Chapter 208. Naloxone and Nalmefene

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 Graphic Jump Location

   Table III-9 Characteristics of Naloxone and Nalmefene

   View Table|Favorite Table|Download (.pdf)

   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

   aHigh doses (eg, >6 mg) may increase the duration of action but are not recommended at this time.

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. Do not use in patients with a known hypersensitivity to either agent (may have cross-sensitivity).

Adverse effects. Human studies have documented an excellent safety record for both drugs. Volunteers have received up to 24 mg of nalmefene intravenously and 50 mg orally.

1. Use in opiate-dependent patients may precipitate acute withdrawal syndrome. This may be more protracted with nalmefene. Neonates of addicted mothers may have more severe withdrawal symptoms, including seizures. Aggressive use of opiate antagonists in so-called rapid opioid detoxification (ROD) and ultra-rapid opioid detoxification (UROD) has been associated with marked increases in ...