Naloxone to the Rescue

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In 2013, overdose deaths overtook motor vehicle collisions as the leading cause of injury-related death in the United States. Over 28,000 people die per year from opioid overdoses, and more than half of those deaths involve prescription opioids. This is the unfortunate tip of the addiction iceberg, with over 2 million people abusing or dependent upon prescription opioids in the United States [1]. The three most common drugs involved in prescription opioid deaths are: Methadone, Oxycodone, and Hydrocodone. Fortunately, we have an effective, rapid-acting antidote for opioid-induced respiratory depression: Naloxone. With the increasing number of opioid overdoses, it is important to know how and when to use naloxone.

How it Works
Naloxone is a competitive antagonist of opioid receptors. It has a very similar chemical structure to morphine. It binds to opioid receptors but does not activate them, blocking the site for the agonists. Naloxone binds primarily to the mu receptor, which is responsible for respiratory depression, and sedation. At higher doses it acts on the kappa and delta receptors, which are responsible for analgesia [2].

Notable History
Naloxone was first approved by the FDA in 1971, and has become widely used by EMS providers and emergency physicians. More recently it was approved for use at home in an auto-injector for high-risk patients.

In the News
The 0.4mg IM naloxone auto-injector (Evzio) was approved for home use in 2014 but costs one hundred times more than a regular 0.4mg IM dose. It was quickly followed by the 4mg intra-nasal spray (Narcan nasal spray) in 2015 [3]. The take-home intra-nasal dispenser and auto-injectors are for use in patients taking chronic opioids or who have opioid addictions or abuse who are at risk of overdose at home. These formulations can be easily administered by friends or family members while EMS is being called. While these rescue devices are most often used for patients who abuse opioids or heroin, they can also be useful for patients who are on high doses of pain medication as part of a palliative care plan [4] or for treatment of chronic pain. The availability of auto-injectors sparked a controversy over the last few years. Some physicians were concerned that providing these to patients might make the patients more reckless with their opioid use, or for heroin abusers, may allow the patients a false sense of comfort with their heroin use [5].

Adverse Events
Patients who are chronic opiate users may experience withdrawal symptoms, such as tachycardia, hypertension, myalgia, hyperthermia, rhinorrhea, diaphoresis, nausea, and vomiting. The lowest possible dose should be used in patients who are chronic users, and treatment should be titrated to respiratory status and ability to protect the airway. There are case reports of ventricular tachycardia following naloxone administration [6]. However the risk seems mostly to occur in patients who have also taken sympathomimetic agents such as cocaine. Naloxone administration decreases CNS depression, leading to a sympathetic surge from the sympathomimetic agent. Care should also be taken in elderly patients and those with underlying cardiac disease, and the lowest possible doses used.

Dosing and adjustments
The initial dose of IV or IM naloxone for patients with respiratory depression due to opioids is 0.04-0.4 mg. One potential side effect of naloxone use is the precipitation of acute opiate withdrawal in chronic users. To avoid withdrawal, use the smallest effective dose of naloxone possible. By mixing 0.4 mg of naloxone with normal saline into a 10mL syringe, sequential doses of 1mL (0.04 mg) can be given until there is resolution of the respiratory depression..

Another common problem encountered with opioid reversal is the short half-life of naloxone and the need for intermittent re-dosing or a naloxone drip. For patients who overdose on long-acting opioids (particularly methadone) or on extended-release products such as oxycontin, the hourly dose of naloxone needed can be estimated  as 2/3 of the initial effective bolus dose. This will usually be around 0.2-0.6 mg/hr) [7]. Fifteen minutes after starting a naloxone infusion, half of the initial bolus dose should be administered to prevent a drop in the naloxone level and potential recurrence of respiratory depression [8]. Patients who have overdosed on buprenorphine, which is a mixed opioid agonist/antagonist may require larger doses of naloxone to reverse the effects, such as 2.5mg -10mg, and full reversal may not occur. The duration of action for naloxone is 30-90 minutes for IV administration.

Example case 1: A 19-year-old male without a history of long-standing opioid use presents after a methadone overdose with a GCS of 3, cyanosis, hypoxia, and a RR of 4 with EMS. He required 2 doses of 0.2mg of naloxone IV with EMS for respiratory stabilization. He should be started on a drip at about 0.25mg/hr. 15 minutes after starting the drip he should receive 0.2mg IV. The dosing should be titrated to respiratory status and to minimize side effects.

Example case 2: A 45 year-old male with a long history of high dose opioid use and heroin use presents after intentional oxycontin overdose. He has a GCS of 5 and a respiratory rate of 6. His respiratory rate improves after 0.04mg of naloxone, but he then develops nausea, vomiting, and agitation. After 30 minutes his respiratory rate begins to drop again and he is treated successfully with 0.02mg of naloxone and started on a drip at 0.013mg/hr, and given an additional 0.01mg bolus 15 minutes after initiation of the drip.

Oral naloxone at doses of 1-12mg has been studied for opioid-induced constipation [9,10]. There is about 3% oral bioavailability, so patients may experience some withdrawal symptoms or decreased analgesia. Naloxone is not yet FDA-approved for this indication. For patients who do have opioid-induced constipation, combination oxycodone/naloxone pills are a potential option. They provide good pain relief and fewer GI side effects [11]. However the only available combination pill currently is only FDA approved in the US in an extended release form, as Targiniq ER, for pain refractory to other treatments [10].

Special Considerations
Naloxone is pregnancy class B/C. The risks to a fetus are low and are far outweighed by the risks associated with respiratory depression in the mother. In nursing mothers it is unknown whether naloxone is secreted into breast milk, but there is little absorption orally so it is unlikely to affect the infant [12].

Cost
Liquid naloxone costs about $20 for a 0.4mg dose. The Narcan Nasal spray is $75 per 4mg dose, and the auto-injector is $2250 per 0.4mg injector [8].


REFERENCES

  1. Centers for Disease Control and Prevention. Injury prevention & control: Opioid overdose. https://www.cdc.gov/drugoverdose/. Updated 2016. Accessed 07/21, 2016.
  2. Nelson LS, Howland MA. Antidotes in depth. In: Hoffman RS, Howland M, Lewin NA, Nelson LS,  Goldfrank LR, eds. Goldfrank’s toxicologic emergencies. 10th ed. McGraw Hill; 2015. Accessed 07/21/2016.
  3. FDA. FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose. US Food and Drug Administration: FDA News Release Web site. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Published 11/18/2015. Accessed 07/21, 2016.
  4. Savarese DMF. What’s new in palliative care? Up To Date Web site. uptodate.com. Published 07/19/2016. Updated 2016. Accessed 07/21, 2016.
  5. Bazazi AR, Zaller ND, Fu JJ, Rich JD. Preventing opiate overdose deaths: Examining objections to take-home naloxone. J Health Care Poor Underserved. 2010;21(4):1108-1113.
  6. Hunter R. Ventricular tachycardia following naloxone administration in an illicit drug misuse. J Clin Forensic Med. 2005;12(4):218-219.
  7. Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986;15(5):566-570. doi: S0196-0644(86)80994-5 [pii].
  8. Lexicomp. Naloxone: Drug information. Up To Date Web site. uptodate.com. Accessed 07/21, 2016.
  9. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: Systematic review and meta-analysis. Am J Gastroenterol. 2013;108(10):1566-74; quiz 1575.
  10. Portenoy RK, Mehta Z, Ahmed E. Cancer pain management with opioids: Prevention and management of side effects. Up To Date Web site. uptodate.com. Published 2016. Updated 2016. Accessed 07/21, 2016.
  11. Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin. 2008;24(12):3503-3512.
  12. Hale TW. Medications and mothers’ milk: A manual of lactational pharmacology. 12th ed. Amarillo, TX: Hale Publishing L.P.; 2012:1331.
ABOUT THE AUTHORS

Dr. Shenvi is an assistant professor in the department of emergency medicine at the University of North Carolina. She authors RX Pad each month in EPM.

Karen Serrano, MD is an assistant professor in the department of emergency medicine at the University of North Carolina.

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