Throughout the long history of opioid drug use by humans, it has been known that opioids are powerful analgesics, but they can cause addiction. It has also been observed, and is now substantiated by multiple reports and studies, that during opioid treatment of severe and short-term pain, addiction arises only rarely. However, when opioids are extended to patients with chronic pain, and therapeutic opioid use is not confined to patients with severe and short-lived pain, compulsive opioid seeking and addiction arising directly from opioid treatment of pain become more visible. Although the epidemiological evidence base currently available is rudimentary, it appears that problematic opioid use arises in some fraction of opioid-treated chronic pain patients, and that problematic behaviors and addiction are problems that need to be addressed. Since the potentially devastating effects of addiction can substantially offset the benefits of opioid pain relief, it seems timely to reexamine addiction mechanisms and their relevance to the practice of long-term opioid treatment for pain. This article reviews the neurobiological and genetic basis of addiction, its terminology and diagnosis, the evidence on addiction rates during opioid treatment of chronic pain and the implications of biological mechanisms in formulating rational opioid treatment regimes.

Opioid dependence and addiction during opioid treatment of chronic pain.

The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer’s disease, stroke, and Parkinson’s disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12–16 years) compared with a non-CNS drug (10–12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

https://link.springer.com/content/pdf/10.1602/neurorx.2.4.554.pdf

Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery

Rationale
Pathological gambling (PG) has recently been considered as a “behavioral” or nonsubstance addiction. A comparison of the characteristics of PG and substance use disorders (SUDs) has clinical ramifications and could help advance future research on these conditions. Specific relationships with impulsivity and compulsivity may be central to understanding PG and SUDs.

/pdf/similarities-and-differences-between-pathological-gambling-4unt4s9pcf.pdf

Similarities and differences between pathological gambling and substance use disorders: a focus on impulsivity and compulsivity

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.

Neural bases for addictive properties of benzodiazepines

Impulse control disorders (ICDs) are characterized by urges and behaviors that are excessive and/or harmful to oneself or others and cause significant impairment in social and occupational functioning, as well as legal and financial difficulties. ICDs are relatively common psychiatric conditions, yet are poorly understood by the general public, clinicians, and individuals struggling with the disorder. Although ICD treatment research is limited, studies have shown ICDs may respond well to pharmacological treatment. This article presents a brief overview about the clinical characteristics of ICDs and pharmacological treatment options for individuals with ICDs.

/pdf/impulse-control-disorders-updated-review-of-clinical-rzwjp63c2z.pdf

Impulse Control Disorders: Updated Review of Clinical Characteristics and Pharmacological Management

Objective Several open-label and double-blind studies have suggested that selective serotonin reuptake inhibitors may be useful in the treatment of pathological gambling. The purpose of this study was to evaluate the efficacy of sertraline in the treatment of pathological gambling. Method Sixty patients meeting the DSM-IV criteria for pathological gambling were treated for 6 months in a double-blind, flexible-dose, placebo-controlled study of sertraline 50 to 150 mg/day. Data were collected from November 1998 to January 2001. The primary outcome measure assessing change in clinical status was the responder rate with respect to the Criteria for Control of Pathological Gambling Questionnaire (CCPGQ). Secondary measures included the Clinical Global Impressions scale (CGI) (Severity of Illness and Improvement subscales), and Visual Analogue Scales assessing gambling frequency, severity, amount, and improvement. Concomitant medication and psychotherapy were not allowed during the study. Results At the end of the study, 23 sertraline-treated subjects (74%) and 21 placebo-treated subjects (72%) were considered as responders on the CCPGQ (p = .9). Similar results were obtained when the CGI-Improvement scale limited to symptoms of pathological gambling was used as an outcome measure. Sertraline was well tolerated throughout the study. Conclusion Sertraline was not statistically significantly superior to placebo in the overall sample. The power of the study was limited by the high placebo-response rate and the small sample size.

Margarita M. Gómez

Papers

Sertraline treatment of pathological gambling: a pilot study.