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A Mistaken Dose of Naloxone 

Erika Cutler, PharmD, and Delani Gunawardena, MD | December 18, 2019
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The Case

A 55-year-old man with widely metastatic gastric cancer presented to his oncologist's office for a follow-up appointment. He had just completed cycle 2 of FOLFOX chemotherapy and reported feeling relatively well. His symptoms included some fatigue in the week after chemotherapy, but his abdominal and bony pain due to metastases was well controlled with opioid therapy (approximately 200 oral morphine equivalents per day). Examination and imaging confirmed that the disease was responding, so they planned to continue chemotherapy with the next dose scheduled for the following week.    

At the end of the visit, the oncologist electronically ordered refills of the patient's pain medications, and a best practice alert (BPA) prompted him to also prescribe naloxone (a medication that can reverse an opioid overdose) intranasal spray. The naloxone BPA was part of the cancer center's new initiative to reduce opioid-related adverse events. The oncologist followed the prompt and ordered the naloxone but did not inform the patient or educate him on its indication and appropriate use. The patient then picked up his medications at his usual local pharmacy, but the pharmacist also did not provide any naloxone education to the patient. 

Upon arriving home, the patient took out his new medications and administered an intranasal dose of naloxone (4 mg). Within a minute, he developed severe abdominal pain and bone pain. He called the 24 x 7 cancer center helpline and described what happened. They diagnosed the patient as having developed a pain crisis due to the effects of the naloxone and advised him to come to the urgent care center, where intravenous opioids were administered for uncontrolled pain. He was monitored for a few hours, and his home pain regimen was reinitiated. 

 A root cause analysis was performed by the hospital's safety committee, which revealed that pharmacists were tasked with reviewing naloxone prescriptions and providing education for patients within the health system's pharmacies, but no such mechanism existed for "outside pharmacies." They identified a need for alternative, proactive education plans for situations in which prescriptions are sent to pharmacies outside the health system. Additionally, they realized BPAs should be paired with sufficient staff training and clear role designations for prescribing physicians, pharmacists, and nurses.   

The Commentary

By Erika Cutler, PharmD, and Delani Gunawardena, MD 

More than 700,000 US residents died from a drug overdose between 1999 and 2017.1 In 2017 alone, drug overdoses resulted in over 70,000 deaths, of which 67.8% involved opioids – a 12% increase from 2016.1 This opioid overdose epidemic is due to use of illicit drugs, highly potent synthetic opioids, mixing of illicit and prescription opioid or sedative drugs, and misused prescription opioids. Drug-alcohol or drug-drug interactions (e.g. concurrent use of benzodiazepines) can increase the risk of accidental overdose even when these pain medications are taken as prescribed. To mitigate this risk, there have been increasing efforts to expand access to naloxone, an opioid antagonist that temporarily reverses the effects of an opioid overdose.2 In 2018, the U.S. Surgeon General issued an advisory urging increased naloxone availability, recommending that the public—especially those who are personally at risk for an opioid overdose and their families and friends—carry naloxone to decrease overdose deaths.3 Prescribers and pharmacists play important roles in increasing access to a potentially life-saving intervention.  
In 2016, the CDC published guidelines on prescribing opioids for chronic pain and included a recommendation that clinicians consider offering naloxone when there is an increased risk for opioid overdose (e.g. history of overdose, history of substance use disorder, opioid dosages ≥50 morphine milligram equivalents per day, or concurrent benzodiazepine use).2 In California, prescribers are required to offer a prescription for naloxone hydrochloride, or another comparable drug approved by the United States Food and Drug Administration (FDA), to a patient when certain conditions that increase the risk of overdose are present.4 This law, which went into effect January 1, 2019, also requires a prescriber to provide education to a patient and his or her designee on overdose prevention and the use of this drug.  
One strategy to aid healthcare professionals in achieving important clinical interventions is to use clinical decision support tools and best practice alerts (BPAs). Health systems often employ these tools to guide prescribing practices and remind healthcare professionals of important monitoring or patient education requirements. Order panels can also be utilized to link multiple medications or lab orders together. For example, when an opioid is prescribed, a concurrent BPA could remind the prescriber both to consider ordering naloxone and to educate the patient and caregiver on its use. The responsibility to provide education falls on both the prescriber and the dispensing pharmacist. Unfortunately, this case scenario illustrates that an alert alone does not ensure optimal care and may result in patient harm.  
BPAs are ineffective if healthcare providers are not adequately educated about the intervention that is recommended. A recent systematic review indicated that common barriers to prescribing naloxone in primary care settings include lack of knowledge around prescribing and discomfort with counseling on its use.5  Moreover, appropriate counseling requires extensive education of not only the patient but also their family and/or caregivers. This education should include how to recognize the signs and symptoms of overdose, in addition to how to administer the medication. Provider training can have a significant impact on expanding access to this intervention; following implementation of an overdose education and naloxone distribution program in one health system, the number of naloxone prescriptions increased from 4.5 per month to 46 prescriptions per month.6  Even though it is the legal duty of a pharmacist to provide patient counseling, limitations, including lack of knowledge or clinical skills, lack of access to training programs, and lack of personnel or resources for pharmacists to provide the necessary education may still exist and inhibit patient counseling.7  Furthermore, patients can decline the mandatory pharmacist counseling. Use of multiple layers of systematic education may provide necessary redundancy. These could include leveraging electronic medication ordering systems to emphasize need for pharmacist counseling, use of patient education materials provided as part of the after-visit summary, and appropriate educational materials dispensed from the pharmacy. Use of video-assisted patient educational materials may benefit patients and their caregivers in some circumstances.8 

Moreover, BPAs may cause alert fatigue, leading to errors or lack of improvement in practices following implementation. A recent study found that implementation of BPAs in the EHR was not associated with a clinically detectable improvement in the Beers criteria for potentially inappropriate medications.9 Another recent study documented alert fatigue, identified inaccurate alerts, and concluded there is a need for controlled, de-escalation of the use of BPAs.10  Research into development and customization of drug-drug interaction alerts has also been conducted in an effort to decrease alert fatigue by suppressing low priority alerts in the EHR.11 In this case, improved recognition of patients at high risk for opioid overdose would have limited the number of alerts providers see when prescribing opioids but, unfortunately, it remains difficult to identify patients who would most benefit from naloxone co-prescription.  

Naloxone Prescribing in Other Settings

There is evidence for the effectiveness of preventing opioid-related overdose deaths at the community level through community-based distribution of naloxone to persons at risk for overdose.12 Risk, in this study, was primarily associated with illicit drug use and the intervention was comprised of education about overdose and naloxone distribution through community service agencies. Based on this evidence from high-risk populations in community settings, it is conceivable that a benefit could also be observed in high-risk patients on long-term prescription opioids in outpatient settings.  

While policies such as the requirement of co-prescribing naloxone are intended to improve public safety, policies that lack the information needed to operationalize these actions may lead to poor outcomes as it did in this case. In addition to addressing opioid-related harm, the 2016 CDC guidelines provided recommendations on the use of opioids for the treatment of chronic pain, resulting in some unintended consequences. While these the guidelines were well-intentioned and geared toward improving opioid stewardship, rapid opioid tapers managed by providers trying to adhere to guidelines may lead to poor outcomes in some patients. This prompted a group of the CDC guidelines’ authors to publish a follow-up article urging a patient-centered approach to opioid tapering.13 

The government, healthcare professionals, and professional organizations need to work together to provide education to prescribers that will improve the care of patients who use opioids and that includes appropriate use of naloxone and when not to use this medication. Through the use of layered learning, professional development, and appropriate clinical decision support, the appropriate prescribing and use of naloxone to prevent accidental overdose can be achieved. 

Take-Home Points

  • Co-prescribing naloxone with opioids may result in patient harm if appropriate education isn’t provided.   

  • BPAs and clinical decision support within the EHR need to be designed to work without creating alert fatigue. 

  • There may be a knowledge gap in both prescribing and counseling patients on naloxone. The BPA should address both prescribing and counseling. 

  • Healthcare systems and providers should use multi-layered education to inform patients about appropriate naloxone use.14,15 

  • Individual providers and healthcare systems need to do a better job of identifying patients who are at higher risk for overdose.  


Erika Cutler, PharmD
Pharmacy and Therapeutics Coordinator 
University of California, Davis  
Assistant Clinical Professor of Pharmacy 
University of California San Francisco School of Pharmacy   

Delani Gunawardena, MD  
Associate Physician 
Department of Internal Medicine 
University of California, Davis  


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This project was funded under contract number 75Q80119C00004 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services. The authors are solely responsible for this report’s contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report. View AHRQ Disclaimers
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