Opioid Use Disorder (OUD)
This section focuses on neurobiological changes seen in OUD that likely contributes to drug craving and impaired control over use.
OUD Diagnosis
According to the DSM-5-TR, diagnosis of OUD requires meeting at least two of eleven criteria, indicating a problematic pattern of use resulting in significant impairment or distress.
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Some of these criteria are categorized and summarized here.
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As opioids are prescribed for many pain conditions, the pharmacological criteria is not solely considered for diagnosis of OUD; tolerance and withdrawal may occur even when the individual is using opioids under appropriate medical supervision.
Impaired Control Over Use
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Using more, or over a longer period, than intended
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Craving/strong desire to use opioids
Social Impairment
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Opioid use continues despite social or interpersonal problems caused or exacerbated by opioids
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Giving up or reducing social, occupational, or recreational activities because of opioid use
Risky Use
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Continuing opioid use despite knowledge of having physical or psychological consequences of opioids
Pharmacological Criteria
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Tolerance (more of the opioid is needed to achieve intoxication or desired effects)
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Withdrawal syndrome (may include dysphoria, pain and irritability, restlessness and insomnia, pupil dilation, runny nose, chills, increased anxiety, and craving)
Opiates, Opioids, & Endorphins
Opiates
Drugs derived from the opium poppy, such as the "natural narcotics" in the image below.
Opioids
An umbrella term encompassing synthetic substances, endorphins, and opiates that bind to opioid receptors.
Endorphins
Endogenous neuropeptides known to regulate reward, mood, stress, and pain.
Pharmacological Effects of Opioids
Opioids exert their effects through various mechanisms, including inhibition of nerve activity. Endorphins, for instance, bind to receptors that activate G proteins, leading to the opening of potassium channels and hyperpolarization of postsynaptic cells, ultimately reducing firing rates (Meyer et al., 2023). Additionally, opioid receptors on nerve terminals activate G proteins, which close calcium channels, thereby reducing neurotransmitter release. Presynaptic autoreceptors also activate G proteins, reducing the release of co-localized neurotransmitters. This process may involve closing calcium channels or opening potassium channels, leading to presynaptic cell hyperpolarization (Meyer et al., 2023).
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The pharmacological effects of opioids range from pain relief and pupil constriction at low to moderate doses to increased sedation and respiratory depression at higher doses. Gastrointestinal motility is often decreased, accompanied by nausea and vomiting. Opioids can also affect the brainstem's respiratory center, potentially causing respiratory failure in cases of overdose.
Theories of Craving
OUD development involves various genetic, biological, and environmental factors. Structural diversity among opioids contributes to differences in potency and effects, including variations in receptor affinity and agonist/antagonist properties. The interaction between opioid receptors and endogenous opioids complicates research on the cellular mechanisms responsible. Nonetheless, the reward circuitry plays a central role in OUD, with MOR activation disinhibiting DA neurons in the VTA (Volkow et al., 2019). This leads to dopamine release in the brain's reward circuit, reinforcing opioid use. Tolerance, both metabolic and behavioral, as well as cross-tolerance among opioids, commonly occurs in OUD.
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Craving in OUD involves mechanisms such as incentive salience and the recruitment of the anti-reward system. Incentive salience theory emphasizes the distinction between 'liking' and 'wanting,' suggesting a shift from pleasure (liking) to desire (wanting) in addiction. The posterior ventral pallidum (VP) in the basal ganglia seems to mediate liking, while the mesolimbic pathway drives wanting (Lueptow et al., 2021). Chronic opioid misuse is believed to strengthen the wanting pathway while bypassing the liking center (Lueptow et al., 2021; Meyer et al., 2023).
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The anti-reward system, including changes in the extended amygdala and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, contributes to stress and dysphoria in OUD, particularly during withdrawal (Meyer et al., 2023). Hyperactivity of the HPA axis and increases in dynorphin and corticotropin-releasing factor (CRF) enhance stress responses (Meyer et al., 2023). Additionally, while CRF levels rise with repeated opioid exposure, neuropeptide Y (NPY), which exhibits opposing effects to CRF, appears to be downregulated in the extended amygdala. Studies have also shown a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in cases of OUD (Lueptow et al., 2021; Meyer et al., 2023). Acute opioid administration reduces anxiety levels and HPA-axis-related hormones, reinforcing the desire to seek the drug (Lueptow et al., 2021).
Future Directions
The most successful treatment approach for OUD are multifaceted, often incorporating support and counseling with medication management (Meyer et al., 2023). Naloxone, a life-saving opioid receptor antagonist that can be used to rapidly reverse opioid overdose. Education and availability of this medication can save lives while mechanisms of SUDs are still being discovered.
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CRF antagonists have shown promise in reducing drug intake in animals, but have not been approved by the FDA for use in treating SUDs (Meyer et al., 2023).
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Mechanisms of neuroplasticity involved in SUDs are currently being investigated (Volkow et al., 2019).