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• Continued use despite knowledge of having a persistent or recurrent physical or psychologic problem that is likely to have been caused by or exacerbated by use • Tolerance or a markedly diminished effect with continued use of the same amount • A need for markedly increased amounts to achieve intoxication or desired effect • Withdrawal Note: The criteria for tolerance and withdrawal are not consid- ered to be met for those taking opioids solely under appropriate medical supervision. NATURAL HISTORY AND PATHOPHYSIOLOGY Although the time from initiation to daily use and opioid use disorder varies, the different stages are clearly delineated. These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these differ- ent processes is crucial to develop an understanding of the therapeutic strategies [70]. Opioid dependence is best described as a central nervous sys- tem disorder characterized by neurobiologic changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opioids cease to function and degenerate, causing the user to become physically dependent on exogenous opioids [71]. According to the classical theory of addiction, opioid depen- dence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are inde- pendent of the intensity and pattern of the physical symptoms of withdrawal [72]. Alternative hypotheses focus on the role of the mesocortico- limbic dopamine system, an anatomical pathway that origi- nates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex [72]. Dependence on most drugs of abuse is characterized by an altered physiologic state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence [73].
OPIOID MISUSE AND USE DISORDER
DEFINITIONS A confusing aspect of the body of research on opioid abuse and dependence is the inconsistent use of important termi- nology that describes the nature and severity of involvement with therapeutic and illicit opioids. In 2013, the APA released the Diagnostic and Statistical Manual of Mental Disorders , fifth edition, (DSM-5) combined the separate definitions of opioid abuse and opioid dependence into an overall diagnosis of opi- oid use disorder, reaffirmed in the text revision published in 2022 (DSM-5-TR). The APA describes opioid misuse disorder as a patient’s use of an opioid that departs from intended pre- scribing, including use for an unintended purpose, exceeding the prescribed amount, or taking the drug more frequently or for longer than prescribed. This term largely replaces outdated terms such as abuse, addiction, and dependence [69]. Opioids include natural opioids (e.g., morphine, codeine), semisynthetic derivatives (e.g., heroin, oxycodone), and syn- thetic compounds with morphinelike effects (e.g., methadone, fentanyl). Mild, moderate, and severe cases of opioid use dis- order are determined according to the number of symptoms that individuals using these substances may present (e.g., craving; drug-seeking behavior; social and other dysfunction caused by opioid use; tolerance; withdrawal, etc.); the number ranges from a minimum of two symptoms for mild cases to more than six for severe. The DSM-5-TR indicates that opioid use disorder should be diagnosed if a patient exhibits two or more of the following within a 12-month period [69]: • Opioids taken in larger amounts or over a longer period than was intended • A persistent desire or unsuccessful efforts to cut down or control use • A great deal of time is spent in activities necessary to obtain, use, or recover from use • Craving, or a strong desire or urge to use • Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home • Continued use despite having persistent or recurrent social or interpersonal problems caused by or exacerbated by use • Important social, occupational, or recreational activities are given up or reduced because of use • Recurrent use in situations in which it is physically hazardous, such as driving under the influence of opioids
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