The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction

Accumulating evidence suggests that glutamate, as one of the most important excitatory neurotransmitters in the brain, plays a key role in drug addiction including opioid addiction. There is substantial evidence for glutamatergic projections into mesocorticolimbic dopaminergic neurons, which are associated with opioid psychological dependence and are also the key regions of enhancement effect. Glutamate may be involved in the process of opioid addiction not only by acting on its ionotropic and metabotropic glutamate receptors that activate several signal transduction pathways, but also by interacting with other neurotransmitters or neuropeptides such as opioids, dopamine, γ-aminobutyric acid and substance P in the mesocorticolimbic dopaminergic regions. Studies on the role of glutamate and its receptors in opioid addiction will provide a new strategy for the exploitation of drugs for the treatment of opioid addiction.     

Evidenced-based treatment of opioid-dependent patients.

OBJECTIVE: To provide an overview of treatment options for opioid-dependent patients. METHOD: We screened all published studies on the treatment of opioid dependence, with a special focus on systematic literature reviews, formal metaanalyses, and recent trials. RESULTS: Both clinical experience and neurobiological evidence indicate that opioid dependence is a chronic relapsing disorder. Treatment objectives depend on the pursued goals: crisis intervention, abstinence-oriented treatment (detoxification and relapse prevention), or agonist maintenance treatment. The high quality of solid evidence in the literature demonstrates that there are numerous effective interventions available for the treatment of opioid dependence. Crisis intervention, frequently necessary owing to the high overdose rate, can be effectively handled with naloxone. Abstinence-oriented interventions are effective for only a few motivated patients with stable living conditions and adequate social support. Agonist maintenance treatment is considered the first line of treatment for opioid dependence. Numerous studies have shown efficacy for methadone and buprenorphine treatment, while maintenance with other agonists is also becoming available to a greater extent. Maintenance treatment with diamorphine should be made available for the small group of treatment-resistant, severely dependent addicts. Other harm-reduction measures can serve to engage individuals with opioid addiction who are not in treatment. CONCLUSION: Opioid dependence is a chronic relapsing disease that is difficult to cure, but effective treatments are available to stabilize patients and reduce harm, thereby increasing life expectancy and quality of life.     

Innovations in agonist maintenance treatment of opioid-dependent patients

PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. SUMMARY: Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatment-resistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life.     

Is the bipolar spectrum the psychopathological substrate of suicidality in heroin addicts?

BACKGROUND: To describe the prevalence and the risk factors of suicidal ideation in a cohort of Italian opioid addicts presenting for treatment. METHOD: Systematic cross-sectional clinical data on suicidal ideation, socio-demographic variables, psychiatric status, social adjustment, status and history of addiction in 616 patients were gathered. RESULTS: Suicidal thoughts during the past week were reported by 29.1%. Suicidal thoughts were more frequent in patients with bipolar spectrum diagnoses (OR = 1.42) and in patients with depressive and aggressive symptoms (multiple R = 0.47). The odds of having suicidal thoughts were also higher for subjects receiving public welfare benefits (OR = 1.69), unemployed patients (OR = 1.37), those with early onset of heroin dependence (OR = 1.36), living alone (OR = 1.33), and experiencing problems in organizing social contacts and leisure time (OR = 1.28). CONCLUSION: Current suicidal ideation was a common feature of patients with opioid addiction. Depression and hostility as part of the bipolar spectrum - in the context of early-onset drug dependence, work and social/leisure problems - appear independently associated with suicidal ideation. Given the elevated rates of completed suicide in heroin addiction, these data have implications for preventing suicide in patients with this type of addiction. Prospective data are needed to further address this important clinical and public health agenda.     

Developing a vaccine against multiple psychoactive targets: a case study of heroin

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.     

Intrathecal Opioid Therapy for Pain: Efficacy and Outcomes

Although opioid therapy has been accepted for the treatment of patients with cancer pain, its use for nonmalignant pain is still regarded as controversial due to concerns about the development of tolerance and psychological dependence. However, recent studies indicate that there is a low incidence of addiction in patients who do not have a history of addictive disorders, and opioid use is increasing for long-term treatment in patients with nonmalignant pain. This paper reviews the results from recent studies that evaluated the efficacy of intrathecal opioid delivery using a number of outcome measures. These studies demonstrate that intrathecal opioid delivery produces short-term relief of specific symptoms and improves long-term outcomes such as patient functioning (measured by increases in activities of daily living [ADLs] and capacity to work), mood, treatment satisfaction, and quality of life, as well as decreases in oral opioid use. Furthermore, these studies showed there was no development of tolerance or addiction in patients who received long-term intrathecal opioid delivery.     

Compulsivity and obsessionality in opioid addiction

Seventy-one individuals with opioid dependence undergoing ambulatory treatment participated in a personal interview assessing the importance of their opioid-use rituals, the severity of compulsivity and obsessionality in relation to their drug use, and the number of obsessive compulsive disorder (OCD) symptoms. The level of compulsivity and obsessionality in opioid dependence was comparable to that found in OCD and alcohol addiction. The importance of rituals was inversely related to the number of opioid lapses during rehabilitation treatment and positively correlated with the number of non-drug-related OCD symptoms. Based on established norms for OCD symptoms, we estimated that 11.4% of our sample would meet diagnostic criteria for OCD, a rate which is over 4 times higher than the rate of OCD in the general population.     

Pharmacotherapy for opioid addiction in community corrections

Abstract

Pharmacotherapy for opioid addiction with methadone, buprenorphine, and naltrexone has proven efficacy in reducing illicit opioid use. These treatments are under-utilized among opioid-addicted individuals on parole, probation, or in drug courts. This paper examines the peer-reviewed literature on the effectiveness of pharmacotherapy for opioid addiction of adults under community-based criminal justice supervision in the US. Compared to general populations, there are relatively few papers addressing the separate impact of pharmacotherapy on individuals under community supervision. Tentative conclusions can be drawn from the extant literature. Reasonable evidence exists that illicit opioid use and self-reported criminal behaviour decline after treatment entry, and that these outcomes are as favourable among individuals under criminal justice supervision as the general treatment population. Surprisingly, there is no conclusive evidence regarding the extent to which pharmacotherapy impacts the likelihood of arrest and incarceration among individuals under supervision. However, given the proven efficacy of these three medications in reducing illicit opioid use and the evidence that, in the general population, methadone and buprenorphine treatment are associated with reduction in overdose mortality, the use of all three pharmacotherapies among patients under criminal justice supervision should be expanded while more data are collected on their impact on arrest and incarceration.     

Barriers to Use of Pharmacotherapy for Addiction Disorders and How to Overcome Them

Substance use disorders are highly prevalent, debilitating conditions for which effective pharmacotherapies exist with a broad evidence base, yet pharmacotherapy for the treatment of addiction disorders is underutilized. The goals of this review are to describe the barriers that may contribute to poor adoption and utilization of pharmacotherapy for alcohol and opioid dependence at the system, provider, and patient level and to discuss ways to overcome those barriers. Multifaceted efforts directed at all three levels may be needed to speed pharmacotherapy adoption. More research is needed to help us better understand barriers from patients’ perspectives. Strategies to promote adoption of pharmacotherapy for addiction disorders should be modified to fit the needs of the practice, system, and individual patients. Pharmacotherapy is a valuable tool in the clinical armamentarium of addiction treatment; thus, overcoming barriers to implementation may improve clinical and social outcomes.     

Opioid addiction: Who are your real friends?

Opioid addiction is a chronic and relapsing mental health disorder. However, only some individuals exposed to opioids, either recreationally or during the course of pain management, will develop addiction. The reasons why some individuals develop addiction and some are spared are not fully understood. Studies indicate that it is likely a combination of genetic predispositions and environmental conditions. Given the role of environmental factors in human addiction, this review examines the role of social environments and social interactions in the development of opioid addictive-like behaviors in rodent studies. To date, three major behavioral approaches have been used in these studies, namely social isolation, environmental enrichment, and social housing with a variety of cage-mates that differ in their drug administration conditions. This review highlights the importance of an individual’s social network in influencing the outcomes of drug abuse and the need to further elucidate the molecular mechanisms underlying these effects. Better understanding is likely to contribute to the development of novel and more effective treatments for addiction disorders.     

Le point sur l’addiction à la cocaïne et au crack

There is an increase in the use of cocaine and crack by the populations of Western Europe and in the demand for treatment. The absence of specific medicinal treatments, and in particular of suitable substitutes for this type of drug addiction, makes their treatment more difficult. Our purpose is to present a focus on cocaine and crack addiction.     

Benzodiazepine use, abuse, and dependence

Although benzodiazepines are invaluable in the treatment of anxiety disorders, they have some potential for abuse and may cause dependence or addiction. It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines. However, this dependence, which generally manifests itself in withdrawal symptoms upon the abrupt discontinuation of the medication, may be controlled and ended through dose tapering, medication switching, and/or medication augmentation. Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction.     

Addiction and personality

Within the field of substance abuse, it is now widely admitted that the addictive personality does not exist. No one personality type is predisposed to addiction. The predisposition to drug dependence involves many different factors: psychological, social, familial, biological. None of these factors can be the sole determinant of drug dependence. Keeping that in mind, it is of interest to review the recent data on the relationship between personality traits or disorders and opiate and cocaine dependence. Using DSM and ICD categorical assessment, no single personality disorder emerged, instead a range of personality disorders has been evaluated in opiate and cocaine dependent subjects. Every type of personality disorders (PD) existed but cluster BPD were the most common (especially antisocial personality disorder in opiate addicts). However, it is noteworthy that a large minority to a majority of subjects did not display any king of PD. The implication of these results is that antisocial PD is probably over-diagnosed in drug dependence clinical settings. The studies reviewed failed to demonstrate that personality disorders were strong predictors of outcome in opiate or cocaine dependence. However, opiate dependent PD subjects entering treatment had more severe problems and lower retention rate than non PD subjects. But the amount of improvement was not significantly different between PD subjects and non PD subjects. This demonstrated that substance dependent PD patients could benefit from treatment whose intensity and duration must be adjusted. There is good support for the idea that Sensation Seeking trait is a vulnerability factor to substance abuse. But after dependence develops, sensation seeking is probably irrelevant to continued use of the drugs. This break between the psychopathology of vulnerability of substance abuse and the psychopathology of dependence raises the question of the existence of dramatically different factors involved in both phases of addiction.     

Does maintenance treatment reduce the mortality rate of opioid addicts?

Reduction of mortality is a basic goal of methadone maintenance treatment (MMT) for opioid addicts. During the last years, however, there have been reports about drug related deaths of MMT patients and of untreated drug addicts who had consumed illegally purchased methadone. To evaluate the supposed beneficial effect of MMT on mortality, data from a multicentre trial in the German state of North Rhine-Westphalia were analysed. 244 patients with long histories of opioid addiction and previous failures in at least two abstinence oriented treatments were observed for at least four years and up to eight years after admission to MMT. With 32 deaths out of 244 participants, the mortality rate for the whole sample was 2.5 % p.a. This rate is not remarkably different from estimations for opioid addicts in general. However, addicts in continuous maintenance treatment had a mortality rate of only 1.6 % p.a., in contrast to a rate of 8.1 % p.a. for addicts who had left treatment. These results are supported by other long-term studies with large patient samples. Therefore it is concluded that methadone maintenance treatment is a measure to reduce the mortality in opioid addicts. Attainment of this goal is threatened, however, by deviations from safety standards, especially if take-home privileges are granted too widely.     

男女海洛因依赖者成瘾严重程度的比较

目的：了解男女海洛因依赖者成瘾严重程度的差异,为针对不同性别海洛因依赖者制定干预措施提供依据。方法：采用自制个案调查表和成瘾行为严重度指数量表（addiction severity index,ASI）对199例男性和239例女性海洛因依赖者进行评估,比较不同性别海洛因依赖者ASI量表中各维度分值的差异。结果：女性依赖者ASI中因子4（药物使用）评分平均为（0.52±0.28）分和因子7（精神健康状况）平均（0.15±0.24）分显著高于男性的（0.43±0.34）分和（0.08±0.19）分（P〈0.05或P〈0.01）;男性依赖者因子5（法律状况）评分平均（0.07±0.13）分高于女性的（0.03±0.10）分（P〈0.01）。将年龄、首次吸毒年龄及吸毒时间与ASI分量表进行偏相关分析发现,年龄（r=-0.182）、吸毒时间（r=0.158）与因子4（药物使用）分数存在显著相关;进一步相关分析发现,年龄与吸毒时间存在显著相关（r=0.364,P〈0.01）。结论：男女海洛因依赖者在成瘾行为严重程度方面存在差异,临床治疗与康复过程中应针对不同性别特征制定个体化的治疗方案以满足不同性别患者的需求。     

Safety and Feasibility of Nucleus Accumbens Surgery for Drug Addiction: A Systematic Review

BackgroundSubstance addiction encompasses the incapacity to discontinue urgent drug use; many severely disabled patients might be considered appropriate candidates for surgery due to the high rates of relapse despite conservative treatment. A crucial finding in the brain of these patients is increased extracellular concentrations of dopamine in the nucleus accumbens (NAcc).ObjectivesTo determine the efficacy and safety of NAcc surgery for the treatment of substance dependence.Materials and MethodsAdhering to PRISMA guidelines, we performed a systematic review to identify all original studies in which NAcc surgery was performed to treat relapsing drug addiction with a minimum follow-up of six months. From database inception to April 10, 2020, we searched PubMed, Scopus, and LILACS. Two reviewers independently selected studies and extracted data. The main outcome was the relapse rate. The GRADE methods were applied to evaluate the quality of evidence. This study was registered with PROSPERO CRD42020177054.ResultsFifteen studies involving 359 participants met inclusion criteria; eight (56%) included NAcc deep brain stimulation (DBS) in 13 patients with addiction for alcohol (N = 6, 46.1%), opioid (N = 4, 30.7%), and nicotine (N = 3, 15.3%); seven studies (N = 346, 44%) performed NAcc radiofrequency (RF) ablation for opioid (N = 334) and alcohol (N = 12) dependence. Relapse rates were 38.4% for DBS and 39% for RF ablation.ConclusionsDespite available studies reporting a benefit in the treatment of drug addictions with NAcc surgery, this systematic review stresses the need for carefully planned prospective studies in order to further address the efficacy and indications.     

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Substance Use and Related Disorders. Part 2: Opioid dependence

Abstract

Objectives. To develop evidence-based practice guidelines for the pharmacological treatment of opioid abuse and dependence. Methods. An international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) developed these practice guidelines after a systematic review of the available evidence pertaining to the treatment of opioid dependence. On the basis of the evidence, the Task Force reached a consensus on practice recommendations, which are intended to be clinically and scientifically meaningful for physicians who treat adults with opioid dependence. The data used to develop these guidelines were extracted primarily from national treatment guidelines for opioid use disorders, as well as from meta-analyses, reviews, and publications of randomized clinical trials on the efficacy of pharmacological and other biological treatments for these disorders. Publications were identified by searching the MEDLINE database and the Cochrane Library. The literature was evaluated with respect to the strength of evidence for efficacy, which was categorized into one of six levels (A–F). Results. There is an excellent evidence base supporting the efficacy of methadone and buprenorphine or the combination of buprenorphine and naloxone for the treatment of opioid withdrawal, with clonidine and lofexidine as secondary or adjunctive medications. Opioid maintenance with methadone and buprenorphine is the best-studied and most effective treatment for opioid dependence, with heroin and naltrexone as second-line medications. Conclusions. There is enough high quality data to formulate evidence-based guidelines for the treatment of opioid abuse and dependence. This task force report provides evidence for the efficacy of a number of medications to treat opioid abuse and dependence, particularly the opioid agonists methadone or buprenorphine. These medications have great relevance for clinical practice.     

Ethical Issues Raised by Proposals to Treat Addiction Using Deep Brain Stimulation

Deep brain stimulation (DBS) has been proposed as a potential treatment of drug addiction on the basis of its effects on drug self-administration in animals and on addictive behaviours in some humans treated with DBS for other psychiatric or neurological conditions. DBS is seen as a more reversible intervention than ablative neurosurgery but it is nonetheless a treatment that carries significant risks. A review of preclinical and clinical evidence for the use of DBS to treat addiction suggests that more animal research is required to establish the safety and efficacy of the technology and to identify optimal treatment parameters before investigating its use in addicted persons. Severely addicted persons who try and fail to achieve abstinence may, however, be desperate enough to undergo such an invasive treatment if they believe that it will cure their addiction. History shows that the desperation for a “cure” of addiction can lead to the use of risky medical procedures before they have been rigorously tested. In the event that DBS is used in the treatment of addiction, we provide minimum ethical requirements for clinical trials of its use in the treatment of addiction. These include: restrictions of trials to severely intractable cases of addiction; independent oversight to ensure that patients have the capacity to consent and give that consent on the basis of a realistic appreciation of the potential benefits and risks of DBS; and rigorous assessments of the effectiveness and safety of this treatment compared to the best available treatments for addiction.     

Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol‐dependent and polysubstance‐dependent individuals

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance‐dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened ‘top‐down’ control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no‐go (GNG) task, we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent polysubstance‐dependent (poly‐SUD) individuals and controls during a randomised double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly‐SUD groups respectively. Self‐reported trait impulsivity in the poly‐SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly‐SUD groups, which are predicted by trait impulsivity in the poly‐SUD group.