embase and PsychINFO.



Randomized controlled trials with persons dependent or abusing substance. Interventions were MI or motivational enhancement therapy. The outcomes were extent of substance abuse, retention in treatment, motivation for change, repeat conviction.



Three authors independently assessed studies for inclusion, and two authors extracted data. Results were categorized into (1) MI versus no-treatment control, (2) MI versus treatment as usual, (3) MI versus assessment and feedback, and (4) MI versus other active treatment. Within each category, we computed meta-analyses separately for post-intervention, short, medium and long follow-ups.



We included 59 studies with a total of 13,342 participants. Compared to no treatment control MI showed a significant effect on substance use which was strongest at post-intervention SMD 0.79, (95% CI 0.48 to 1.09) and weaker at short SMD 0.17 (95% CI 0.09 to 0.26], and medium follow-up SMD 0.15 (95% CI 0.04 to 0.25]). For long follow-up, the effect was not significant SMD 0.06 (95% CI-0.16 to 0.28). There were no significant differences between MI and treatment as usual for either follow-up post-intervention, short and medium follow up. MI did better than assessment and feedback for medium follow-up SMD 0.38 (95% CI 0.10 to 0.66). For short follow-up, there was no significant effect . For other active intervention there were no significant effects for either follow-up.There was not enough data to conclude about effects of MI on the secondary outcomes.



MI can reduce the extent of substance abuse compared to no intervention. The evidence is mostly of low quality, so further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

title: Contingency Management interventions for non-prescribed drug use during treatment for opiate addiction: A systematic review and meta-analysis
abstract: Highlights • Contingency management (CM) reduces other drug use in opiate addiction treatment.• Meta-analyses did not find evidence of effectiveness for non-prescribed opiate use.• CM is effective for cocaine, tobacco, opiates + cocaine, tobacco, polysubstance use.• Evidence is lacking for long-term effects.

title: Comparison of behavioral treatment conditions in buprenorphine maintenance.
abstract: The Controlled Substances Act requires physicians in the United States to provide or refer to behavioral treatment when treating opioid-dependent individuals with buprenorphine; however, no research has examined the combination of buprenorphine with different types of behavioral treatments. This randomized controlled trial compared the effectiveness of four behavioral treatment conditions provided with buprenorphine and medical management (MM) for the treatment of opioid dependence.



After a 2-week buprenorphine induction/stabilization phase, participants were randomized to one of four behavioral treatment conditions provided for 16 weeks: cognitive behavioral therapy (CBT = 53); contingency management (CM = 49); both CBT and CM (CBT + CM = 49); and no additional behavioral treatment (NT = 51).



Study activities occurred at an out-patient clinical research center in Los Angeles, California, USA.



Included were 202 male and female opioid-dependent participants.



Primary outcome was opioid use, measured as a proportion of opioid-negative urine results over the number of tests possible. Secondary outcomes include retention, withdrawal symptoms, craving, other drug use and adverse events.



No group differences in opioid use were found for the behavioral treatment phase (χ2  = 1.25, P = 0.75), for a second medication-only treatment phase, or at weeks 40 and 52 follow-ups. Analyses revealed no differences across groups for any secondary outcome.



There remains no clear evidence that cognitive behavioural therapy and contingency management reduce opiate use when added to buprenorphine and medical management in opiate users seeking treatment.

title: Cognitive-behavioural therapy for heroin and cocaine use: Ecological momentary assessment of homework simplification and compliance.
abstract: The purpose of this study was to evaluate the effects of homework-task difficulty and electronic-diary reminders on written homework completion during cognitive-behavioural therapy (CBT) for addiction. Completion of homework is an important element in CBT that may affect outcome.



All participants received all combinations of our two interventions in a factorial 2 × 2 counterbalanced Latin-square design.



Methadone-maintained cocaine and heroin users were given homework between each of 12 weekly CBT sessions and carried electronic diaries that collected ecological momentary assessment (EMA) data on craving and exposure to drug-use triggers in four 3-week blocks assessing two levels of homework difficulty and prompted and unprompted homework.



Neither simplified (picture-based) homework nor electronic reminders increased homework completion. In EMA reports, standard but not simplified homework seemed to buffer the craving that followed environmental exposure to drug cues. EMA recordings before and after the CBT intervention confirmed a decrease over time in craving for cocaine and heroin.



These findings demonstrate the utility of EMA to assess treatment effects. However, the hypothesis that simplified homework would increase compliance was not supported.



Our simplifications of homework assignments for cognitive-behavioural therapy were mostly ineffective, or even counterproductive, perhaps because they did not engage sufficient depth of processing or because they were perceived as too simplistic. Our reminder beeps for homework were mostly ineffective, or even counterproductive, suggesting that mobile electronic interventions for substance-use disorders may need to be more interactive.

title: Are Mindfulness-Based Interventions Effective for Substance Use Disorders? A Systematic Review of the Evidence
abstract: Mindfulness-based interventions (MBIs) are increasingly suggested as therapeutic approaches for effecting substance use and misuse (SUM). The aim of this article is to review current evidence on the therapeutic efficacy of MBIs for SUM. A literature search was undertaken using four electronic databases and references of retrieved articles. The search included articles written in English published up to December 2011. Quality of included trials was assessed. In total, 24 studies were included, three of which were based on secondary analyses of previously investigated samples. Current evidence suggests that MBIs can reduce the consumption of several substances including alcohol, cocaine, amphetamines, marijuana, cigarettes, and opiates to a significantly greater extent than waitlist controls, non-specific educational support groups, and some specific control groups. Some preliminary evidence also suggests that MBIs are associated with a reduction in craving as well as increased mindfulness. The limited generalizability of the reviewed findings is noted (i.e., small sample size, lack of methodological details, and the lack of consistently replicated findings). More rigorous and larger randomized controlled studies are warranted.

title: Mindfulness-based Relapse Prevention for Substance Use Disorders: A Systematic Review and Meta-analysis
abstract: Substance use disorder (SUD) is a prevalent health issue with serious personal and societal consequences. This review aims to estimate the effects and safety of Mindfulness-based Relapse Prevention (MBRP) for SUDs.  We searched electronic databases for randomized controlled trials evaluating MBRP for adult patients diagnosed with SUDs. Two reviewers independently assessed citations, extracted trial data, and assessed risks of bias. We conducted random-effects meta-analyses and assessed quality of the body of evidence (QoE) using the Grading of Recommendations Assessment, Development, and Evaluation approach.  We identified 9 randomized controlled trials comprising 901 participants. We did not detect statistically significant differences between MBRP and comparators on relapse (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.46–1.13, low QoE), frequency of use (standardized mean difference [SMD] 0.02, 95% CI −0.40 to 0.44, low QoE), treatment dropout (OR 0.81, 95% CI 0.40 to 1.62, very low QoE), depressive symptoms (SMD −0.09, 95% CI −0.39 to 0.21, low QoE), anxiety symptoms (SMD −0.32, 95% CI −1.16 to 0.52, very low QoE), and mindfulness (SMD −0.28, 95% CI −0.72 to 0.16, very low QoE). We identified significant differences in favor of MBRP on withdrawal/craving symptoms (SMD −0.13, 95% CI −0.19 to −0.08, I2 = 0%, low QoE) and negative consequences of substance use (SMD −0.23, 95% CI −0.39 to −0.07, I2 = 0%, low QoE). We found negligible evidence of adverse events.  We have limited confidence in estimates suggesting MBRP yields small effects on withdrawal/craving and negative consequences versus comparator interventions. We did not detect differences for any other outcome. Future trials should aim to minimize participant attrition to improve confidence in effect estimates.

title: The Clinical Efficacy of Mindfulness-Based Treatments for Alcohol and Drugs Use Disorders: A Meta-Analytic Review of Randomized and Nonrandomized Controlled Trials
abstract: The current study aims to evaluate if and to what extent mindfulness-based interventions (MBIs) could promote an incremental effectiveness compared to interventions usually provided in clinical practice to treat Alcohol and Drugs Use Disorders. In line with this aim, we accomplished a meta-analytic review of randomized and nonrandomized controlled trials, considering primary and secondary outcomes that comprehensively operationalize treatment efficacy.  We conducted the online research up to August 31st 2017. Adequate procedures for Cohen’s d computation were applied. Heterogeneity indexes, moderators, bias of publication, and Orwin’s fail-safe number were also estimated.  Thirty-seven studies were included (n = 3,531 patients). We observed null effect sizes for attrition rate and overall mental health. Small effect sizes were detected in abstinence, levels of perceived stress, and avoidance coping strategies. Moderate effect sizes were revealed in anxiety and depressive symptoms. Large effect sizes were associated to levels of perceived craving, negative affectivity, and post-traumatic symptoms.  MBIs seemed to show clinically significant advantages compared to other clinical approaches in relation to specific primary and secondary outcomes. Conversely, treatment retention was independent of the therapeutic approach.

title: Mindfulness treatment for substance misuse: A systematic review and meta-analysis.
abstract: High rates of relapse following substance misuse treatment highlight an urgent need for effective therapies. Although the number of empirical studies investigating effects of mindfulness treatment for substance misuse has increased dramatically in recent years, few reviews have examined findings of mindfulness studies. Thus, this systematic review examined methodological characteristics and substantive findings of studies evaluating mindfulness treatments for substance misuse published by 2015. The review also includes the first meta-analysis of randomized controlled trials of mindfulness treatments for substance misuse. Comprehensive bibliographic searches in PubMed, PsycInfo, and Web of Science, identified 42 pertinent studies. Meta-analytic results revealed significant small-to-large effects of mindfulness treatments in reducing the frequency and severity of substance misuse, intensity of craving for psychoactive substances, and severity of stress. Mindfulness treatments were also effective in increasing rates of posttreatment abstinence from cigarette smoking compared to alternative treatments. Mindfulness treatment for substance misuse is a promising intervention for substance misuse, although more research is needed examining the mechanisms by which mindfulness interventions exert their effects and the effectiveness of mindfulness treatments in diverse treatment settings.

title: Autonomic and Affective Mediators of the Relationship Between Mindfulness and Opioid Craving Among Chronic Pain Patients
abstract: Prescription opioid misuse among chronic pain patients is undergirded by self-regulatory deficits, affective distress, and opioid-cue reactivity. Dispositional mindfulness has been associated with enhanced self-regulation, lower distress, and adaptive autonomic responses following drug-cue exposure. We hypothesized that dispositional mindfulness might serve as a protective factor among opioid-treated chronic pain patients. We examined heart-rate variability (HRV) during exposure to opioid cues and depressed mood as mediators of the association between dispositional mindfulness and opioid craving. Data were obtained from a sample of chronic pain patients (N = 115) receiving long-term opioid pharmacotherapy. Participants self-reported opioid craving and depression, and HRV was measured during an opioid-cue dot-probe task. Dispositional mindfulness was significantly positively correlated with HRV, and HRV was significantly inversely associated with opioid craving. Dispositional mindfulness was significantly negatively correlated with depression, and depression was significantly positively correlated with opioid craving. Path analysis revealed significant indirect effects of dispositional mindfulness on craving through both HRV and depression. Dispositional mindfulness may buffer against opioid craving among chronic pain patients prescribed opioids; this buffering effect may be a function of improved autonomic and affective responses.

title: Dispositional mindfulness and prescription opioid misuse among chronic pain patients: Craving and attention to positive information as mediating mechanisms.
abstract: Opioid-treated chronic pain patients may be at risk for prescription opioid misuse due to heightened opioid craving coupled with deficits in attention to naturally rewarding, positive stimuli. Conversely, dispositional mindfulness, which is associated with reduced craving and increased responsiveness to natural rewards, may serve as a protective factor and buffer opioid misuse risk. The current investigation aimed to examine the association between mindfulness and opioid misuse, and to test opioid craving and attention to positive information as mediators of this relationship.



This cross-sectional analysis examined data obtained from a sample of civilian opioid-treated chronic pain patients in the Southeastern U.S. (Sample 1: N = 115), as well as civilian (Sample 2: N = 141) and military samples in the Intermountain West (Sample 3: N = 44). Pearson correlations and path analyses were employed to test relations among participant self-reports on the Current Opioid Misuse Measure (COMM), the Five Facet Mindfulness Questionnaire (FFMQ), two measures of opioid craving, and the Attention to Positive and Negative Information Scale (APNIS).



Across all three samples, dispositional mindfulness was significantly inversely associated with opioid misuse (N = 300, r = -0.36, p < .001). Reduced opioid craving and increased attention to positive information mediated the association between dispositional mindfulness and opioid misuse.



Dispositional mindfulness may buffer opioid misuse risk by attenuating opioid craving and enhancing attention to naturally rewarding stimuli.

title: Mindfulness-oriented recovery enhancement for chronic pain and prescription opioid misuse: results from an early-stage randomized controlled trial.
abstract: Opioid pharmacotherapy is now the leading treatment for chronic pain, a problem that affects nearly one third of the U.S. population. Given the dramatic rise in prescription opioid misuse and opioid-related mortality, novel behavioral interventions are needed. The purpose of this study was to conduct an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), a multimodal intervention designed to simultaneously target mechanisms underpinning chronic pain and opioid misuse.



Chronic pain patients (N = 115; mean age = 48 ± 14 years; 68% female) were randomized to 8 weeks of MORE or a support group (SG). Outcomes were measured at pre- and posttreatment, and at 3-month follow-up. The Brief Pain Inventory was used to assess changes in pain severity and interference. Changes in opioid use disorder status were measured by the Current Opioid Misuse Measure. Desire for opioids, stress, nonreactivity, reinterpretation of pain sensations, and reappraisal were also evaluated.



MORE participants reported significantly greater reductions in pain severity (p = .038) and interference (p = .003) than SG participants, which were maintained by 3-month follow-up and mediated by increased nonreactivity and reinterpretation of pain sensations. Compared with SG participants, participants in MORE evidenced significantly less stress arousal (p = .034) and desire for opioids (p = .027), and were significantly more likely to no longer meet criteria for opioid use disorder immediately following treatment (p = .05); however, these effects were not sustained at follow-up.



Findings demonstrate preliminary feasibility and efficacy of MORE as a treatment for co-occurring prescription opioid misuse and chronic pain.

title: Mindfulness-Based Relapse Prevention for Substance Use Disorders: A Pilot Efficacy Trial
abstract: The current study is the first randomized-controlled trial evaluating the feasibility and initial efficacy of an 8-week outpatient Mindfulness-Based Relapse Prevention (MBRP) program as compared to treatment as usual (TAU). Participants were 168 adults with substance use disorders who had recently completed intensive inpatient or outpatient treatment. Assessments were administered pre-intervention, post-intervention, and 2 and 4 months post-intervention. Feasibility of MBRP was demonstrated by consistent homework compliance, attendance, and participant satisfaction. Initial efficacy was supported by significantly lower rates of substance use in those who received MBRP as compared to those in TAU over the 4-month post-intervention period. Additionally, MBRP participants demonstrated greater decreases in craving, and increases in acceptance and acting with awareness as compared to TAU. Results from this initial trial support the feasibility and initial efficacy of MBRP as an aftercare approach for individuals who have recently completed an intensive treatment for substance use disorders.

title: Substance use outcomes for mindfulness based relapse prevention are partially mediated by reductions in stress: Results from a randomized trial.
abstract: Mindfulness based relapse prevention (MBRP) has demonstrated efficacy in alleviating substance use, stress, and craving but how MBRP works for marginalized young adults has not been investigated. The current study used a novel rolling group format for MBRP as an additional intervention for young adults in residential treatment. We tested the hypothesis that MBRP (plus Treatment as usual (TAU)) would reduce stress, craving, and substance use among young adults in residential treatment relative to treatment-as-usual plus 12-step/self-help meetings (TAU only). Further, we examined whether reduced stress during treatment was a potential mechanism of change operating in MBRP.



Seventy-nine young adults (Mage = 25.3,SD = 2.7;35 % female) were randomly assigned to MBRP (n = 44) or TAU (n = 35). Follow-up assessments were conducted bi-monthly for self-reported measures of stress, craving, and substance use.



At treatment completion young adults receiving MBRP had lower substance use (d = -0.58, [-0.91, -0.26]), craving (d = -0.58, [-1.0, -0.14]), and stress (d = -0.77 [-1.2, -0.30]) relative to TAU condition. Reduced stress during treatment partially mediated observed outcome differences between MBRP and TAU for substance use (βindirect = -0.45 [-0.79, -0.11]).



Results suggest that MBRP is a useful and appropriate intervention for marginalized young adults. Further, our results suggest that the effects of MBRP on long-term substance use outcomes may be partially explained by reduced stress.

title: Effects of mindfulness training on levels of cortisol in cancer patients.
abstract: The aims of this study were to examine the effects of a mindfulness-based stress reduction (MBSR) training intervention among cancer patients on levels of salivary cortisol, and further to explore if changes in psychological variables mediate intervention effects on cortisol.



Patients with a previous cancer diagnosis (n = 71) were recruited and randomized into an intervention group or a waiting-list control group. The intervention consisted of an 8-week MBSR training course.



There were no overall effects of the intervention on cortisol levels at 3-month or 6-month follow-up. However, a significant effect of moderation was found showing a different intervention effect on awakening cortisol among participants with varying baseline level of cortisol. Among those with initial low levels of cortisol, there was an increase from baseline to 3-month follow-up, and among those with initial high levels there was a decreased level of cortisol at 3-month follow-up. There was no association between changes in psychological outcomes and cortisol levels.



The results suggest an adjustment of cortisol levels as a result of MBSR. The study gives preliminary support indicating that MBSR can influence the hypothalamic-pituitary-adrenocortical (HPA) axis functioning. The importance of these findings for future research in the field of mindfulness and stress reduction among cancer patients are discussed.

title: Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients
abstract: This study investigated the relationships between a mindfulness-based stress reduction meditation program for early stage breast and prostate cancer patients and quality of life, mood states, stress symptoms, and levels of cortisol, dehydroepiandrosterone-sulfate (DHEAS) and melatonin.



Fifty-nine patients with breast cancer and 10 with prostate cancer enrolled in an eight-week Mindfulness-Based Stress Reduction (MBSR) program that incorporated relaxation, meditation, gentle yoga, and daily home practice. Demographic and health behavior variables, quality of life, mood, stress, and the hormone measures of salivary cortisol (assessed three times/day), plasma DHEAS, and salivary melatonin were assessed pre- and post-intervention.



Fifty-eight and 42 patients were assessed pre- and post-intervention, respectively. Significant improvements were seen in overall quality of life, symptoms of stress, and sleep quality, but these improvements were not significantly correlated with the degree of program attendance or minutes of home practice. No significant improvements were seen in mood disturbance. Improvements in quality of life were associated with decreases in afternoon cortisol levels, but not with morning or evening levels. Changes in stress symptoms or mood were not related to changes in hormone levels. Approximately 40% of the sample demonstrated abnormal cortisol secretion patterns both pre- and post-intervention, but within that group patterns shifted from "inverted-V-shaped" patterns towards more "V-shaped" patterns of secretion. No overall changes in DHEAS or melatonin were found, but nonsignificant shifts in DHEAS patterns were consistent with healthier profiles for both men and women.



MBSR program enrollment was associated with enhanced quality of life and decreased stress symptoms in breast and prostate cancer patients, and resulted in possibly beneficial changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. These pilot data represent a preliminary investigation of the relationships between MBSR program participation and hormone levels, highlighting the need for better-controlled studies in this area.

title: Influence of Mindfulness Practice on Cortisol and Sleep in Long-Term and Short-Term Meditators
abstract: There is growing scientific interest in assessing the biological correlates of non-pharmacological interventions such as mindfulness. Examinations of the beneficial effects of mindfulness on hypothalamus-pituitary-adrenocortical system activity (HPA SA) and sleep are sparse. The aim of the present study was to explore the impact of long- and short-term meditation experience on HPA SA and sleep.  There were 20 participants, 9 of whom had long-term experience in meditation (mean = 264 months) and 11 novices. Novices underwent an 8-week course in Mindfulness-Based Stress Reduction (MBSR), and cortisol samples were taken in the lab at the beginning and end of the course. To assess the cortisol awakening response, 4 morning cortisol samples were collected. Sleep and mindfulness were assessed by self-rating questionnaires.  Among participants with long-term meditation experience, morning cortisol decreased with length of experience. For novices, after an 8-week introductory MBSR course, morning cortisol levels had decreased, while both sleep and self-attribution of mindfulness significantly improved. Cortisol levels did not, however, change between the beginning and end of individual MBSR sessions.  The pattern of results lends support to the view that MBSR/meditation has a favorable influence both on biomarkers of stress regulation, such as cortisol secretion, and on sleep.

title: Effects of Mindfulness-Based Interventions on Salivary Cortisol in Healthy Adults: A Meta-Analytical Review
abstract: The aim of the present study was to elucidate the effects of Mindfulness-based interventions (MBIs) on salivary cortisol levels in healthy adult populations.  We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), published between January 1980 and June 2015 in PubMed, EMBASE, PsycINFO and the Cochrane library. The PRISMA and Cochrane guidelines were followed. The pooled effect sizes were calculated with the random-effects model, using Hedges' g-values, and heterogeneity was measured using the I2 statistic. The contribution of different characteristics of participants and programmes were assessed by meta-regression models, using beta coefficients.  Five RCTs with 190 participants in total were included in this systematic review. The overall effect size (ES) for improving the state of health related to cortisol levels was moderately low (g = 0.41; p = 0.025), although moderate heterogeneity was found (I2 = 55; p = 0.063). There were no significant differences between active (g = 0.33; p = 0.202) and passive (g = 0.48; p = 0.279) controls, but significant differences were found when comparing standard (g = 0.81; p = 0.002) and raw (g = 0.03; p = 0.896) measures. The percentage of women in each study was not related to ES. Nevertheless, age (beta = −0.03; p = 0.039), the number of sessions (beta = 0.33; p = 0.007) and the total hours of the MBI (beta = 0.06; p = 0.005) were significantly related to ES, explaining heterogeneity (R2 = 1.00).  Despite the scarce number of studies, our results suggest that MBIs might have some beneficial effect on cortisol secretion in healthy adult subjects. However, there is a need for further RCTs implemented in accordance with standard programmes and measurements of salivary cortisol under rigorous strategies in healthy adult populations.

title: Change in Stress Levels Following Mindfulness-based Stress Reduction in a Therapeutic Community
abstract: ObjectivesThis pilot was designed to study identified changes in the psychologic and physiological stress response of individuals who participated in a Mindfulness-Based Stress Reduction intervention while in treatment of substance abuse in a therapeutic community. MethodsTwenty-one participants in a residential therapeutic community received the intervention, which consisted of training in 5 mindfulness practices. Stress response was assessed by measuring awakening salivary cortisol and the Perceived Stress Scale (PSS) pre- and post-intervention. ResultsAwakening salivary cortisol levels were significantly lower (P < 0.0001) following the intervention. Although there was a decrease in self reported stress between the baseline measurement and the post-intervention measurement, the change in the PSS was not statistically significant (P = 0.65). ConclusionsThese results suggest that a Mindfulness-Based Stress Reduction intervention may influence the physiological response to stress for individuals in a therapeutic community. The results also support the use of salivary cortisol as an indicator of the stress response in this setting. Future studies are needed to determine the value of this intervention as an adjunct to therapeutic community treatment.

title: Stress reduction correlates with structural changes in the amygdala.
abstract: Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable.

title: Mindfulness practice leads to increases in regional brain gray matter density
abstract: Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular, but to date little is known about neural mechanisms associated with these interventions. Mindfulness-Based Stress Reduction (MBSR), one of the most widely used mindfulness training programs, has been reported to produce positive effects on psychological well-being and to ameliorate symptoms of a number of disorders. Here, we report a controlled longitudinal study to investigate pre-post changes in brain gray matter concentration attributable to participation in an MBSR program. Anatomical magnetic resonance (MR) images from 16 healthy, meditation-naïve participants were obtained before and after they underwent the 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry, and compared with a waiting list control group of 17 individuals. Analyses in a priori regions of interest confirmed increases in gray matter concentration within the left hippocampus. Whole brain analyses identified increases in the posterior cingulate cortex, the temporo-parietal junction, and the cerebellum in the MBSR group compared with the controls. The results suggest that participation in MBSR is associated with changes in gray matter concentration in brain regions involved in learning and memory processes, emotion regulation, self-referential processing, and perspective taking.