Opioid Use Disorder __________________________________________________________________________
OPIOID RECEPTORS Opioids produce their effects through activity at three major receptor subtypes: mu, kappa, and delta. These G-protein- coupled receptors are linked to adenylate cyclase. The endog- enous ligands for these receptors, beta-endorphin, enkephalin, and dynorphin, are expressed heterogeneously throughout the central and peripheral nervous systems, with a distribution pattern parallel with that of opioid receptors. Opioid receptors are also found in the central respiratory centers. Functional studies have revealed substantial parallels between mu and delta receptors and dramatic contrasts between mu/delta and kappa receptors [51]. Most opioid therapeutics, and all opioids with abuse poten- tial, are selective for mu receptors, reflecting their similarity to morphine. However, drugs that are relatively selective at standard doses can interact with additional receptor subtypes at higher doses, resulting in divergent pharmacologic profiles [9]. A large number of endogenous ligands activate a small number of opioid receptors, a pattern strikingly different from most other neurotransmitter systems, in which a single ligand interacts with a large number of receptors that have different structures and second messengers [9]. ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION Typically, opioids are readily absorbed from the gastrointestinal tract. The more lipophilic opioids are easily absorbed through the nasal or buccal mucosa. The most lipophilic opioids can be absorbed transdermally [9]. Most opioids, including morphine, undergo variable but significant hepatic first-pass metabolism, limiting oral bioavailability relative to parenteral administra- tion. Most opioids act quickly when given intravenously. Compared with more lipid-soluble opioids, such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate [9].
sensory modalities are not affected. Some patients experi- ence euphoria. When morphine in the same dose is given to a pain-free individual, the experience may be unpleasant. Nausea and vomiting is common, and drowsiness, difficulty in mentation, apathy, and decreased physical activity may occur. The subjective analgesic and toxic effects, including respiratory depression, become more pronounced as the dose is increased. Morphine-class drugs seldom cause slurred speech, emotional lability, or significant motor incoordination [9]. EFFECT ON MOOD AND REWARD Although the mechanisms by which opioids induce euphoria, tranquility, and other alterations of mood (including reward- ing properties) have not been entirely determined, the neural systems mediating opioid reinforcement are distinct from those involved in physical dependence and analgesia [52]. Behavioral and pharmacologic data point to the probable role of dopaminergic pathways, with interactions between opioids and dopamine mediating the opioid-induced reinforcement [9]. NEUROENDOCRINE SYSTEM Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone and corticotropin-releasing hormone (CRH), which decrease circulating luteinizing hor- mone (LH), follicle-stimulating hormone (FSH), ACTH, and beta-endorphin. This in turn reduces the plasma concentra- tions of testosterone and cortisol [9]. RESPIRATION Morphine-like opioids depress respiration in part through a direct effect on the brainstem respiratory centers. Therapeutic doses of morphine depress all phases of respiratory activity and possibly induce irregular and periodic breathing. Clinically significant respiratory depression seldom occurs at standard therapeutic doses. The primary mechanism of respiratory depression involves a diminished responsiveness of the brain- stem respiratory centers to carbon dioxide [9]. GASTROINTESTINAL TRACT Morphine-like drugs directly stimulate the chemoreceptor trigger zone for emesis in the area postrema of the medulla, resulting in the nausea and vomiting experienced by some patients [9]. Morphine also decreases gastric motility; dimin- ishes biliary, pancreatic, and intestinal secretions; and delays digestion of food in the small intestine. In the colon, peristaltic waves are diminished or abolished and tone is increased to the point of spasm, delaying the passage of bowel contents [9]. CARDIOVASCULAR SYSTEM There are no opioid receptors on the heart, so morphine does not act directly on the heart muscle. However, opioid agonists indirectly affect cardiovascular processes through suppression of reflex vasoconstriction, which may result in bradycardia and hypotension [53]. In cases of injecting use, bacterial endocar- ditis can develop [53].
CLINICAL EFFECTS
Morphine and most other opioid agonists share in common the following physiologic effects [9]: • Analgesia • Changes in mood and reward behavior • Disruption of neuroendocrine function • Alteration of respiration • Changes in gastrointestinal and cardiovascular function ANALGESIA Morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding, all without loss of conscious- ness. Patients in pain report that the pain is less intense, less discomforting, or entirely gone when given therapeutic doses of these drugs. The pain relief is fairly selective, and other
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