Before the administration of naloxone, the patient should receive adequate ventilation via a bag valve mask to ensure that they are not hypercapnic. This can prevent some potential adverse effects of the antidote.
Nonopioid-dependent patients: 0.4 mg intravenous (IV) naloxone will reverse the respiratory depressant effect of most opioids and is an appropriate starting dose.
Opioid-dependent patients: It is recommended to start at a lower dose, 0.04 mg IV, and incrementally increase by 0.04 mg to avoid precipitated withdrawal. This can be done by diluting the readily available 0.4 mg/ml formulation with 9 ml of 0.9% sodium chloride, for a total volume of 10 ml, at a concentration of 0.04 mg/ml. If no response is achieved after 0.12 mg is administered, it is reasonable to increase by 0.2-0.4 mg up to a dose of 2 mg IV.
Patients who are apneic do not have time to gradually increase escalating doses as described above, so a 2 mg immediate IV push is appropriate in apneic or hemodynamically unstable individuals.
If there is no response after 2 mg IV, it is often suggested to increase by 2 mg additional doses, up to 10 mg IV.
Failure to respond to 10 mg IV of naloxone suggests that an opioid is not responsible for the respiratory depression.
Dosing for children: 0.1 mg/kg to the adult dose of 2 mg IV. Because there is less potential for opioid dependence in children, and because of the high safety profile of naloxone, initial administration of 2 mg IV is often reasonable. Subcutaneous and intramuscular administration in children is not recommended, as absorption may be erratic or delayed.
Take-home naloxone kits: These are becoming more available in the community and often contain a 2-mg or 4-mg intranasal atomizer device, which can be used on patients of all ages. The appropriate emergency medical personnel should be contacted when naloxone is administered in the community, as respiratory distress may reoccur and the atomizers can be difficult to titrate, especially by untrained individuals.
Duration: Duration of action of naloxone is approximately 90 minutes, with the potential for a recurrence of the respiratory depression, particularly when used with longer-acting opioids (ie, methadone, codeine, controlled-release oxycodone, morphine, and hydromorphone). In patients with recurrent respiratory depression, a naloxone bolus dose can be repeated or airway protection with endotracheal intubation should be considered. Naloxone infusion can be considered but is not recommended – a naloxone infusion relies on an IV catheter to maintain respiratory integrity. IV catheters and infusions are fragile and prone to malfunction. Patients still require ICU-level monitoring while on a naloxone infusion. Titrating a naloxone infusion to provide just enough naloxone to maintain adequate respiration but not enough to induce withdrawal is difficult.
Naloxone is US Food and Drug Administration (FDA) approved and indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids.
Opioid intoxication and overdose manifest with central nervous system (CNS) and respiratory depression and can lead to hypoxic cardiac arrest. The mainstay of therapy to prevent opioid-induced fatality is administration of naloxone. As precipitated withdrawal is possible when used in opioid-tolerant individuals, the goal is to maintain adequate ventilation and not complete CNS arousal.
Adult respiratory distress syndrome occurs after heroin overdose in the absence of naloxone, but it has also been attributed to the use of the antidote. Ventilation of the individual with a bag valve mask prior to antidote administration has been shown in canine studies to decrease the catecholamine response and thus prevent this possible complication.
Naloxone will not reverse the actions of opioids that are not mediated by agonists at the mu receptor, such as histamine release by morphine and potassium channel blockade by methadone.
Naloxone is also used off-label for the treatment of hypotension due to septic shock as well as in the management of overdoses with nonopioids (eg, ethanol, captopril, clonidine, and valproic acid), although the reported improvement is not as dramatic or consistent as in the reversal of opioids.
The only absolute contraindication to the use of this antidote is a hypersensitivity to naloxone or any other ingredient contained in the formulation.
Caution should be taken with administration in an opioid-dependent individual and in women who are pregnant and tolerant on opioids due to the risk of precipitated withdrawal. Naloxone is a pregnancy Category C medication, and a risk-to-benefit analysis should be performed. Doses should be started low and up-titrated to maintenance of respiratory drive, not complete CNS arousal.
Naloxone's duration of action is often shorter compared with the opioid agonist it is used to reverse. This potentially leads to the reoccurrence of respiratory depression in the individual.
After IV administration of naloxone at doses less than 2 mg, observation for 2 hours is typically adequate provided mental status is alert and respiratory and cardiovascular systems are stable. Patients previously on continuous naloxone infusion or those who have received large total doses of naloxone by any route should be observed for longer, typically 4-6 hours.
All patients who required naloxone for opioid reversal should be maintained on cardiopulmonary monitoring, including end-tidal capnography, for the entirety of the emergency department visit.
Precipitated withdrawal, manifesting with yawning, lacrimation, diaphoresis, rhinorrhea, piloerection, mydriasis, vomiting, diarrhea, myalgias, mild elevation in heart rate and blood pressure, and insomnia, can be seen after administration of naloxone to an opioid-dependent individual.
It is important to start dosing low and up-titrate with the goal of increased respiratory drive without CNS arousal when naloxone is required for a patient with a history of opioid dependence. Treatment is supportive, with reassurance that the symptoms will be short-lived. In moderate withdrawal, metoclopramide, clonidine, or a benzodiazepine is usually adequate.
One theory to the development of pulmonary complications, seen mainly in those with apnea, is the sudden release of central catecholamines. High-dose and/or rapidly infused naloxone is believed to cause catecholamine-mediated vasoconstriction and may lead to cardiac arrhythmias and fluid shifts from the systemic circulation to the pulmonary vascular bed, leading to pulmonary edema. The catecholamine response to naloxone was found to be significantly higher in dogs with hypercarbia compared with normocarbic or hypocarbic dogs. Although not studied in humans, it is advised to ventilate a patient with bag valve mask prior to administration of naloxone to ameliorate these potential complications.
In individuals who use a stimulant such as cocaine along with their opioid, the stimulant effect after administration of the opioid antagonist may "unmask" such use. This potential for sympathomimetic excess, including tachycardia, hypertension, agitation, cardiac dysrhythmias, and CNS and myocardial ischemia, should be anticipated. Treatment is usually successful with benzodiazepines.
Caution should be exercised in pregnant women who are opioid dependent, as naloxone crosses the placenta and can lead to precipitated withdrawal in the fetus as well as the mother. As stated previously, dosing should be low to restore adequate ventilation without full CNS arousal.
When administered in usual doses in the absence of opioids in a non-opioid-dependent individual, there is essentially no pharmacologic activity.
Precipitated opioid withdrawal can be seen with administration in an opioid-dependent individual and neonates. (See Adverse Effects.)
Mechanism of Action
Naloxone is a pure competitive opioid antagonist at the mu, kappa, and delta opioid receptors, with greatest affinity at the mu receptor. It is a synthetic congener of oxymorphone, and it differs structurally from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. Naloxone has no agonist activity at the opioid receptor.
The mechanism of action for its use with nonopioids, such as with captopril and clonidine, is suggested to relate to reversal of endogenous opioid peptides at the opioid receptors.
Naloxone has no bioavailability when administered orally due to extensive first-pass metabolism. It has bioavailability if administered intravenously, intramuscularly, or subcutaneously, and it will be absorbed when administered via the intranasal and endotracheal routes.
Naloxone is highly lipophilic, and distribution through the blood brain barrier is rapid. Clinical effects of opioid reversal are seen within 2 minutes when administered by IV and are only slightly delayed when given via alternative routes. The duration of action of naloxone is approximately 20-90 minutes and depends on the dose and route of administration and the rate of elimination of the agonist.
Naloxone rapidly crosses the placenta, but it is unclear if it is excreted into breastmilk.
Naloxone is metabolized in the liver, primarily by glucuronide conjugation. The serum half-life ranges from 30-81 minutes. Approximately 30% of unchanged naloxone is excreted in the urine within 6 hours of IV administration, and the rest of the dose is excreted as conjugated metabolites in the urine.