Prescription lacks addictive potential or danger and is a vital intervention for patients.
You may work in an ED deep in the heart of opioid abuse. The opioid epidemic was responsible for over 47,000 deaths in the U.S. in 2017, and over 130 people die from opioid toxicity in the U.S. daily.[1-5]
Illicit fentanyl and analogs are associated with over half of opioid-related deaths.[3] Frighteningly, patients are at significant risk of death after discharge following nonfatal opioid overdose. A 2019 study found that of 11,557 patients with nonfatal overdose, 1.1% died within a month, and 5.5% died within one year of discharge. The median age of patients who died was 39 years. Most of these deaths were due to accidental drug overdose (approximately 70%).[6]
The onset and duration of action for opioids depends on the type (e.g. morphine, oxycodone, fentanyl and methadone), formulation (e.g. immediate release vs. extended release), dose (e.g. therapeutic use vs. overdose), and route (e.g. intravenous [IV], intranasal [IN], intramuscular [IM]).[7-9] IV heroin peak effects can occur within one- to two-minutes of injection, while oral methadone peak effects can be up to 7.5 hours.[7-9]
Opioids result in sedation and hypoventilation through action at the mu opioid receptor and reduction in cellular excitability. We are well-acquainted with the signs of overdose: miosis (which does not occur 100% of the time), CNS depression, and reduced ventilation which may result in apnea and death. Other issues include QT prolongation (methadone, loperamide), seizures (meperidine, tramadol) and serotonin toxicity (fentanyl, tramadol).[7,8]
Fortunately, naloxone can reverse respiratory and CNS depression.[7-9] It can be administered IV, IM, subcutaneous (SC), interosseus (IO), or IN.[9] The onset of action is approximately two minutes for the IV route and two- to five-minutes for IM or SC routes. The IN route has a similar onset of action as the IM route.[9] The half-life of naloxone is approximately 30- to 60-minutes, with a duration of over 90 minutes.[7,9] Naloxone crosses the blood brain barrier, and only about 50% of receptors need to be blocked with naloxone to restore respirations.[10]
Is intranasal naloxone safe and effective?
We know how to dose IV naloxone, but what about IN? While there are several routes of administration, literature varies concerning route efficacy. A recent article released by Dietze et al. in JAMA Network Open, entitled “Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial” evaluated IN and IM naloxone.[11]
This study asked whether 0.8 milligrams of naloxone hydrochloride administrated via the IN route was as effective as 0.8 milligrams IM in reversing opioid overdose. To answer this, authors performed a double-blind, double-dummy RCT. Patients were recruited at a supervised injection center in Australia and were over 18-years-old with a history of injection drug use.
They were enrolled in the study if they had evidence of opioid overdose needing administration of naloxone. Patients were randomized to receive one of the following: 1) IN naloxone with placebo IM injection or 2) IM injection of naloxone with IN placebo. The IN dose was administered via atomizer with 0.4 milligrams per nostril. The primary outcome was need for a rescue dose of naloxone 10 minutes after the initial therapy, with secondary outcomes including respiratory rate (RR) > 10 breaths per minute and time to GCS > 13.[11]
Among the 197 patients, 173 were male, with mean age 34 years. From there, 93 patients (47.2%) received IM naloxone and 104 (52.8%) received IN naloxone. About 61% of patients reported injecting heroin, 21% pharmaceutical opioids and 13% fentanyl. Authors found that patients randomized to the IM naloxone administration group were less likely to require rescue naloxone (8.6% in the IM group vs. 23.1% in the IN group). The IM group also had faster time to RR > 10 breaths per minute and time to GCS > 13 (nine and seven minutes faster, respectively).[11] While these results are interesting, it isn’t surprising that IM naloxone was more effective in this study based on the doses utilized. This study didn’t evaluate 2-4 milligram IN naloxone doses currently available.
Literature suggests the time to and the maximum plasma concentrations are similar between IN and IM routes when IN naloxone is administered in 2-8 milligram doses with low volumes (0.1-0.2 mL) when compared to a 0.4 milligram IM dose.[12] A study published in 2009 comparing IN and IM routes in doses of 2 milligrams (with a concentration of 2 milligrams/milliliter) found similar rates of response within 10 minutes.[13]
Other studies, including a systematic review published in the Annals of Internal Medicine, found that intranasal naloxone at doses of 2 milligrams in concentrations of 2 milligrams/milliliter has similar efficacy as IM naloxone with no difference in adverse events.[14] A narrative review found all routes of naloxone administration were effective (excluding oral and endotracheal), though there were inconsistencies in data with significant heterogeneity, primarily due to the concentration and method of administration.[15]
Another narrative review recommends an auto-injectable form for naloxone to speed delivery and avoid unnecessary confusion,[16] while another suggests intranasal dosing may be appropriate when considering effectiveness, administrator safety and costs.[17]
The atomizer is not the same as the IN spray, as the atomizer comes in several different parts requiring construction before administration. There is evidence that adults are more comfortable administering naloxone using a nasal spray compared to IM or atomizer. One study published in 2019 included 207 adults randomized to administer naloxone via IN spray, IM or nasal atomizer kit.[18] The nasal spray had the highest rate of successful administration compared to the other routes and was significantly faster (median 16 seconds compared to IM 58 seconds and atomizer 113 seconds).[18]
Another study evaluated naloxone nasal spray and nasal atomizer in nonmedical personnel, finding that the nasal spray is easier to administer and may increase the likelihood that nonmedical personnel successfully administer naloxone when necessary.[19]
Table 1 provides key points for administration in the out of hospital environment, whether using the premade IN spray or the IN atomizer.[20,21] The Harm Reduction Coalition (https://harmreduction.org) has several resources with printouts available for patients and providers.
Table 1. in IN administration
| For premade IN spray configuration (Narcan®):
– Administer as soon as available if respiratory depression is present. If the patient is not breathing and the device is not available, start rescue breaths. – If using Narcan 4 milligrams spray, peel back the package to expose the device. Hold device with thumb on the bottom part of the plunger and 2 fingers on the device nozzle. – Place the tip of the nozzle in one nostril until your fingers touch the bottom part of the patient’s nose. – Press the plunger firmly, releasing the dose. – Remove the device from the nostril once the dose is administered. – Check the patient for breathing. – If administered in the out of hospital environment, medical care after naloxone administration is recommended. – Repeat dosing every 2-3 minutes is recommended if signs or symptoms of overdose are present after the first dose, using a different nostril each time administered. A different spray device is needed for every spray. |
| For IN mucosal atomizer:
– Administer as soon as available if respiratory depression is present. If the patient is not breathing and the device is not available, start rescue breaths. – Remove the syringe from the box. – Pull the yellow caps off the syringe. Pull the red cap off the naloxone. – Open the plastic wrapping of the atomizer without removing it. Hold the atomizer through the bag. – Grip the clear plastic wings of the atomizer and screw onto the syringe, and then screw the naloxone capsule into the syringe barrel. – Insert the white cone into one nostril and give a short push on the end of the capsule, which administers the medication. Administer one half of each capsule into the nostril. – Remove the device from the nostril once the dose is administered. – Check the patient for breathing. – If administered in the out of hospital environment, medical care after naloxone administration is recommended. – Repeat dosing every 2-3 minutes is recommended if signs or symptoms of overdose are present after the first dose. |
When is IN dosing potentially less effective? IN dosing is less effective if obstruction or damage to the nares is present, including regular cocaine or methamphetamine use and epistaxis.[22,23] In a study of opioid overdose patients, 17% who received intranasal naloxone for suspected opioid overdose were unresponsive to the treatment, with 56% of the non-responders found to have nasal abnormalities.[24] Physical factors such as nasal septum abnormalities, trauma, epistaxis, excessive mucus and mucosal destruction from other intranasal drug use (i.e., cocaine) may affect the rate and amount of absorption of IN naloxone. Drug abusers may be at higher risk for the nasal abnormalities.[24]
Based on the current literature, IN naloxone seems to be a valid option for reversal of opioid overdose in the out of hospital setting. The safety profile of IN naloxone appears to be no different than that of IM naloxone injection in the treatment of opioid overdose.[23]
Who should be discharged with naloxone?
Would you send a patient with anaphylaxis who is eligible for discharge home without an epinephrine autoinjector? Naloxone is a potentially life-saving prescription, with no addictive potential or danger, and we believe this is a vital intervention for patients.[9,25,26]
Patients who are prescribed naloxone have over 60% fewer opioid-related ED visits per year.[25] Administration via the IN and IM routes is safe and effective with little training.[26] Unfortunately, current literature suggests clinicians inconsistently prescribe naloxone. One study evaluated 138,108 people with high-risk opioid issues.[27]
Of patients with a diagnosis of opioid overdose, less than 5% received naloxone as a prescription.[27] Despite this, literature suggests take-home naloxone programs are associated with reduced mortality in those who abuse opioids.[28-30] The American College of Emergency Physicians recommends we should consider naloxone prescription for the following groups:[30]
- Discharged from the ED after opioid intoxication
- Chronic pain management or taking high doses of opioids
- Need for analgesia, but history of substance abuse
- Using extended release/long-acting opioids
- In mandatory opioid detoxification or abstinence program
- Recent release from incarceration and previous opioid abuser
Among the available patient options is a prefilled intranasal autoinjector with 4 milligrams of naloxone, a self-assembled 2 milligram IN autoinjector, and then 2 IM autoinjectors with 0.4 milligrams naloxone.[9,30] The important aspect of prescription naloxone is to first just consider prescribing patients this life-saving medication. The second is to ensure an appropriate dose is prescribed.
What’s the cost for the patient? It varies based on the medication and route, location and insurance. For the IN spray (Narcan®) and those without insurance, the out-of-pocket cost ranges from $119-$150.[31,32] For those with insurance, costs can be as high as $20.[33] With generic naloxone, the cost for most patients will be less than Narcan®, but patients still require the atomizer component. Generic naloxone is prescribed in 2 doses of 2 milligrams/2 milliliters with a prefilled, Luer-Lock needleless syringe. There are several organizations that can assist, including Project Lazarus (and many others).[34]
Take Home Points:
- Opioid overdose is an epidemic and a major cause of death.
- Naloxone can save lives, no matter the route provided.
- Both IM and IN routes are effective as a take home prescription.
- IN naloxone should be administered in 2-8 milligram doses with low volumes (0.1-0.2 milliliters).
- Prescribing naloxone in an auto-injectable form is recommended if discharging the patient.
References:
1. Scholl L, Seth P, Kariisa M, et al. Drug and opioid-involved overdose deaths – United States, 2013-2017. MMWR Morb Mortal Wkly Rep. 2018;67(5152):1419-1427.
2. Centers for Disease Control and Prevention, National Center for Health Statistics. CDC WONDER. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease; 2018. Available at https://www.cdc.gov/drugoverdose/images/data/OpioidDeathsByTypeUS.PNG. Accessed December 7, 2019.
3. Rubin R. Illicit Fentanyl Driving Opioid Overdose Deaths. JAMA. 2017;318(22):2174.
4. Kolodny et al. 2015. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction. Annual Review of Public Health, 36, 559-74.
5. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in Drug and Opioid Overdose Deaths – United States, 2000-2014. MMWR 2016, 64(50); 1378-82.
6. Weiner SG, Baker O, Bernson D, Schuur JD. One-Year Mortality of Patients After Emergency Department Treatment for Nonfatal Opioid Overdose. Ann Emerg Med. 2019 Jun 19. pii: S0196-0644(19)30343-9. doi: 10.1016/j.annemergmed.2019.04.020. [Epub ahead of print]
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8. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146–155.
9. FDA. Naloxone for Treatment of Opioid Overdose. Available at: https://www.fda.gov/media/100429/download. Accessed December 7, 2019.
10. Melichar JK, Nutt DJ, Malizia AL. Naloxone displacement at opioid receptor sites measured in vivo in the human brain. Eur J Pharmacol. 2003 Jan 17;459(2-3):217-9.
11. Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial. JAMA Netw Open. 2019 Nov 1;2(11):e1914977.
12. Krieter P, Chiang N, Gyaw S, et al. Pharmacokinetic Properties and Human Use Characteristics of an FDA Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose. J Clin Pharmacol. J Clin Pharmacol. 2016 Oct;56(10):1243-53.
13. Kerr D, Kelly AM, Dietze P, et al. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009 Dec;104(12):2067-74.
14. Chou R, Korthuis PT, McCarty D, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. 2017 Dec 19;167(12):867-875.
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16. Elzey MJ, Fudin J, Edwards ES. Take-home naloxone treatment for opioid emergencies: a comparison of routes of administration and associated delivery systems. Expert Opin Drug Deliv. 2017 Sep;14(9):1045-1058.
17. Weaver L, Palombi L, Bastianelli KMS. Naloxone Administration for Opioid Overdose Reversal in the Prehospital Setting: Implications for Pharmacists. J Pharm Pract. 2018 Feb;31(1):91-98.
18. Eggleston W, Calleo V, Kim M, et al. Naloxone Administration by Untrained Community Members. Pharmacotherapy. 2020 Jan;40(1):84-88.
19. Tippey KG, Yovanoff M, McGrath LS, Sneeringer P. Comparative Human Factors Evaluation of Two Nasal Naloxone Administration Devices: NARCAN® Nasal Spray and Naloxone Prefilled Syringe with Nasal Atomizer [published correction appears in Pain Ther. 2019 May 6;:]. Pain Ther. 2019;8(1):89-98. doi:10.1007/s40122-019-0118-0
20. Narcan. Available at https://www.narcan.com/patients/how-to-use-narcan#isi_anchor. Accessed February 10, 2020.
21. Administer Naloxone. Harm Reduction Coalition. Available at https://harmreduction.org/issues/overdose-prevention/overview/overdose-basics/responding-to-opioid-overdose/administer-naloxone/. Accessed February 10, 2020.
22. Millard DR, Mejia FA. Reconstruction of the nose damaged by cocaine. Plast Reconstru Surg. 2001 Feb;107(2):419-24.
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24. Barton E, Colwell C, Wolfe T, et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med 2005;29:265-71.
25. Coffin PO, Behar E, Rowe C, et al. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain. 2016 Aug 16;165(4):245-52.
26. Hawk KF, Vaca FE, D’Onofrio G. Reducing Fatal Opioid Overdose: Prevention, Treatment and Harm reduction Strategies. Yale J Biol Med. 2015 Sep; 88(3):235-45.
27. Follman S, Arora VM, Lyttle C, et al. Naloxone Prescriptions Among Commercially Insured Individuals at High Risk of Opioid Overdose. JAMA Netw Open. 2019;2(5):e193209.
28. Chimbar L, Moleta Y. Naloxone Effectiveness: A Systematic Review. J Addict Nurs. 2018 Jul/Sep;29(3):167-171.
29. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction. 2016;111(7):1177–1187.
30. Naloxone prescriptions by emergency physicians. American College of Emergency Physicians website. https://www.acep.org/patient-care/policy-statements/naloxone-prescriptions-by-emergency-physicians/ Accessed December 7, 2019.
