Endogenous Opioids at the Intersection of Opioid Addiction, Pain, and Depression: The Search for a Precision Medicine Approach (original) (raw)
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Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches
Molecular Psychiatry
The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics that have a low or absent risk of abuse and addiction relative to µ-opioid agonists. Moreover, agents targeting the endogenous opioid system would be expected to yield clinical benefits qualitatively different from conventional monaminergic antidepressants. The development of safe and effective agents to treat MDD-associated endogenous opioid dysregulation may represent a distinct and currently underappreciated means of addressing treatment resistant depression with the potential to attenuate the ongoing opioid crisis.
The endogenous opioid system: A common substrate in drug addiction
Drug and Alcohol Dependence, 2010
Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.
Drug and alcohol dependence, 2015
Opioid therapy is one component of an effective pain management regimen for patients with chronic pain and the majority of these patients use their medications responsibly. However, there are a growing number of these patients who develop an opioid use disorder and in some cases require opioid replacement therapy. Managing these patients is complex and the underlying mechanisms of pain and addiction are not well understood. Developing an effective interdisciplinary treatment program for the individual with pain and an opioid use disorder will depend on enhancing our knowledge of the psychophysiology of pain and addiction. Authors gathered key empirical and theoretical papers examining the psychophysiology of comorbid pain and opioid misuse disorders. This article reviews the current theory of the effect of pain on patients with pain and concomitant addiction, the psychophysiology of pain, opioid use and addiction, and future research in this area. Individuals with a history of opioi...
Neuropsychological Functions of μ- and δ-Opioid Systems
ISRN Addiction, 2013
Brain opioid innervation is involved in many pathophysiological processes related to drug addiction. The main idea of the present review is that -/ -opioid innervation is an intrinsic component of the motor/approach behavior network, which is activated synergetically with dopaminergic mesocorticolimbic network. Contribution of opioid innervation to the motor/approach behavior processing includes generation of positive emotions and inhibition of pain and stress reactions in order that the individual would be able to reach the vital goal. We cite the neuroanatomical data which showed that motor subcortical nuclei contain the most abundant opioid innervation and its activation is an obligatory component of positive emotions. In the majority of life situations, motor/approach behavior network concomitantly activates pain/stress control opioid network. Intensive cognitive activity induces activation of opioid innervation as well, and both enhancing and impairing effects of opioid agonists on cognitive functioning were demonstrated. Overall, the functioning of endogenous opioid networks may be summarized as following: NO physical/cognitive activity = NO positive emotions plus NO pain/stress control. We suppose that contemporary findings concerning neuropsychological functions of endogenous opioid system explain many controversial issues in neuropsychiatric conditions predisposing to drug addiction and neurological mechanisms of opioid addiction.
The Science of Addiction Through the Lens of Opioid Treatment for Chronic Noncancer Pain
Pain Management Nursing, 2019
Addiction is a chronic, relapsing brain disease. It is not the same as physical dependence (i.e., withdrawal) and tolerance, but is characterized by loss of control over the use of the substance, continued use despite consequences, compulsive use, and cravings. Addiction involves functional changes to brain pathways involved in reward, stress and learning, and these changes can last a long time after the addictive substance is no longer used. Repeated interruption of normal brain function from repetitive use of addictive substances can hijack normal reward mechanisms resulting in fundamental alterations in brain structure and function. Over time, addictive substances can bring about a false fixed prediction error that cannot be rectified during learning. And, for individuals who develop an addiction, initial impulsive drug use progresses to compulsive drug use and this progression also has neurobiological underpinnings. Drug addiction is partly heritable, although there is no single gene coding specifically for the disease of addiction. Genetic factors contribute to a vulnerability to develop both addiction and addiction comorbidities, and play an appreciable role in responses to and metabolism of addictive substances, and most likely, the experience of rewarding effects. Patients with pain who are addicted to opioids have, in addition to the pain disorder, a chronic relapsing brain disease that can be life-threatening. Addiction can be treated and controlled, but not cured. Treatment of pain in individuals with addiction is a complex clinical challenge. Holistic assessment, interprofessional approaches, use of established guidelines, and non-pharmacological complementary modalities are needed.
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2005
Unraveling the pathways and neurobiological mechanisms that underlie the regulation of physical and emotional stress responses in humans is of critical importance to understand vulnerability and resiliency factors to the development of a number of complex physical and psychopathological states. Dysregulation of central stress response circuits have been implicated in the establishment of conditions as diverse as persistent pain, mood and personality disorders and substance abuse and dependence. The present review examines the contribution of the endogenous opioid system and A-opioid receptors to the modulation and adaptation of the organism to challenges, such as sustained pain and negative emotional states, which threaten its internal homeostasis. Data accumulated in animal models, and more recently in humans, point to this neurotransmitter system as a critical modulator of the transition from acute (warning signals) to sustained (stressor) environmental adversity. The existence of pathways and regulatory mechanisms common to the regulation of both physical and emotional states transcend classical categorical disease classifications, and point to the need to utilize dimensional, ''symptom''-related approximations to their study. Possible future areas of study at the interface of ''mind'' (cognitive -emotional) and ''body'' (physical) functions are delineated in this context. D
Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice
Frontiers in Psychiatry, 2019
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.
Current Pharmaceutical Design, 2009
The pathophysiology of mood disorders involves several genetic and social predisposing factors, as well as a dysregulated response to a chronic stressor, i.e. chronic pain. Our present view that depression involves a dysfunction of the monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. In fact, current pharmacological treatment for depression is based on the use of drugs that act mainly by enhancing brain serotonin and noradrenaline neurotransmission by the blockade of the active reuptake mechanism for these neurotransmitters. However, a substantial number of patients do not respond adequately to antidepressant drugs. In view of this, there is an intense search to identify novel targets (receptors) for antidepressant therapy. Opioid peptides and their receptors are potential candidates for the development of novel antidepressant treatment. In this context, endogenous opioid peptides are coexpressed in brain areas known to play a major role in affective disorders and in the action of antidepressant drugs. The actions of endogenous opioids and opiates are mediated by three receptor subtypes ( , and ), which are coupled to different intracellular effector systems. Also, antidepressants which increase the availability of noradrenaline and serotonin through the inhibition of the reuptake of both monoamines lead to the enhancement of the opioid pathway. Tricyclic antidepressants show an analgesic effect in neuropathic and inflammatory pain that is blocked by the opioid antagonist naloxone. A compilation of the most significant studies will illustrate the actual and potential value of the opioid system for clinical research and drug development.