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 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, 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 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 acute respiratory distress syndrome (ARDS). Because of its poor oral bioavailability, oral naloxone may be used to treat patients with opioid induced constipation. Methylnaltrexone, a parenteral medication, and alvimopan, an oral capsule, are effective in reversing opioid-induced constipation without inducing opioid withdrawal. This is because neither is able to enter the central nervous system (CNS). Naltrexone is used orally for patients after opioid detoxification to maintain opioid abstinence and as an adjunct to achieve ethanol abstinence. Nalmefene, no longer available in the United States, has a duration of action between those of naloxone and naltrexone.
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-Allyl norcodeine was the first opioid antagonist synthesized (in 1915), and N-allylnormorphine (nalorphine) was synthesized in the 1940s.37,66 Nalorphine was recognized as having both agonist and antagonist effects in 1954. Naloxone was synthesized in 1960, and naltrexone was synthesized 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 this therapy. Since the mid 1990s, there has been a steady increase in the use of naloxone that has been prescribed or directly dispensed to heroin users for administration by bystanders in case of overdose.10
Minor alterations can 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.35 Naloxone, naltrexone, and nalmefene are derivatives of oxymorphone with antagonist properties resulting from addition of organic or other functional groups.35,39 Relatedly, nalmefene is a 6-methylene derivative of naltrexone.