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Naloxone, naltrexone, and methylnaltrexone are pure competitive opioid antagonists at the mu (µ), kappa (κ), and delta (δ) receptors. Opioid antagonists prevent the actions of opioid agonists, reverse the effects of both endogenous and exogenous opioids, and cause opioid withdrawal in opioid-dependent patients. Naloxone is the primary opioid antagonist used to reverse respiratory depression in patients manifesting opioid toxicity. The parenteral dose should be titrated to maintain adequate airway reflexes and ventilation. By titrating the dose, in small increments based on clinical response, abrupt opioid withdrawal should be prevented. This titrated low dose method of administration limits withdrawal-induced adverse effects, such as vomiting and the potential for aspiration pneumonitis, and a surge in catecholamines with the potential for cardiac dysrhythmias and the acute respiratory distress syndrome (ARDS). Because of its poor oral bioavailability, oral naloxone was previously suggested as treatment for patients with opioid-induced constipation. Methyl-naltrexone, a parenteral medication, and naloxegol, an oral formulation, are effective in reversing opioid-induced constipation without inducing opioid withdrawal. This is because their central nervous system (CNS) entry is restricted. Naltrexone is used both orally and intramuscularly in patients after opioid detoxification to maintain opioid abstinence and as an adjunct to achieve ethanol abstinence.


The understanding of structure–activity relationships led to the synthesis of many new molecules in the hope of producing potent opioid agonists free of abuse potential. Although this goal is not yet realized, opioid antagonists and partial agonists resulted from these investigations. N-Allylnorcodeine was the first opioid antagonist synthesized (in 1915), and N-allylnormorphine (nalorphine) was synthesized in the 1940s.40,82 Nalorphine was recognized as having both agonist and antagonist effects in 1954. Naloxone was synthesized in 1960, and naltrexone in 1963. The synthesis of opioid antagonists that are unable to cross the blood–brain barrier (sometimes called peripherally restricted) allowed patients receiving long-term opioid analgesics to avoid opioid-induced constipation, one of the most uncomfortable side effects associated with opioid therapy. Since the mid-1990s and the reappearance of the opioid epidemic of the 21st century, there has been a steady increase in the use of naloxone that is prescribed or directly dispensed to users of any opioid who are at risk of overdose as well as for administration by bystanders.14



Minor structural alterations are used to convert an agonist into an antagonist. The substitution of the N-methyl group on morphine by a larger functional group led to nalorphine and converted the agonist levorphanol to the antagonist levallorphan.38 Naloxone and naltrexone are derivatives of oxymorphone with antagonist properties resulting from addition of organic or other functional groups.38,42

Mechanism of Action

The mu receptors are responsible for analgesia, sedation, miosis, euphoria, respiratory depression, and decreased gastrointestinal (GI) motility. Kappa receptors are responsible ...

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