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.
The μ receptors are responsible for analgesia, sedation, miosis, euphoria, respiratory depression, and decreased gastrointestinal (GI) motility. The κ receptors are responsible for spinal analgesia, miosis, dysphoria, anxiety, nightmares, and hallucinations. The 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 durations of action than naloxone, and both have adequate oral bioavailability to produce systemic effects. Methylnaltrexone can be given orally or parenterally but is excluded from the CNS and only produces peripheral effects. Selective antagonists for μ, κ, and δ are available experimentally and are undergoing investigation.
The bioavailability of sublingual naloxone is only 10%.5 In contrast, naloxone is well absorbed by all parenteral routes of administration, including the intramuscular (IM), subcutaneous (SC), endotracheal, intranasal, intralingual, and inhalational (nebulized) routes. The onset of action with the various routes of administration are as follows: intravenous (IV), 1 to 2 minutes; SC, approximately 5.5 minutes; intralingual, 30 seconds; intranasal, 3.4 minutes; inhalational, 5 minutes; endotracheal, 60 seconds; and IM, 6 minutes.23,41,53,73 The distribution half-life is rapid (~5 minutes) because of its high lipid solubility. The volume of distribution (Vd) is 0.8 to 2.64 L/kg.31
A naloxone dose of 13 μg/kg in an adult occupies approximately 50% of the available opioid receptors.54 The duration of action of naloxone is approximately 20 to 90 minutes and depends on the dose of the agonist, the dose and route of administration of naloxone, and the rates of elimination of the agonist and naloxone.5,25,68 Naloxone is metabolized by the liver to several compounds, including a glucuronide. The elimination half-life is 60 to 90 minutes in adults and approximately two to three times longer in neonates.
Naltrexone is rapidly absorbed with an oral bioavailability of 5% to 60%, and peak serum concentrations occur at 1 hour.34 Distribution is rapid, with a Vd of approximately 15 L/kg and low protein binding.45 Naltrexone is metabolized in the liver to β-naltrexol (with 2%–8% activity) and 2-hydroxy, 3-methoxy-β-naltrexol and undergoes an enterohepatic cycle.72 The plasma elimination half-life is 10 hours for β-naltrexone and 13 hours for β-naltrexol, with terminal phases of elimination of 96 hours and 18 hours, respectively.70
Nalmefene has an oral bioavailability of 40%, with peak serum concentrations usually reached within 1 to 2 hours.21 After SC administration, peak concentrations do not occur for more than 2 hours, although therapeutic concentrations are reached within 5 to 15 minutes. A 1 mg parenteral dose blocks more than 80% of opioid receptors within 5 minutes. The apparent Vd is 3.9 L/kg for the central compartment and 8.6 L/kg at steady state. Protein binding is approximately 45%.20 Nalmefene has a redistribution half-life of 41 ± 34 minutes and a terminal half-life of 10.8 ± 5 hours after a 1 mg IV dose. It is metabolized in the liver to an inactive glucuronide conjugate that probably undergoes enterohepatic recycling, accounting for approximately 17% of drug elimination in the feces. Less than 5% is excreted unchanged in the urine.
Methylnaltrexone is a quaternary amine methylated derivative of naltrexone that is peripherally restricted because of its poor lipid solubility and inability to cross the blood–brain barrier.79 After SC administration, peak serum concentrations occur in about 30 minutes. The drug has a Vd of 1.1 L/kg and is minimally protein bound (11%–15%). Although there are several metabolites, 85% of the drug is eliminated unchanged in the urine.79
In the proper doses, pure opioid antagonists reverse all of the effects at the μ, κ, and δ receptors of endogenous and exogenous opioid agonists, except for those of buprenorphine, which has a very high affinity for and slow rate of dissociation from the μ receptor.54 Actions of opioid agonists that are not mediated by interaction with opioid receptors, such as direct mast cell liberation of histamine or the potassium channel blocking effects of methadone, are not reversed by these antagonists.2 Chest wall rigidity from rapid fentanyl infusion is usually reversed with naloxone.14 Opioid-induced seizures in animals, such as from propoxyphene, tend to be antagonized by opioid antagonists, although seizures caused by meperidine (normeperidine) and tramadol are exceptions.30 The benefit in humans is less clear. A report of two newborns who developed seizures associated with fentanyl and morphine infusion demonstrated abrupt clinical and electroencephalographic resolution after administration of naloxone.17
Opioids operate bimodally on opioid receptors.15 At very low concentrations, μ opioid receptor agonism is excitatory at this receptor and actually may increase pain. This antianalgesic effect is modulated through a Gsprotein and usually is less important clinically than the well-known inhibitory actions that result from coupling to a Go protein at usual analgesic doses. For this reason, extremely low doses of opioid antagonists (ie, 0.25 μg/kg/h of naloxone) enhance the analgesic potency of opioids, including morphine, methadone, and buprenorphine.16,29 Naloxone also attenuates or prevents the development of tolerance and dependence.29 Coadministration of these very low doses of antagonists with the opioid also limits opioid-induced adverse effects such as nausea, vomiting, constipation, and pruritus.79
The opioid antagonists may reverse the effects of endogenous opioid peptides, including endorphins, dynorphins, and enkephalins. Endogenous opioids are found in tissues throughout the body and may work in concert with other neurotransmitter systems to modulate many physiologic effects.26,67 For instance, during shock, the release of circulating endorphins produces an inhibition of central sympathetic tone by stimulating κ receptors within the locus coeruleus, resulting in vasodilation. Vagal tone is also enhanced through stimulation of opioid receptors in the nucleus ambiguus.
Research investigating the cardioprotective effects of opioid agonists through their action at the sarcolemmal and mitochondrial K+-ATP (adenosine triphosphate) channels is ongoing.27 Nonselective opioid antagonists may negate these protective effects.