Doses as low as 0.04 mg per aliquot have been recommended by some, with repeated dosing every minute or so as needed. The goal is to have the patient slowly and progressively become stable without producing withdrawal. On the other hand, the ever-increasing contamination of street heroin with potent fentanyl and methadone overdose has precipitated opioid poisoning that requires much more naloxone for reversal.
EMS frequently has the opportunity to administer naloxone, and for years IV or IM use has been the norm. Large doses can precipitate acute withdrawal, making life miserable for the patient and the rescuer. One way to titrate the dose of naloxone in the patient who still has a pulse and is breathing is the use of intranasal (IN) medication using a nebulizer for lung absorption or a catheter injection for nasal mucosal absorption. IN naloxone is applicable for prehospital care, primarily for ease of use and to decrease needle sticks, but the IN drug also can be used in the ED to reverse the opioid overdose slowly.
Randomized Controlled Trials Comparing the Effectiveness and Safety of Intranasal and Intramuscular Naloxone tor the Treatment of Suspected Heroin Overdose
Kerr D, Kelly AM, et al
These authors studied the benefit of prehospital intranasal administration of naloxone because of its ease of application, greatly reduced risk of needle stick injury, and the potential for prehospital use. The study sought to determine the effectiveness and safety of a 2 mg/ml concentrated solution of naloxone given intranasally compared with intramuscular naloxone. The authors aimed to compare the two preparations in response time, side effects, need for additional doses of rescue naloxone, and final outcome. This was a randomized, prospective, unblinded clinical trial conducted in Australia.
An eligible patient had to have altered consciousness, pinpoint pupils, and respiratory depression (respirations less than 10/min). The Glasgow Coma Scale had to be 12 or less with no sign of facial trauma, blocked nasal passages, or epistaxis. A mucosal atomization device was used to deliver 2 mg naloxone solution, specifically 1 mg/0.5 ml directly into in each nostril. The IM dose was likewise a 2 mg injection. Subjects were eligible for the rescue dose of 0.8 mg IM naloxone if they failed to respond to either IM or IN naloxone after 10 minutes. The primary outcome was the proportion of patients with an adequate response within 10 minutes of antidote administration.
Response was defined as spontaneous respirations at 10 per minute or greater or a Glasgow Coma Scale of 13 or greater. Secondary outcomes included time to adequate response, need for hospitalization, or requiring rescue naloxone because of inadequate primary response.
Eighty-three patients received the IN antidote and 89 received the IM injection of the 172 studied. The median age was 29 years, and 74 percent were male. Overall, three-quarters of the patients received an adequate response within 10 minutes from either the IN (73%) or the IM drug (77%). The mean response time was similar in both groups. Eighteen percent of those receiving IN naloxone received rescue naloxone compared with only 4.5 percent in the IM group receiving rescue naloxone. Only minor adverse events occurred in both groups, and about seven percent in each group experienced agitation, nausea, or vomiting consistent with withdrawal. No needle stick injuries were sustained during IM administration.
The authors believe that both routes are clinically effective for naloxone administration, yet IN administration would decrease the incidence of bloodborne exposure to EMS personnel. Both groups had the same non-response rate, but the reason for this was not clarified in the report. The response time for the IM naloxone was rather long: eight minutes. Those receiving IN naloxone were 4.8 times more likely to receive rescue naloxone, but the decision to use this was made by the paramedic's judgment at the scene. The authors conclude that their study demonstrated that the IN route is an effective and safe intervention for initially managing heroin overdose. This option offers a needleless option for EMS providers.
Comment: This was a rather primitive study in which liquid naloxone in concentrated form was simply squirted into each nostril. Intranasal medications have been used for a variety of reasons, such as midazolam for pediatric seizures, and they are generally well absorbed. Absorption and clinical effect, however, are erratic and occur more slowly than with the IV or IM route. Some of the drug is likely swallowed, and it may be difficult to place the liquid from the syringe accurately onto an absorbable area of mucosa. The delayed time for clinical effect demonstrates that both routes have a less rapid onset than the IV route. Longtime heroin users often have inadequate venous access because of vein scarring, so an alternate route of administration would be nice. Heroin users have a high rate of hepatitis that is easily transmitted by a needle stick, and HIV is a concern as well. Both the IM and IN routes would certainly decrease needle sticks among EMS personnel.
It makes most sense in the ED, though, to administer naloxone intravenously. One can argue about the dose, but the onset of action is usually less than a minute in someone with an intact circulation. The current trend is to use smaller amounts and to repeat as needed to keep the patient awake yet not precipitate withdrawal. That's easier said than done, however, in a busy ED. Obviously the subject has to have a blood pressure for any route to be effective. Current CPR guidelines from the AHA state that survival of an opioid-caused cardiac arrest is not dependent on naloxone but on intubation and CPR only. Once breathing, opioid-poisoned patients are generally not in danger of dying.
I would not recommend the intranasal route for someone who is seriously poisoned. Alternatives to peripheral venous access would be sublingual or the external jugular, saphenous, or femoral veins, but one would not expect EMS personnel to use these routes. Naloxone can also be given down the ET tube, but dosing is not well studied. I suggest starting with 2 mg if the ET tube is used. The saphenous vein of the ankle is an IV route rarely used by drug addicts, and this site should be considered in someone with difficult venous access, at least for the administration of naloxone.
Can Nebulized Naloxone be Used Safely and Effectively by EMS for Suspected Opioid Overdose?
Webber J, Tataris KL, et al
Prehosp Emerg Care
This study was conceived to determine whether nebulized naloxone could be used safely and effectively by prehospital EMS for patients with suspected opioid overdose. The effectiveness of intranasal naloxone solutions has been previously studied, and nebulized naloxone has some support in the literature but has not previously been studied in the prehospital setting. EMS providers in Chicago was trained to give nebulized naloxone as an alternative to the IV or IM routes. All cases in which this occurred over a six-month period were studied.
Specifically, 2 mg of naloxone was diluted with 3 ml of saline and given via a protocol-specified nebulization. Most suspected opioid overdoses were those with respiratory depression but not severe cardiorespiratory compromise. Patients were given 0.8 to 2 mg of the antidote IM or IV if they didn't respond to nebulized naloxone. The primary outcome was the patient response, graded as complete, partial, or no improvement. Another outcome studied was the use of rescue IV/IM antidote or the need for assisted ventilation.
The results were analyzed in 105 cases that met the inclusion criteria primarily for suspected opioid overdose and also for an unknown diagnosis with symptoms consistent with opioid effect. Twenty-two percent of those administered nebulized naloxone had a complete response, 59 percent had a partial response, and 19 percent had no response. Rescue naloxone was given to 11 cases, and five had a complete response, four had a partial response, and two had no response. No patient required intubation or assisted ventilations, and no adverse events occurred. The authors concluded that nebulized naloxone is a safe and effective needleless antidote for the prehospital treatment of suspected opioid overdose in patients who still had spontaneous respirations.
No patients signed out against medical advice, and all patients were transported to the hospital following the naloxone administration. The authors believe that most ALS and BLS systems have adequate nebulization equipment, and adapting COPD/asthma masks for naloxone use is simple. The major shortcoming of this study was that it did not confirm whether the patient actually suffered an opioid overdose.
Comment: Placing 2 mg of naloxone and saline diluent in a nebulizer, the one commonly used for asthma bronchodilators, is a relatively simple task, but one that has not been widely adopted by EMS. It provides a steady low-dose administration of naloxone that is inhaled and absorbed systemically via the lungs. It can reverse opioid intoxication if the patient is still breathing, and has the benefit of providing a proven antidote by means other than a large IV bolus. Obviously, this method cannot be used in those with severe respiratory depression. Interestingly, the nebulization of naloxone could be delivered via a side port during bag-valve-mask ventilation if IV access is not readily available.
Some hospital EDs use nebulized naloxone in a similar method. Very little is available in the literature describing this technique, but it obviously works. The only concern is that the dose absorbed may be too small to prevent further deterioration, and careful observation is required. I don't know whether this method would produce acute withdrawal any less frequently than the alternative methods of administration, but it's a technique worth considering in someone who has poor venous access but is otherwise clinically stable. Note that neither route of naloxone administration discussed here is FDA-approved.
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AHA Guidelines for CPR and Cardiovascular Care
The American Heart Association released guidelines in 2010 for cardiopulmonary resuscitation and emergency cardiovascular care for patients with opioid toxicity, noting that “no data ... support the use of specific antidotes in the setting of cardiac arrest due to opioid overdose.” The guidelines continue, “Resuscitation from cardiac arrest should follow standard BLS and ACLS algorithms. Naloxone is a potent antagonist of the binding of opioid medications to their receptors in the brain and spinal cord. Administration of naloxone can reverse central nervous system and respiratory depression caused by opioid overdose.” (Circulation 2010;122[18 Suppl 3]:S829.)
The AHA clearly states that naloxone has no role in managing cardiac arrest.
“Administration of naloxone can produce fulminate opioid withdrawal in opioid-dependent individuals, leading to agitation, hypertension, and violent behavior,” according to the guidelines. “For this reason, naloxone administration should begin with a low dose (0.04 to 0.4 mg), with repeat dosing or dose escalation to 2 mg if the initial response is inadequate. Some patients may require much higher doses to reverse intoxication with atypical opioids, such as propoxyphene, or following massive overdose ingestions. Naloxone can be given IV, IM, intranasally, and into the trachea.”
Note: The AHA does not consider naloxone to be a CPR medication. Saying that it has “no role” is a bit strong, and many clinicians likely would give the antidote along with CPR and other ACLS interventions, or shortly thereafter, if opioid poisoning were considered present. Survival from cardiac arrest is not from naloxone but from vigorous support of respirations. — JRR
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Naloxone Nebulizers for ODs
Dr. Roberts: As an ED nurse turned ED NP, I have discovered a few tricks when it comes to narcotics overdose. Obtaining an intravenous line proves to be difficult in patients with a history of intravenous drug abuse. Why not consider using a naloxone nebulizer while your nurses or techs search for an intravenous line? Not only does it work, it allows an overdose patient to come out of his narcotic coma gradually, which means he is usually less combative. (“Fentanyl-Laced Heroin: A Deadly Combination,” EMN 2014;36:13; http://bit.ly/1dVrv7S.)
A recent study in the American Journal of Emergency Medicine found that nebulized naloxone was “well-tolerated and led to a reduction in the need for supplemental oxygen as well as improved median GCS and RASS scores in patients with suspected opioid intoxication.” (2013;31:585.) We all practice universal precautions because bloodborne pathogen rates in IV drug abusers are known to be high. Suggest naloxone nebulizers for EMS providers, too. Obtaining a line on a difficult stick in the ambulance can be tricky and potentially unsafe, especially with an unruly patient. Studies have shown and proven that naloxone nebulizers are a safe and effective needle-less way to provide care to all narcotic overdoses prior to hospital arrival. — Martha Roberts, ACNP, CEN, Arlington, VA
Dr. Roberts responds: Excellent suggestion!
Praise for Article on ProCESS Trial
Dr. Roberts: I read with interest your piece on our trial. (“Interventions for Sepsis: The ProCESS Trial,” EMN Breaking News Blog; http://bit.ly/1iHgIK6.) Thanks for spending your time, intellect, good writing, and pages on this. Your summary reflects the important message. The key points are two. First, how one resuscitates after the simples steps is less important than those simple steps: looking hard to recognize septic shock (including in the non-hypotensive patient), giving antibiotics early, and giving fluids to restore perfusion. Second, ED care by sharp emergency physicians who recognize that this disease is deadly and an emergency is what really matters.
Your insights distinguish you, and buttress the durable parts of original Rivers data and the subsequent Surviving Sepsis Campaign efforts. A central catheter and one prescriptive approach based on that catheter isn't the key; simple, aggressive care is. Let's maintain and grow the attention in the ED and do the important things to drive mortality lower. It remains too high. — Donald M. Yealy, MD, Pittsburgh
Dr. Roberts responds: Dr. Yealy, thank you for a superb study as well as the feedback and accolades. It seems like a CVP reading might still be useful at some point, perhaps in the ICU when you question whether fluid resuscitation has been accomplished. But your results are spot on and very elucidating regarding ED care.
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