AHFS Class:

• Opoid Antagonists 28:10

Generic Name(s):

• Naloxone Hydrochloride

Naloxone hydrochloride is an opioid antagonist.113,120,127,404,405

Opioid-induced Depression and Acute Opioid Overdosage

Naloxone is used for the complete or partial reversal of opioid-induced depression, including respiratory depression, caused by natural and synthetic opioids (e.g., codeine, diphenoxylate, fentanyl citrate, heroin, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, concentrated opium alkaloids, propoxyphene) and certain opioid partial agonists (e.g., butorphanol, nalbuphine, pentazocine).113,127,120,404,405 Reversal of respiratory depression resulting from overdosage of opioid partial agonists (e.g., buprenorphine, pentazocine) may be incomplete and require higher or more frequent doses of naloxone.127,113,120,404,405

The availability of naloxone as prefilled syringes and as nasal spray formulations facilitates administration by family members or other caregivers; such treatment is not a substitute for emergency medical care.127,404,405 Administration of naloxone should be accompanied by other resuscitative measures such as administration of oxygen, mechanical ventilation, or artificial respiration.127,113,120,404,405 When administering naloxone outside of a supervised medical setting, always seek emergency medical assistance after the first dose is administered.127

Naloxone is used in both adults and pediatric adults (including neonates) to reverse the effects of opioids.113,120,127,404,405 Naloxone has been given to the mother shortly before delivery†, but it is preferable to administer the drug directly to the neonate if needed after delivery.113

Naloxone hydrochloride injection containing 5 mg per 0.5 mL (Zimhi^®) is a higher concentration of the drug for IM or subcutaneous use in adults and pediatric patients for emergency treatment of known or suspected opioid overdose.145,404 The preparation is commercially available as single-dose prefilled syringes that are administered using a delivery device.404 Naloxone hydrochloride 5 mg/0.5 mL was developed in response to increasing reports indicating that multiple 2-mg doses of naloxone have been required in resuscitations.145 Efficacy of this preparation for community use is supported by pharmacokinetic bridging studies.145

Clinical Perspective

Deaths associated with the use of prescription opioid analgesics increased in the US from 1999 through 2019, with nearly 69,000 deaths involving any opioid occurring in 2020; approximately 16,000 of these deaths involved prescription opioids.283 Deaths due to opioid overdose can be prevented with the use of naloxone, and distribution of naloxone through community-based programs that provide overdose education has been associated with decreased opioid-related mortality rates.131,136,137,144 When administered at usual doses for opioid overdose, serious adverse effects of naloxone are rare.500

The 2022 Centers for Disease Control and Prevention (CDC) clinical practice guideline on prescribing opioids for pain recommends that clinicians discuss the risk of opioid-related harms with their patients, including risk mitigation strategies such as naloxone for overdose reversal.500 Many experts including CDC recommend the administration of naloxone in the event of a known or suspected opioid overdose.135,406,407 Clinicians should offer naloxone and provide overdose prevention education to patients receiving opioid analgesics who are at increased risk of opioid overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opioid or substance use disorder, those with medical conditions that could increase sensitivity to opioid effects, those who have experienced a prior opioid overdose, those taking higher dosages of opioids [e.g., ≥50 morphine mg equivalents/day, and those at risk of returning to a high dose to which they have lost tolerance [e.g., patients undergoing tapering or recently released from prison]).131,132,135,137,197,500,750 Naloxone also should be offered when patients receiving opioids have household members who are at risk for accidental ingestion or overdosage.750

Although naloxone historically has been administered mainly by trained medical personnel in hospitals or ambulances, naloxone increasingly is being administered by nonmedical personnel in community (nonmedical) settings for emergency treatment of known or suspected opioid overdosage, as manifested by respiratory and/or CNS depression.124,125,126,127,136,137,144 Experts recommend that additional first responders (e.g., other emergency medical service personnel, police officers, fire fighters) be trained and authorized to administer naloxone following known or suspected opioid overdosage135,137,142,143 and support greater access to naloxone by workers in settings where opioid overdoses may be witnessed (e.g., nursing homes, home visiting nurses, school nurses and college campuses, outreach programs, substance abuse treatment programs, halfway houses, homeless shelters, correctional facilities).137,143 Commercially available naloxone prefilled syringes and nasal spray formulations facilitate administration of the drug by family members or other caregivers in such settings and are available for community use; however, such treatment is not a substitute for emergency medical care.127,404,405

Diagnosis of Suspected or Known Acute Opioid Overdosage

Naloxone is used for the diagnosis of suspected or known acute opioid overdosage.113,120

Septic Shock

Naloxone hydrochloride injection is FDA-labeled for adjunctive use in the management of septic shock.113,120 Naloxone has been shown to produce a rise in blood pressure that may last up to several hours in some cases of septic shock; however, use of the drug in this setting has not resulted in improved survival and has been associated with adverse effects (e.g., agitation, nausea, vomiting, pulmonary edema, hypotension, cardiac arrhythmias, seizures).113,120 Because of limited experience with this use, optimal dosage and treatment regimens have not been established.113

Naloxone therapy is not included in the current Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock; fluid resuscitation and vasopressors (e.g., norepinephrine, vasopressin) are used first-line in hemodynamic management.130 If a decision is made to use naloxone for management of septic shock, the manufacturers state that the drug should be used with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance.113

Naloxone Challenge Test

To avoid precipitating opioid withdrawal following administration of naltrexone, naloxone has been used as a screening test (naloxone challenge test†) to document the absence of physiological dependence and reduce the risk of precipitated withdrawal.135 The naloxone challenge test is not recommended in pregnant patients.135

Other Uses

A combination of pentazocine hydrochloride and naloxone hydrochloride in a ratio of 100:1 is commercially available for oral use as an analgesic.115 (See Pentazocine 28:08.12.) Combinations of buprenorphine hydrochloride and naloxone hydrochloride in a ratio of 4:1 for sublingual administration or approximately 6:1 for intrabuccal administration are commercially available for use in the management of opioid dependence.114,133,134 (See Buprenorphine 28:08.12.)

Naloxone has been used in the prevention of opioid-induced pruritus† in children and adolescents.414,415

General

Patient Monitoring

• Carefully monitor patients who have responded to naloxone; the duration of action of most opioids may exceed that of naloxone and may result in recurrent respiratory and CNS depression.127,404,405 Administer repeated doses of naloxone when necessary.113,120,127,404,405
• Monitor pediatric patients who have responded to naloxone for at least 24 hours.113,120,127,404,405
• Monitor for development of opioid withdrawal symptoms (e.g., abdominal cramps, body aches, diarrhea, fever, increased blood pressure, nausea or vomiting, nervousness, runny nose, piloerection, restlessness or irritability, shivering or trembling, sneezing, sweating, tachycardia, weakness, yawning).113,120,127,404,405

Other General Considerations

• Resuscitative measures such as maintenance of a patent airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary in the treatment of opioid overdose.113
• State naloxone laws vary, and may permit prescribing and dispensation to patients with risk factors for overdose or to lay persons (including nonmedical first responders, potential bystanders, and family and friends of opioid users).139 Consult state law for further information.139
• Carefully instruct patients and their family members or close contacts regarding clinical manifestations requiring naloxone administration, proper administration technique, and the importance of seeking emergency care immediately following administration of the initial dose.127,135,404,405 Advise caregivers, household members, and other close contacts of where naloxone is stored, and to ensure the location is easily accessible during an emergency (e.g., naloxone should not be stored in a locked container with the opioid).750
• Advise patients taking doses of opioid analgesics when away from home to carry naloxone with them and to advise individuals who are with them of the availability of the drug and its proper use.750

Administration

Naloxone may be administered by IV, subcutaneous, or IM injection; by IV infusion; or intranasally.113,127,196 The drug also has been administered via endotracheal tube†412 and by intraosseous† (IO) injection.412

Parenteral Administration

Naloxone may be administered via IV, IM, or subcutaneous routes, depending on the product formulation.113,120,404,113,120 The American Academy of Pediatrics (AAP) does not endorse subcutaneous or IM administration for emergency medical management of opioid intoxication in children or neonates since hypotension, hypoperfusion, and/or peripheral vasoconstriction may result in erratic or delayed absorption of the drug.110,113,120

Continuous IV infusions of naloxone may be most appropriate in patients who require higher doses, continue to experience recurrent respiratory or CNS depression after effective therapy with repeated doses, and/or in whom the effects of long-acting opioids are being antagonized.406 For continuous IV infusion, the manufacturers state that 2 mg of naloxone hydrochloride may be diluted in 500 mL of 0.9% sodium chloride or 5% dextrose injection to produce a solution containing 0.004 mg/mL (4 mcg/mL).113,120 Titrate the rate of IV infusion in accordance with the patient's response.113,120 Other concentrations have been recommended (see Standardize 4 Safety under Dosage and Administration).249 Following dilution in 5% dextrose or 0.9% sodium chloride injection to a concentration of 0.004 mg/mL (4 mcg/mL), naloxone solutions are stable for 24 hours; after 24 hours, discard any unused solution.113,120

Naloxone hydrochloride 5 mg/0.5 mL injection (Zimhi^®) is administered by IM or subcutaneous injection into the anterolateral aspect of the thigh, through clothing if necessary, using the prefilled syringes and accompanying delivery device.404 When administered to pediatric patients younger than 1 year of age, pinch the thigh muscle while administering the prefilled syringe.404 This preparation is intended to be administered by individuals ≥12 years of age since younger individuals with limited hand strength may find the device difficult to use.404

Prior to administration, carefully inspect parenteral solutions of naloxone for the presence of particulate matter or discoloration.113,120

Store vials, ampuls, and prefilled syringes containing naloxone hydrochloride injection at 20-25°C and protect from light.113,120,404

Intranasal Administration

Naloxone may be administered intranasally for the emergency treatment of known or suspected opioid overdose.127,405 To administer the intranasal formulation, place the patient in a supine position and then remove the nasal spray unit from the carton and blister package.127,405 Tilt the patient's head back, with one hand supporting the neck.127,405 Do not prime or test the device prior to administration.127,405 Gently insert the tip of the nasal spray unit into one nostril until the fingers on either side of the nozzle are against the patient's nose, and press the device plunger firmly to administer the dose.127,405 Remove the nozzle from the nostril following administration of the drug, place the patient in the recovery position, and closely monitor.127,405 If additional doses are required, administer each dose into alternate nostrils using a new nasal spray unit.127,405 Call for emergency medical assistance immediately after administration of the first dose of naloxone nasal spray.127,405 Consult the prescribing information for formulation-specific administration instructions.127,405

Store naloxone nasal spray (Narcan^®) below 25°C (excursions permitted up to 40°C).127 Store naloxone nasal spray (Kloxxado^®) at 20-25°C (excursions permitted at 5-40°C ).405 Do not freeze or expose intranasal naloxone to temperatures above 40°C.127,405 Protect from light.127,405 If the nasal spray freezes (e.g., if stored below -15°C), the device will not spray.127,405 If this occurs, do not wait for the nasal spray to thaw; seek emergency medical help immediately.127,405 Naloxone nasal spray may still be used if it has been thawed after previously being frozen.127,405

Endotracheal and Intraosseous Administration

When IV access cannot be established in emergency situations, naloxone can also be administered effectively via an endotracheal tube† in adults or pediatric patients110,403,412,416 or by IO† injection for opioid overdosage in pediatric patients.403,412

Standardize 4 Safety

Standardize 4 safety (S4S) is a national patient safety initiative to standardize drug concentrations to reduce medication errors, especially during transitions of care.249,250 Multidisciplinary expert panels were convened to determine recommended standard concentrations.249 Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.249,250 For additional information on S4S (including updates that may be available), see [Web].249,250

Dosage

Naloxone is commercially available as naloxone hydrochloride; dosage is expressed in terms of the salt.113,120,127,404,405

Postoperative Opioid Depression in Pediatric Patients

Parenteral

When naloxone hydrochloride is used to partially reverse opioid depression following the use of opioids during surgery in pediatric patients, the usual initial dosage recommended by the manufacturers is 0.005-0.01 mg IV, given at 2- to 3-minute intervals until the desired response (i.e., adequate ventilation and alertness without substantial pain or discomfort) is obtained.113 Additional doses may be necessary at 1- to 2-hour intervals depending on the response of the patient and the dosage and duration of action of the opioid administered.113

Opioid-induced Depression in Neonates

Parenteral

When used to reverse opioid-induced depression in neonates, the usual initial dosage of naloxone hydrochloride is 0.01 mg/kg, administered IV, IM, or subcutaneously at 2- to 3-minute intervals to the desired degree of reversal.113,120

Known or Suspected Opioid Overdosage in Children

Parenteral

Children may receive an initial IV naloxone hydrochloride dose of 0.01 mg/kg; if this dose does not produce the desired degree of response, a subsequent dose of 0.1 mg/kg may be administered.113,120

Since the duration of action of the opioid is often longer than that of naloxone, the depressant effects of the opioid may return as the effects of naloxone diminish, and additional doses of naloxone may be required.113

The dosage delivered by the initial dose of naloxone hydrochloride prefilled syringes for IM or subcutaneous use (Zimhi^®) is 5 mg; if the desired response is not obtained after 2 or 3 minutes of administration, an additional dose may be administered every 2 to 3 minutes until emergency medical assistance arrives.404 Observe the patient closely and seek emergency care immediately following administration of the initial dose.127,404,405 If necessary, perform supportive and/or resuscitative measures until emergency care arrives.127,405

Intranasal

The recommended initial dose of naloxone hydrochloride nasal spray in pediatric patients is one spray (2, 4, or 8 mg) administered intranasally into one nostril.127,405 If the patient fails to respond or responds but subsequently relapses back into respiratory depression before emergency assistance arrives, administer additional doses every 2-3 minutes using a new nasal spray unit into the alternating nostril until emergency personnel arrive.127,405

The requirement for repeat doses depends upon the amount, type, and route of administration of the opioid being antagonized.127,405

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require higher doses of naloxone hydrochloride or repeated administration using a new nasal spray.127,405

Endotracheal, Intraosseous

Some experts suggest an endotracheal† or IO† dose of 0.1 mg/kg in pediatric patients younger than 5 years of age or weighing 20 kg or less or a dose of 2 mg in pediatric patients 5 years of age or older or weighing more than 20 kg;403 however, the optimum dose of naloxone administered via an endotracheal tube† remains to be established and higher (e.g., double or triple) doses may be necessary.403

Postoperative Opioid Depression in Adults

Parenteral

When naloxone hydrochloride is used to partially reverse opioid depression following the use of opioids during surgery in adults, the usual initial dosage recommended by the manufacturers is 0.1-0.2 mg IV, given at 2- to 3-minute intervals until the desired response (i.e., adequate ventilation and alertness without substantial pain or discomfort) is obtained.113,120 Additional doses may be necessary at 1- to 2-hour intervals depending on the response of the patient and the dosage and duration of action of the opioid administered.113,120

The manufacturers state that supplemental IM doses of naloxone produce a more prolonged effect than repeated IV doses of the drug.113,120 For continuous IV infusion, titrate the rate of IV infusion in accordance with the patient's response.113,120

Known or Suspected Opioid Overdosage in Adults

Parenteral

For the treatment of known or suspected opioid overdosage, the usual initial adult dosage of naloxone hydrochloride is 0.4-2 mg IV, administered at 2- to 3-minute intervals if necessary; if no response is observed after a total of 10 mg of the drug has been administered, the depressive condition may be caused by a drug or disease process not responsive to naloxone.113 Naloxone hydrochloride 2 mg may also be administered IM or subcutaneously using naloxone prefilled syringes.113

Since the duration of action of the opioid is often longer than that of naloxone, the depressant effects of the opioid may return as the effects of naloxone diminish, and additional doses of naloxone may be required.113

The dosage delivered by the initial dose of naloxone hydrochloride prefilled syringes for IM or subcutaneous administration (Zimhi^®) is 5 mg; if the desired response is not obtained after 2 or 3 minutes of administration, an additional dose may be administered every 2 to 3 minutes until emergency medical assistance arrives.404

Intranasal

The recommended initial dose of naloxone hydrochloride nasal spray in adults is one spray (2, 4, or 8 mg) administered intranasally into one nostril.127,405 If the patient fails to respond or responds but subsequently relapses into respiratory depression before emergency personnel arrive, administer additional 2-, 4-, or 8-mg doses using a new nasal spray unit every 2-3 minutes into alternating nostrils until emergency personnel arrive.127,405 Prescribe the 2-mg strength for opioid-dependent patients expected to be at risk for severe opioid withdrawal only when the risk for accidental or intentional opioid exposure by household contacts is low.127

Endotracheal

The optimal dosage of most drugs, including naloxone, via endotracheal administration is not established; however, the typical dose given by the endotracheal route is 2-2.5 times the recommended IV dose.416

Diagnosis of Suspected or Known Acute Opioid Overdosage

The manufacturers make no specific recommendations at this time for dosage in diagnosis of suspected or known acute opioid overdosage.113,120,127,404,405 However, if no response is observed after administration of 10 mg of naloxone, the diagnosis of opioid-induced toxicity should be questioned.113,120

Septic Shock

Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established. 113,120

Naloxone Challenge Test

Administration of naloxone hydrochloride 0.4-0.8 mg before initiating treatment with naltrexone may assist in documenting the absence of physiological dependence and minimizing the risk for withdrawal.135

Opioid-induced Pruritus

When naloxone hydrochloride was used in the prevention of opioid-induced pruritus† in children and adolescents, dosages ranged from 0.25-1.0 mcg/kg per hour via continuous IV infusion.414,415

Special Populations

Hepatic Impairment

The manufacturers make no specific dosage recommendations for patients with hepatic impairment.113,120,127,404,405

Renal Impairment

The manufacturers 249 recommend using caution when administering naloxone injection to patients with renal impairment.113,120

Geriatric Patients

The manufacturers 249 recommend using caution when selecting a dose of naloxone for geriatric patients.113,120,127,404,405

Contraindications

• Patients with known hypersensitivity to the drug or any ingredient in the formulation.113,120,127,404,405

Warnings/Precautions

Other Resuscitative Measures

When naloxone is used in the management of acute opioid overdosage, other resuscitative measures (e.g., maintenance of an adequate airway, artificial respiration, cardiac massage, vasopressor agents) should be readily available and used when necessary.113,120,127,404,405

Excessive Doses in Postoperative Patients

Following the use of opioids during surgery, excessive doses of naloxone hydrochloride may result in significant reversal of analgesia and cause agitation.113,120,127,404,405

Use in Patients with Cardiovascular Disorders

Hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients receiving naloxone, sometimes resulting in death, coma, or encephalopathy.113,127 These events have been observed mainly in patients with preexisting cardiovascular disorders or who were receiving other drugs with similar adverse cardiovascular effects.113,127

Use naloxone with caution in patients with preexisting cardiovascular disease or in those receiving potentially cardiotoxic drugs; monitor such patients for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema.113,127

Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists

Reversal of respiratory depression resulting from overdosage of opioid partial agonists (e.g., buprenorphine, pentazocine) may be incomplete and require higher or repeated doses of naloxone.113,120,127,404,405

Precipitation of Severe Opioid Withdrawal

Administer naloxone with caution to patients known or suspected to be physically dependent on opioids (including neonates born to women who are opioid dependent), particularly in patients with cardiovascular disease, because the drug may precipitate severe withdrawal symptoms.113,120,127,404,405

Abrupt postoperative reversal of opioid effects may induce nausea, vomiting, sweating, tremor, tachycardia, increased blood pressure, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest, which may result in death.113,120,127,404,405 These events have been observed mainly in patients with preexisting cardiovascular disorders or who were receiving other drugs with similar adverse cardiovascular effects.113,127 (See Use in Patients with Cardiovascular Disorders under Cautions.)

Risk of Recurrent Respiratory and CNS Depression

The duration of action of most opioids may exceed that of naloxone resulting in a return of respiratory and/or CNS depression after an initial improvement.113,120,127,404,405 Carefully monitor patients and administer repeated doses of naloxone when necessary.113,120,127,404,405 Some experts state that while a brief observation period may be adequate following overdosage of certain opioids with a shorter duration of action (morphine, heroin), patients who have presented with life-threatening overdosage of a long-acting or extended-release opioid may require longer periods of observation.196 The manufacturers state that pediatric patients who have responded to naloxone must be carefully monitored for at least 24 hours.113,120,127,404,405

Risk of Accidental Needlestick Injury

After using naloxone prefilled syringes for IM or subcutaneous injection (Zimhi^®), the needle is exposed until the safety guard is deployed.404 A needlestick injury could occur during use in emergency situations.404 If an accidental needlestick occurs, seek medical attention.404 Seek immediate evaluation by a medical professional for potential exposure to blood borne pathogens (e.g., HIV, hepatitis B virus, hepatitis C virus).404 Stress to patients the importance of familiarizing themselves with the device and its operation prior to experiencing an emergency situation.404

Specific Populations

Pregnancy

There are limited data to date on use of naloxone in pregnant women.113,120,127,404,405 Naloxone should be used during pregnancy only when clearly needed.113,120,127,404,405 Reproduction studies in mice and rats using naloxone hydrochloride dosages of 4 and 8 times, respectively, a human dosage of 10 mg daily in a 50-kg individual demonstrated no embryotoxic or teratogenic effects.113,120,404 Furthermore, no adverse effects were reported in the offspring of rats receiving naloxone hydrochloride subcutaneously at dosages of 2 or 10 mg/kg (up to 12 times a human dosage of 8 mg daily) from gestation day 15 to postnatal day 21.127 No embryotoxic or teratogenic effects were observed in mice and rats during the period of organogenesis with the 8 mg/0.1 mL nasal spray at doses 3 and 6 times a human dose of 16 mg.405

The risk-benefit ratio must be considered before naloxone is administered to a pregnant woman who is known or suspected to be dependent on opioids, since maternal dependence may often be accompanied by fetal dependence.113,120 Naloxone crosses the placenta and may precipitate withdrawal symptoms in both the fetus and the pregnant woman.113,120,127,404,405 Use of naloxone in opioid-dependent pregnant women should be accompanied by monitoring for fetal distress.127

It is not known if naloxone affects the duration of labor and/or delivery.113,120 However, published reports indicate that administration of naloxone during labor did not adversely affect maternal or neonatal status.113,120 Carefully monitor patients with mild to moderate hypertension who receive naloxone during labor, as severe hypertension may occur.113,120

Lactation

It is not known whether naloxone is distributed into milk or has any effect on the breast-fed infant or on milk production; use naloxone with caution in nursing women.113,120 The drug does not affect prolactin or oxytocin concentrations in nursing women, and oral bioavailability of naloxone is minimal.127,404,405

Females and Males of Reproductive Potential

Animal studies revealed no evidence of impaired fertility.127,404,405 Reproduction studies in mice and rats using naloxone hydrochloride dosages of 4 and 8 times, respectively, a human dosage of 10 mg daily in a 50-kg individual (based on body surface area) revealed no evidence of impaired fertility.404 In addition, studies in rats using intranasal naloxone hydrochloride dosages of 2 or 10 mg/kg (up to 12 times a human dosage of 8 mg daily) administered for 60 days prior to mating in males or administered for 14 days prior to mating and then throughout gestation in females revealed no evidence of impaired fertility.127 Studies using the 8 mg/0.1 mL nasal spray in mice and rats at doses 3 and 6 times, respectively, a human dose of 16 mg/day demonstrated no adverse effects on fertility.405

Pediatric Use

Naloxone hydrochloride injection may be used to reverse the effects of opioids in pediatric patients, including neonates.113,120,404 In addition, safety and efficacy of naloxone hydrochloride prefilled syringes for IM or subcutaneous use (Zimhi^®) or nasal spray (e.g., Narcan^®, Kloxxado^®) have been established in pediatric patients of all ages for the emergency treatment of known or suspected opioid overdosage manifested by respiratory and/or CNS depression.127,404,405 Use of naloxone for reversal of opioid effects in pediatric patients is supported by adult bioequivalence studies and evidence from the safe and effective use of other naloxone hydrochloride products.404

As in adults, naloxone may precipitate opiate withdrawal in pediatric patients who are physically dependent on opiates; however, unlike opiate withdrawal in adults, neonatal opiate withdrawal may be life-threatening and should be treated according to protocols developed by neonatology experts.127,405 To avoid abrupt precipitation of neonatal opiate withdrawal syndrome, use of a naloxone preparation that can be dosed based on weight and titrated to effect may be preferred over a preparation that delivers a fixed dose of the drug (e.g., auto-injector, nasal spray) in neonates with known or suspected exposure to maternally administered opiates.127,405

Absorption of naloxone following intranasal administration or IM or subcutaneous injection in pediatric patients may be erratic or delayed.127,404,405 Pediatric patients who have responded to naloxone must be carefully monitored for at least 24 hours, since relapse may occur as the opioid antagonist is metabolized.113,120,127,404,405

Safety and efficacy of naloxone hydrochloride injection in the management of hypotension associated with septic shock have not been established in pediatric patients.113,120 In a study of 2 neonates with septic shock, treatment with naloxone produced a positive pressor response; however, one patient subsequently died after intractable seizures.113,120

Geriatric Use

Clinical studies of naloxone did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.113,120,127,404,405 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.113,120,127,404,405 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.113,120,127,404,405

Hepatic Impairment

Safety and efficacy of naloxone in patients with hepatic impairment have not been established in well-controlled clinical trials.113,120 Use naloxone with caution in these patients.113,120

Renal Impairment

Safety and efficacy of naloxone in patients with renal impairment have not been established in well-controlled clinical trials.113,120 Use naloxone with caution in these patients.113,120

Common Adverse Effects

Intranasal naloxone: Adverse effects reported in clinical trials of intranasally administered naloxone include abdominal pain, asthenia, dizziness, headache, increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, nasal congestion, nasal discomfort, nasal dryness, nasal edema, nasal inflammation, presyncope, rhinalgia, and xeroderma.127,405

Parenteral naloxone: Adverse effects, including serious and fatal cases, reported in clinical trials of parenterally administered naloxone for postoperative patients include cardiac arrest, dyspnea, hypotension, hypertension, pulmonary edema, and ventricular tachycardia and fibrillation.113,120 Excessive doses of naloxone in postoperative patients may result in agitation caused by significant reversal of analgesia.113,120 Adverse effects reported in clinical trials of parenterally administered naloxone after abrupt reversal of dependence are related to acute withdrawal syndrome, which may include the following signs and symptoms: abdominal cramps, body aches, diarrhea, fever, increased blood pressure, nausea or vomiting, nervousness, runny nose, piloerection, restlessness or irritability, shivering or trembling, sneezing, sweating, tachycardia, weakness, yawning.113,120 Abrupt reversal of opioid depression may result in cardiac arrest, increased blood pressure, nausea, pulmonary edema, seizures, sweating, tachycardia, tremulousness, ventricular tachycardia and fibrillation, and vomiting.113,120 In the neonate, opioid withdrawal may also include convulsions, excessive crying, and hyperactive reflexes.113,120 Adverse effects reported in clinical trials of naloxone hydrochloride injection for IM or subcutaneous use (Zimhi^®) included dizziness, elevated bilirubin, lightheadedness, and nausea.404

Naloxone is metabolized in the liver primarily by glucuronide conjugation.113,120,127,404,405

Buprenorphine

Buprenorphine has a long duration of action; therefore, large doses of naloxone are required to antagonize buprenorphine.113,120,127,404,405

Methohexital

Methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in patients with opioid addiction.113,120

Description

Naloxone hydrochloride is an opioid antagonist.113,120,127,404,405 The precise mechanism of action of the drug's opioid antagonist effects is not fully understood.113,120 Naloxone is thought to act as a competitive antagonist at µ, κ, and σ opiate receptors in the CNS; it is thought that the drug has the highest affinity for the µ receptor.113

Naloxone can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.113,120,127,404,405 Because the duration of action of naloxone is generally shorter than that of the opioid, the effects of the opioid may return as the effects of naloxone dissipate.113,120,127,404,405

Naloxone does not produce tolerance or physical or psychological dependence.113,120 In patients who are dependent on opioids, parenteral administration of naloxone will precipitate opioid withdrawal symptoms, which may appear within minutes of naloxone administration and subside in about 2 hours.113,120 The severity and duration of the withdrawal symptoms are related to the dose of naloxone and the degree and type of opioid dependence.113,120

The onset of action of naloxone is within 2 minutes following parenteral administration, and is shorter for IV compared to IM or subcutaneous routes of administration.113,120,404 The duration of action depends on the dose and route of administration and is more prolonged following IM administration than after IV administration.113,120,404

Following intranasal administration of naloxone hydrochloride (2, 4, or 8 mg) nasal spray in healthy adults, the median time to peak plasma concentration was similar to that observed following IM injection of a 0.4-mg dose of the drug and the dose-normalized bioavailability relative to that of the IM injection ranged from 43-54%.127 Peak plasma concentrations and AUC of naloxone were substantially higher following intranasal administration of a 2-mg dose as a single spray in one nostril (approximately 3.3- and 2.6-fold higher, respectively), a 4-mg dose as a single spray in one nostril (approximately 5.5- and 4.4-fold higher, respectively), a 4-mg dose as one 2-mg spray in each nostril (approximately 7.2- and 5.4-fold higher, respectively), or an 8-mg dose as one 4-mg spray in each nostril (approximately 11- and 8.7-fold higher, respectively) than following IM injection of a 0.4-mg dose.127

Following intranasal administration of naloxone hydrochloride (Kloxxado^®) 8 mg (single spray) in healthy adults, the median time to peak plasma concentration was similar to that observed following IM injection of a 0.4-mg dose of the drug and the dose-normalized bioavailability relative to that of the IM injection ranged from 42-47%.405 Peak plasma concentrations and AUC of naloxone were substantially higher following intranasal administration of an 8-mg dose (approximately 12- to 13-fold and 17- to 19-fold higher, respectively) than following IM injection of a 0.4-mg dose.405

Following parenteral administration, naloxone is rapidly distributed into body tissues and fluids.113,120,127,404,405 Naloxone is weakly bound to plasma proteins (mainly albumin).113,120,127,404,405 In humans, the drug readily crosses the placenta.113,120,127,404,405 It is not known whether naloxone is distributed into breast milk.113,120,127,404,405 The half-life of naloxone has been reported to be 30-81 minutes in adults and about 3 hours in neonates.113,120 The mean plasma half-life of naloxone was 1.5 hours following IM or subcutaneous injection of naloxone 5 mg using a prefilled syringe (Zimhi^®).404 Following intranasal administration, naloxone exhibits a slightly longer half-life compared with the IM route (1.8-2.7 versus 1.2-1.4 hours).127,405 Naloxone is rapidly metabolized in the liver, principally by conjugation with glucuronic acid.113,120,127,404,405 The major metabolite is naloxone-3-glucuronide.113,120,127,404,405 Limited studies with radiolabeled naloxone indicate that 25-40% of an oral or IV dose of the drug is excreted as metabolites in urine in 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.113,120,127,404,405

Advice to Patients

• Advise patients, family members, and caregivers to read the FDA-approved patient labeling and to become familiar with all information related to appropriate administration of the provided naloxone formulation.127,404,405
• Instruct patients and family members or close contacts regarding clinical manifestations requiring naloxone administration, proper administration technique, and the importance of seeking emergency care immediately following administration of the initial dose.127,135,404,405
• Advise caregivers, household members, and other close contacts of where naloxone is stored, and to ensure the location is easily accessible during an emergency (e.g., naloxone should not be stored in a locked container with the opioid).750
• Instruct patients and their family members or caregivers on recognition of signs and symptoms of opioid overdose (e.g., extreme somnolence, respiratory depression, miosis, bradycardia, hypotension).127,404,405
• Advise patients of the risk of recurrent respiratory and CNS depression, and to seek immediate emergency medical assistance after the first dose of naloxone and to continually monitor the patient.127,404,405
• Advise patients of the potential limited efficacy of naloxone administration when used to reverse respiratory depression caused by partial agonists or mixed agonists/antagonists such as buprenorphine and pentazocine, and that higher doses or additional administration of naloxone may be required.127,404,405
• Instruct patients that administration of naloxone in patients who are opioid-dependent may precipitate severe opioid withdrawal accompanied by symptoms such as body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and hypertension.127,404,405 Instruct patients that opioid withdrawal may be life-threatening in neonates if not recognized and properly treated; instruct patients on these signs and symptoms (e.g., convulsions, excessive crying, hyperactive reflexes).127,404,405
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.127,404,405
• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.127,404,405
• Inform patients of other important precautionary information.127,404,405

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

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