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Content Update: Xylazine. November 2023

Xylazine, a central α-2-agonist, a nonopioid anesthetic/analgesic used in veterinary medicine, has emerged as a common adulterant in opioids and other street drugs. Clinical effects of xylazine and emerging non-fentanyl synthetic opioids are discussed in Special Considerations under Xylazine.

Detailed discussion of Opiate Withdrawal treatment is found in Chapter 292, and Figure 292-4.


Opioids refers broadly to all compounds related to opium that possess analgesic and sedative properties. Opiate describes the alkaloids codeine and morphine found naturally in the opium poppy plant, Papaver somniferum. Narcotic refers to a broader group of soporific drugs, a term predominantly used by law enforcement to refer to controlled substances with abuse or addictive potential; use of this term in medical practice is discouraged.

Opioid use and opioid use disorder are significant public health issues in the United States with a dramatic increase in ED visits related to opioids in the past 20 years.1,2 Over 80,000 people died in the United States from opioid overdose in 2021. In recent years, opioid overdose deaths are primarily due to the rise in synthetic opioids, including fentanyl. Synthetic opioids were reported in over 70,000 US deaths in 2021.3


Opioids modulate nociception at the terminals of afferent nerves in the CNS, peripheral nervous system, and GI tract. Opioids are agonists at the three primary opioid receptors: µ (mu), κ (kappa), and δ (delta). Opioid receptors are similar to other G protein-coupled receptors; transmembrane proteins that undergo conformation change when activated by external molecules that then alters some aspect of intracellular function. Opioid receptors vary widely in morphology and distribution. In addition, the specificity and affinity of an opioid for a particular receptor are variable. For example, tramadol possesses 1/6000th the affinity of morphine at the µ-receptor site.

Stimulation of the µ-receptors results in analgesia, sedation, miosis, respiratory depression, cough suppression, euphoria, and decreased GI motility. Stimulation of κ-receptors results in weaker analgesia, sedation, miosis, decreased intestinal motility, dysphoria, and hallucinations. Stimulation of the δ-receptors results in some analgesia and antidepressant effect. All currently available opioid agonists possess µ-receptor activity and result in some degree of respiratory depression.

Opioids can be categorized as naturally occurring compounds (termed opiates), chemical modifications of natural compounds (semisynthetic), and the synthetic derivatives (Table 186-1). Some opioids are agonists at all opioid receptors (e.g., morphine and hydromorphone), whereas others are partial agonists–antagonists (e.g., pentazocine, butorphanol, nalbuphine, and buprenorphine) at the opioid receptors.

TABLE 186-1Classification and Characteristics of Major Pharmaceutical Opioids

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