Pharmacology. Naloxone and nalmefene are pure opioid antagonists that competitively block mu-, kappa-, and delta-opiate receptors within the CNS. They have no opioid agonist properties and can be given safely in large doses without producing respiratory or CNS depression. Naltrexone is another potent competitive opioid antagonist that is active orally and used to prevent recidivism in patients detoxified after opioid abuse. It has also been used to reduce craving for alcohol. It is not used for the acute reversal of opioid intoxication and will not be discussed further in this handbook.

1. 
   

   Naloxone, a synthetic N-allyl derivative of oxymorphone, undergoes extensive first-pass metabolism and is not effective orally but may be given by subcutaneous, intramuscular, intravenous, endotracheal, or even intranasal routes. After intravenous administration, opioid antagonism occurs within 1–2 minutes and persists for approximately 1–4 hours. The plasma half-life ranges from 31 to 80 minutes.

   
   
2. 
   

   Nalmefene, an injectable methylene analog of naltrexone, was approved in 1995. It is 4 times more potent than naloxone at mu receptors and slightly more potent at kappa receptors. It has a longer elimination half-life (ranging from approximately 8 to 11 hours after IV dosing) and a duration of action of 1–4 hours (Table III–9). The prolonged effects of nalmefene are related to the slow dissociation from the opioid receptor, which is not reflected in the area under the curve (AUC) in plasma.

   
   
   
   
   
   

   
   

   Table III-9 Characteristics of Naloxone and Nalmefene 
   

   
   

   Table III-9 Characteristics of Naloxone and Nalmefene
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   	Naloxone	Nalmefene
   Elimination half-life	60–90 min	10–13 h
   Duration of action	1 h	1–4 ha
   Metabolism	Liver (glucuronidation)	Liver (glucuronidation)
   Advantages	Lower cost, shorter duration of action,	Longer duration lowers risk for
   	more human experience	recurrent respiratory depression with
   		most (but not all) opioids
   Disadvantages	More frequent dosing or constant	Cost; may cause prolonged opioid
   	infusion	withdrawal

   
   
   
   
   
   

Indications

1. 
   

   Reversal of acute opioid intoxication manifested by coma, respiratory depression, or hypotension.

   
   
2. 
   

   Empiric therapy for stupor or coma suspected to be caused by opioid overdose.

   
   
3. 
   

   Anecdotal reports suggest that high-dose naloxone may partially reverse the CNS and respiratory depression associated with clonidine (See Clonidine and Related Drugs), ethanol (See Ethanol), benzodiazepine (See Benzodiazepines), or valproic acid (See Valproic acid) overdoses, although these effects are inconsistent.

Contraindications.

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