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Introduction

  1. Pharmacology. Naloxone is a synthetic N-allyl derivative with pure opioid antagonist activity that competitively blocks mu-, kappa-, and delta-opiate receptors within the CNS. It has no opioid agonist properties and can be given safely in large doses without producing respiratory or CNS depression.
    1. Naloxone undergoes extensive first-pass metabolism and is not effective orally, but may be given by intravenous, intramuscular, subcutaneous, nebulized, intranasal, and intraosseous routes. After intravenous administration, opioid antagonism occurs within 1-2 minutes and persists for approximately 30-120 minutes. The plasma half-life ranges from 30 to 81 minutes. Table III-11 is a comparison of the routes of administration for naloxone.
    2. Nalmefene is a pure opioid antagonist that has been used to treat acute opioid intoxication. It has a longer elimination half-life and duration of action than naloxone. However, its production was discontinued in 2008 and is no longer available in the United States.
    3. 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.
  2. 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, ethanol, benzodiazepine, or valproic acid overdoses, although these effects are inconsistent.
  3. Contraindications. Do not use in patients with a known hypersensitivity to naloxone or components of its formulation.
  4. Adverse effects. Human studies have documented an excellent safety record for naloxone.
    1. Use in opiate-dependent patients may precipitate acute withdrawal syndrome (eg, pain, hypertension, diaphoresis, piloerection, muscle cramping, diarrhea, nausea, vomiting, and agitation). 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 plasma corticotropin, cortisol, and catecholamine levels and in sympathetic activity; pulmonary edema; acute renal failure; ventricular bigeminy; psychosis; delirium; and death.
    2. Pulmonary edema or ventricular fibrillation occasionally occurs shortly after naloxone administration in opioid-intoxicated patients. Pulmonary edema may develop with postanesthetic use of naloxone, especially when catecholamines and large fluid volumes have been administered.
    3. Reversing the sedative effects of an opioid may amplify the toxic effects of other drugs. For example, agitation, hypertension, and ventricular irritability can occur after naloxone administration to persons high on a “speedball” (heroin plus cocaine or methamphetamine).
    4. There has been one case report of hypertension after naloxone administration in a patient with clonidine overdose. Hypertension has been associated with postoperative use of naloxone. Use caution in patients with cardiovascular risk factors, especially patients with a previous history of uncontrolled hypertension.
    5. Use in pregnancy. FDA Category B (Introduction). Naloxone may produce an acute opioid withdrawal syndrome in both mother and fetus and may precipitate labor in an opioid-dependent mother.
  5. Drug or laboratory interactions. Naloxone antagonizes the analgesic effect of opioids. Naloxone does not give a positive urine screen for opiates.
  6. Dosage and method of administration.
    1. Adults
      1. Initial dose. Administer 0.4-2 mg IV; repeat every 2-3 minutes until achieving the desired response. Titrate carefully in opioid-dependent patients; to avoid precipitation of acute withdrawal, start at 0.04 mg. Note: To facilitate administration of such low doses, dilute 1 mL of 0.4 mg/mL vial in 9 mL of normal saline to a total volume of 10 mL resulting in a final concentration of 0.04 mg/mL.
        1. The total dose required to reverse the effects of the opioid is highly variable and dependent on the concentration and receptor affinity of the opioid. Some drugs (eg, propoxyphene, diphenoxylate-atropine [Lomotil], buprenorphine, pentazocine, and the fentanyl derivatives) do not respond to usual doses of naloxone. However, if no response is achieved by a total dose of 10-15 mg, the diagnosis of opioid overdose should be questioned.
        2. Caution: Recurrent sedation can occur when the naloxone wears off in 0.5-2 hours. Repeated doses of naloxone may be required to maintain reversal of the effects of opioids with prolonged elimination half-lives (eg, methadone) or sustained-release formulations; they may also be required when packets or vials have been ingested.
      2. Continuous infusion. Give 0.4-0.8 mg/h, titrated to clinical effect. Another method is to estimate two-thirds of the initial dose needed to awaken the patient and give that amount each hour. If recurrent sedation occurs, repeat the initial bolus dose and increase the infusion rate. The manufacturer recommends diluting 2 mg of naloxone in 500 mL of NS or D5W, resulting in a concentration of 4 mcg/mL. However, concentrations of up to 40 mcg/mL have been used without any reported problems.
    2. Pediatric dosing
      1. Total reversal required (narcotic toxicity secondary to overdose): Give 0.1 mg/kg (maximum dose: 2 mg) IV every 2 minutes as needed until desired response is achieved.
      2. Total reversal not required (eg, reversal of respiratory depression associated with therapeutic use): 0.001-0.005 mg/kg IV; titrate to desired effect.
      3. Maintain reversal: 0.002-0.16 mg/kg/h IV infusion.
    3. Note: Although naloxone can be given by the intramuscular or subcutaneous route, absorption is erratic and incomplete. Naloxone is not effective orally for acute opioid intoxication. The nebulized and intranasal routes have been successfully used in prehospital and emergency department settings when IV access is unavailable. However, its onset is delayed compared to the IV route.
TABLE III-11. COMPARISON OF ROUTES OF ADMINISTRATION OF NALOXONE
RouteAdvantagesDisadvantages
IntravenousRapid onset and best predictable dose and bioavailabilityRequires IV access; higher likelihood of precipitating withdrawal in opioid-dependent patient.
Intramuscular/subcutaneousDelivery via syringe or autoinjector (with electronic voice to guide use); option for take-home naloxone programSlower onset; systemic absorption depends on blood flow at injection site and may be erratic.
IntranasalDelivery via nasal spray or mucosal atomizer device (circumvents needle); option for take-home naloxone program; onset is comparable to IMSlower onset; systemic absorption depends on blood flow at nasal mucosal surface and open nasal passage (may be limited if topical vasoconstrictor used prior to administration, eg, snorting cocaine or use of nasal decongestant, or presence of epistaxis); requires assembly.
Nebulized/endotracheal Unpredictable dose delivered and more variable in hypoventilating patient. Least desirable for ED management.