Naloxone: Drug Whys

A comprehensive examination of naloxone uses, pharmacology, pharmacokinetics, administration routes and dosing


Generic Name: naloxone (multiple generics available)
Common Brand Names: Narcan, Evzio
Class: opioid antagonist

The labeled indications, which means U.S. Food and Drug Administration approved uses, for naloxone include partial or complete reversal of natural and synthetic opioid induced respiratory or central nervous system (CNS) depression. Naloxone is also indicated for diagnosis of suspected acute opioid overdoses. A positive response suggests opioids were present. 

Naloxone also has approval as an adjunctive agent to increase blood pressure in septic shock, although this use is no longer recommended. Off-label uses include treatment of opioid induced pruritus (itching) and prevention of urinary retention in post-operative patients using opioid dispensing patient controlled analgesia (PCA) devices.

A nasal-administered dose of Narcan. (AP Photo/Stephan Savoia)
A nasal-administered dose of Narcan. (AP Photo/Stephan Savoia)

Naloxone is readily broken down by stomach acids and has no effect when taken orally. Manufacturers often add naloxone to oral opioid analgesics to prevent clever opioid abusers from crushing the tablets and injecting the medication. 

For 41 years, naloxone was marketed by Endo Pharmaceuticals under the brand name Narcan. In July 2013, Endo discontinued Narcan, creating a shortage that has since been filled by the two remaining manufacturers, Amphastar and Hospira

In April 2014, the Food and Drug Administration (FDA) approved the first naloxone auto-injector, marketed under the brand name Evzio for known or suspected opioid overdose manifested by respiratory and/or CNS depression. Evzio is intended for immediate friend or layperson administration as emergency treatment in settings where opioids may be present and is NOT a substitute for emergency medical care. The device has a voice instruction system that talks the user through proper administration. 

Two naloxone nasal sprays are currently on fast track for FDA approval.

Public health problem
Opioid overdoses are a major public health problem, surpassing motor vehicle crashes as a major cause of death for the past several years. Between 1996 and 2010, community prevention programs trained 53,032 laypersons, mostly friends and family of known opioid uses, in naloxone administration, resulting in 10,171 overdose reversals. 

Former Attorney General Eric Holder labeled the rise in heroin overdoses a, "public health crisis," in March 2014, urging law enforcement agencies and first responders to carry naloxone. This set the stage for not only law enforcement, but also fire and EMS to implement intranasal naloxone programs. Between laypeople and emergency responders, there is one opioid overdose reversal for every five to six intranasal naloxone kits distributed. 

Opioid types and effects
Opioids are substances with morphine-like activity. Prescription opioids include morphine, fentanyl, codeine, buprenorphine, hydrocodone, hydromorphone, tramadol, meperidine, methadone, oxycodone, oxymorphone, loperamide, and others. 

Heroin is a natural opioid made from the resin of poppy plants. Designer opioids come from makeshift laboratories that change designs frequently to evade legislation and law enforcement. Examples of designer opioids include 3-methylfentanyl (aerosolized during the Moscow theater hostage situation in 2002) and α-fentanyl (known as "China White"). 

Opioids depress the central nervous system, provide analgesia (pain control) and can cause feelings of euphoria. Both prescription and nonprescription opioids are involved in recreational misuse, abuse, addiction, dependence, and overdoses. Opioids like heroin are abused for the sensation of pleasure they create, often described as a "rush".  This feeling is often accompanied by warm, flushed skin, dry mouth, a heavy feeling in the arms and legs, and occasionally nausea, vomiting and or severe itching. 

Chronic opioid users develop tolerance, meaning they need increasingly larger doses to achieve the same effects. Dependence also results from long-term use: the body adapts to presence of opioids and withdrawal symptoms develop if use suddenly decreases. Withdrawal symptoms include restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, and cold sweats accompanied by goose bumps (hence the term, "cold turkey").

Opioid overdoses
Opioid overdoses occur for a variety of reasons and require a high level of suspicion and consideration of history. Classic symptoms include pinpoint pupils (miosis), respiratory and CNS depression, flushing, hypotension and decreased bowel sounds. Miosis typically lasts about 6 hours, but may not be present if the patient co-ingests a stimulant or if respiratory depression is prolonged and deep enough to result in a hypoxic brain injury. Other, less common findings of an opioid overdose include non-cardiogenic pulmonary edema, bradycardia, and rhabdomyolysis. 

Fortunately, death from opioid overdoses is uncommon, occurring immediately less than 15 percent of the time. The usual cause of death is hypoxia resulting from respiratory depression. While there is limited understanding of the actual pathophysiology that occurs with opioid overdose deaths, there appears to be a typical window of 40 to 50 minutes during which interventions, such as ventilation and naloxone administration, are likely to be successful. Hence the push to get naloxone into the hands of friends, families and nonmedical emergency responders, like cops and firefighters.

Layperson naloxone administration
Naloxone is in the hands of some laypersons, law enforcement officers (LEOs), BLS and ALS providers. There are advantages and potential pitfalls to use of naloxone by each. 

Laypeople given naloxone are trained in CPR and signs and symptoms of overdose, stressing the need to call for EMS. Widespread distribution of naloxone to laypersons has saved thousands of lives.

The primary downside of layperson naloxone administration is recurrence of respiratory depression if emergency care is not sought following naloxone administration. 

Additionally, some argue that easy access to naloxone may encourage drug use. Numerous studies have demonstrated that peers are in the best position to intervene during the critical 40 to 50 minutes following an overdose and, without naloxone, will attempt to revive victims using a host of unorthodox and often dangerous interventions. Equipping peers with naloxone not only provides early appropriate rescue, but seems to encourage drug addiction treatment. 

Law enforcement officer naloxone administration
LEO use of naloxone is predicated on BLS instruction and recognition of opioid overdose. The seeming advantage of putting naloxone in the hands of LEOs is their tendency to be first on scene of overdoses, the fact that they make initial entry into scenes deemed unsafe for fire and EMS responders, and have an earlier window of opportunity to intervene. 

Naloxone administered to someone without opioids on board has virtually no effect and is certainly not harmful.

Naysayers decry the emphasis on pharmaceutical treatment of a condition they believe could be managed with a bag-valve-mask or pocket mask until EMS arrival. There is also concern that the 2 milligram intranasal dosing will cause withdrawal symptoms and precipitate violent behavior. As of yet, none of these concerns have been substantiated in field studies. 

There are numerous anecdotal case reports of more gradual and smoother awakening with intranasal than intravenous or intramuscular naloxone. LEOs are also frequently able to awaken overdose victims and ambulate them to meet EMS responders in less dangerous environments than where they were initially found.

BLS naloxone administration
BLS, including medical first responder, use of naloxone enjoys the same advantages and criticisms seen with LEO use. Depending on the system response paradigm, BLS providers may arrive well ahead of ALS responders and, in some systems, be the only care providers available. 

To surmise that any BLS provider is capable of managing an unprotected airway while providing effective ventilations during patient movement, packaging and transport without the benefits of cardiac monitoring and waveform capnography seems unrealistic. Adequate spontaneous breathing is always preferable to having to provide mechanical ventilation.

An additional worry about BLS-administered naloxone is that patients awakened from an opioid overdose will subsequently refuse transport and be harmed by recurrence of respiratory depression when naloxone wears off before the opioid. This has not been substantiated in studies. In fact, studies of both layperson- and EMS-administered naloxone show very low incidences of death and virtually no requirements for additional naloxone in persons who refuse transport to a health care facility after initial overdose reversal.

ALS naloxone administration
ALS use of naloxone is probably fraught with the greatest potential for adverse events. Paramedics usually administer naloxone intravenously, which, when given too quickly or not titrated carefully, have a well-demonstrated ability to induce acute withdrawal resulting in unpredictable and often violent patient behavior. 

Best practice, as memorialized in many ALS protocol documents, includes room air ventilation (high oxygen levels may result in premature awakening) with a bag valve mask to bring the patient's respiratory rate to 10-12 breaths/minute and slow titration of the minimum dose of naloxone needed to restore adequate spontaneous respiratory rate and depth. If there is suspicion that the patient will elope, an intramuscular dose of naloxone can be administered prior to awakening.  This takes time and patience and familiarity with dilution and naloxone titration. As a result, most adverse events associated with naloxone administration tend to occur with ALS administration.

Naloxone administration
There are a variety of routes available for administration of naloxone. Intravenous administration is preferred, but not always practical or possible. Intramuscular (IM) or subcutaneous (SubQ) routes are also FDA approved. 

Off-label administration routes include nebulized, as well as intranasal and intraosseous (IO). Naloxone can be given endotracheally, but such use is supported by only one published anecdotal care report and should be considered the least desirable route of administration, probably requiring higher doses than other routes. 

Intranasal administration is usually facilitated by a commercial intranasal mucosal atomization device (LMA MAD Nasal). Studies of EMS intranasal naloxone use suggest that it might have more than a few advantages over other routes of administration. A major consideration is safety. In major metropolitan areas, 80 percent of intravenous drug users (IVDU) are HIV or hepatitis C positive, increasing needle stick injury risks to prehospital providers. 

Intranasal administration is also faster than intravenous dosing. Several studies comparing median time from arrival to clinical response report eight minutes for intranasal naloxone versus 10 minutes for IV dosing (factoring in time to obtain venous access). Intranasal naloxone has a comparable response rate to IV of 83 percent, and while not well studied yet, results in a more gradual and slower awakening in many case reports, meaning the potential for violence and aggression is less with intranasal than intravenously dosed naloxone. 

No studies have yet been conducted comparing the Evzio auto-injector to intranasal naloxone although the cost of the auto-injector may price it well out of reach of emergency responders.

Naloxone dosing
Naloxone dosing for opioid overdoses is different from dosing for reversal of respiratory depression resulting from therapeutic opioid administration, such as cancer pain, surgery or procedural pain. It is imperative when administering naloxone to treat an overdose or suspected overdose that it be accompanied by standard BLS and ACLS measures including airway management, ventilation, and chest compressions if indicated. Naloxone alone will not restore life in a patient who is in cardiac arrest or is in the process of transitioning from respiratory arrest to cardiac arrest. 

When administering naloxone for an opioid overdose, or suspected overdose, by intravenous, intramuscular and subcutaneous routes, the recommended adult dose is 0.4 to 2 milligrams, repeated every two to three minutes until reversal of narcotic effect is achieved. Because many opioids have longer durations of action than naloxone, the dose may need to be repeated 20 to 60 minutes after initial administration. Pediatric dosing recommended by naloxone manufacturers calls for an initial dose of 0.01 milligrams per kilogram and, if no response, a second dose of 0.1 milligrams per kilogram. 

Intranasal dosing is 2 milligrams total, administering 1 milligram into each nostril. The onset of action is slightly delayed compared to intravenous or intramuscular administration so repeat dosing is recommended after five minutes if respiratory depression persists. 

When nebulized, 2 milligrams is the recommended dose (diluted in 3 mL of normal saline), repeated as needed with no specified time interval between doses. It would seem reasonable to use the same five-minute spacing recommended for intranasal dosing when nebulizing naloxone.

The Evzio auto-injector delivers 0.4 milligrams intramuscularly or subcutaneously and can be repeated, with an additional auto-injector, every two to three minutes until EMS arrives. 

For treatment of long-acting opioids such as methadone, sustained release products, or symptomatic body packers, it may be necessary to initiate a continuous intravenous naloxone infusion. This should be calculated either based on the effective intermittent dose used and the duration of the response or 2/3 of the initial effective dose administered on an hourly basis (usual range 0.25 to 6.25 milligrams per hour). One-half the initial bolus dose should be readministered 15 minutes after starting a continuous naloxone infusion to prevent a drop in naloxone levels. The infusion can be titrated to assure adequate ventilation and prevent withdrawal symptoms.

To reverse respiratory depression from therapeutic opioid doses, using intravenous, intramuscular or subcutaneous naloxone, initial adult dosing is recommended at 0.04 to 0.4 milligrams, repeated until the desired response is observed. If this is not achieved with a total dose of 0.8 milligrams, it is recommended that the provider consider other causes of respiratory depression besides opioids. 

When attempting to reverse respiratory depression in patients being treated for cancer pain, intravenous naloxone is recommended at 0.04 to 0.08 milligrams (40 to 80 micrograms), given slowly and repeated every 30 to 60 seconds. Once a total dose of 1 milligram is reached, consider other causes of the respiratory depression. 

For postoperative reversal of respiratory depression in adults, 0.1 to 0.2 milligrams of intravenous naloxone is recommended at two- to three- minute intervals until adequate ventilation and level of consciousness, without significant pain, is achieved. Dosing for infants, children and adolescents ranges from 0.005 to 0.01 milligrams per kilogram, also repeated at two- to three- minute intervals. 

Opioid induced pruritus (itching), more commonly seen with epidural or spinal opioid infusions, can be treated with naloxone either as a continuous intravenous infusion, recommended at 0.25 micrograms per kilogram per hour, or as a onetime dose of 2 micrograms per kilogram. Caution is needed to assure that the naloxone is not reversing analgesia and because of the frequency with which this occurs, there are better choices available for pruritus treatment than naloxone.

No naloxone dose adjustments are necessary in patients with renal or liver impairment. Studies are not sufficient yet to determine if dosing adjustments are needed in geriatric patients although the manufacturer recommends, as all pharmaceutical manufacturers do, starting at the lower end of recommended dosing in elderly patients.

Overdoses of field-administered naloxone have not been reported. In human studies, subjects given very high dose naloxone experienced seizures, severe hypertension and hypotension or bradycardia. Subjects also experienced cognitive and behavioral impairments that persisted for two to three days. Patients who receive an overdose of naloxone should be treated symptomatically. 

Naloxone pharmacology, pharmacokinetics and stability
The onset of action and duration of action of naloxone depends on the administration route.

  • Following intravenous administration, naloxone has an onset of action of about two to five minutes (mean 3.7 minutes) with a short duration of action lasting from 30 to 60 minutes.
  • Intramuscular and subcutaneous onset of action is evident in three to seven minutes (mean 4.2 minutes) and lasts longer (up to two hours when given IM).
  • Intranasal naloxone onsets in eight to 13 minutes and lasts up to 90 minutes.
  • Endotracheal administration onsets in two to five minutes and nebulized in five minutes. 

Many opioids have longer durations of action, which is why additional doses of naloxone may, theoretically, be necessary. 

Naloxone is rapidly distributed throughout the body and metabolized in the liver. Most naloxone is excreted as metabolites in the urine over the 72 hours following administration. Naloxone readily crosses the placenta; it is unknown whether naloxone is excreted in human breast milk.

Naloxone is a synthetic derivative of oxymorphone and is a pure opioid antagonist. While its exact mechanism of action is not completely known, it blocks or reverses the effect of opioids at their receptors including respiratory depression, sedation and hypotension (low blood pressure). 

Naloxone has multiple generic forms in the U.S. typically available in 1 and 10 mL vials or ampules containing a 0.4 mg/mL concentration and 2 mL vials or ampules containing a 1 mg/mL concentration. The 1 mg/mL concentration is used for intranasal administration. The Evzio auto-injector contains 0.4 mL of a 0.4 mg per 0.4 mL concentration (total dose is 0.4 milligrams). 

Naloxone should be stored between 68 to 77 F (room temperature) and protected from light. The Evzio auto-injector should be stored in the case provided between 59 and 77 F with excursions between 39 and 104 F permitted.

Giving small aliquots of naloxone can be difficult; dilution is helpful. A 0.4 mg/mL dose of naloxone can be diluted with 9 milliliters of normal saline to make a 10 mL volume of 0.04 mg/mL (40 micrograms per milliliter) concentration. Of note, particularly for critical care transport providers, naloxone is incompatible with pantoprazole, a proton pump inhibitor that inhibits gastic acid secretion.  

Naloxone cautions and warnings
In the absence of opioids, naloxone has no effect, which makes the drug seem relatively safe. However, naloxone must be administered very cautiously to people who are known or suspected to be physically dependent on opioids as it may result in an acute withdrawal syndrome.

Precipitation of opioid withdrawal by naloxone administration is the most common adverse effect. While withdrawal is not usually life threatening except to neonates, the symptoms can be very distressing to patients and people in acute withdrawal can become violent, causing harm to themselves or to others.

The other important consideration when administering naloxone is recurrence of respiratory depression if the opioid involved is longer acting than the naloxone. The only way to assure respiratory depression does not recur is to observe the patient until the risk of recurrence passes.

Important naloxone side effects and interactions
Precipitation of opioid withdrawal by naloxone administration is the most common adverse effect. Signs of opioid withdrawal result from excessive sympathetic tone and include body aches, runny nose, sneezing, yawning, sweating, tachycardia, increased blood pressure, restlessness, nervousness, irritability, shivering, tremors, abdominal cramps, nausea, vomiting and diarrhea. In neonates, withdrawal may also include seizures, excessive crying and hyperactive reflexes. The goal for naloxone dosing in an opioid overdose is to reverse the respiratory depression without precipitating acute withdrawal.

Of particular note, abrupt reversal of opioid effects in postoperative and chronic pain, usually cancer, patients has resulted in extremes of blood pressure (hyper and hypotension), ventricular tachycardia and fibrillation, pulmonary edema and death. Providers are strongly cautioned about excessive doses of naloxone.  

Currently, there are no drug interactions of concern to EMS providers.

Average U.S. naloxone costs
The cost of naloxone has steadily increased for several years. Critics also point to the increase in cost as a reason to restrict access to medical professionals and limit availability to laypersons.

  • 0.4 mg/mL (1 mL vial/ampule) generic naloxone
    Average cost: $18.71 each
  • 1 mg/mL (2 mL preloaded syringe/vial/ampule) generic naloxone
    Average cost: $ 39.60 each
  • 0.4mg/0.4mL (0.4 mL) Evzio Auto-Injector)
    Average cost: $345.00

References

  1. Lexicomp: Wolters Kluwer Health, Hudson, Ohio (accessed October, 2015).
  2. Albany Medical Center Pharmacy, Albany, New York.
  3. U.S. Department of Justice, Public Affairs.  News Release: Attorney General Holder, Calling Rise in Heroin Overdoses ‘Urgent Public Health Crisis,’ Vows Mix of Enforcement, Treatment.  March 10, 2014.  On-line, available at: www.justice.gov/opa/pr/2014/March/14-ag-246.html.  
  4. Kerr D, Dietze P, Kelly A.  Intranasal naloxone for the treatment of suspected heroin overdose.  Addiction.  2008; 103:379-386.
  5. Ashton H, Hassan Z.  Intranasal naloxone in suspected opioid overdose.  Emerg Med J. 2006;23:221-223.
  6. Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A.  Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers.  Ther Drug Monit. 2008;30:490-496.
  7. Weber JM, Tataris KL, Hoffman JD, Aks, SE, Mycyk MB.  Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose?  Prehosp Emerg Care.  2012;16:289-292.
  8. Wermeling DP. A response to the opioid overdose epidemic: naloxone nasal spray.  Drug Deliv Transl Res.  2013;3:63-74.
  9. Centers for Disease Control and Prevention. Community-Based Opioid Overdose Prevention Programs Providing Naloxone — United States, 2010.  MMWR. 2012;61:101-105.  On-line, available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm6106a1.htm.

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