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Naloxone, nalmefene, 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 primarily 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, beginning with 0.04 mg and increasing as indicated to 0.4 mg, 2 mg, and finally 10 mg, abrupt opioid withdrawal can be prevented. This 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 acute lung injury (ALI). Because of its poor oral bioavailability, oral naloxone may be used to treat patients with opioid-induced constipation. Methylnaltrexone is a parenteral medication and alvimopan an oral capsule that fail to enter the central nervous system (CNS) and are uniquely effective in reversing opioid-induced constipation. Naltrexone is used orally for patients after opioid detoxification to maintain opioid abstinence and as an adjunct to achieve ethanol abstinence. Nalmefene is available for parenteral use with a duration of action between those of naloxone and naltrexone.

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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 has not yet been achieved, 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.39,83 Nalorphine was recognized as having both agonist and antagonist effects in 1954. Naloxone was synthesized in 1960, and naltrexone was synthesized in 1963.

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Minor alterations can convert an agonist into an antagonist.38 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.35Naloxone, naltrexone, and nalmefene are derivatives of oxymorphone with antagonist properties resulting from addition of organic or other functional groups.35,42 Relatedly, nalmefene is a 6-methylene derivative of naltrexone.

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The μ receptors are responsible for analgesia, sedation, miosis, euphoria, respiratory depression, and decreased gastrointestinal (GI) motility. κ receptors are responsible for spinal analgesia, miosis, dysphoria, anxiety, nightmares, and hallucinations. δ receptors are responsible for analgesia and hunger. The currently available opioid receptor antagonists are most potent at the μ receptor, with higher doses required to affect the κ and δ receptors. They all bind to the opioid receptor in a competitive fashion, preventing the binding of agonists, partial agonists, or mixed agonist–antagonists without producing any independent action. Naloxone, naltrexone, and nalmefene are similar in their antagonistic mechanism but differ primarily in their pharmacokinetics. Both nalmefene and naltrexone have longer ...

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