An Overview of Using Naloxone and Opioids for Pain Management

Nearly 308 million Americans see a clinician each year primarily because of pain. Of these, 100 million are living with chronic pain, or pain lasting longer than 3 months.¹ An opioid prescription is given to 20% of patients who have nonmalignant acute or chronic pain. In 2012, clinicians wrote 259 million prescriptions for opioid analgesics, equal to the number of adults in the United States. From 2007 to 2012, the number of opioid prescriptions written increased 7.3% per capita. Rates of prescribing increased more in primary care practices than in specialty practices.^2,3 More than 50% of patients who have received uninterrupted opioid therapy for 3 months are still receiving it after 4 years.³ After the implementation of strategies to reduce opioid prescribing, the number of prescriptions written decreased to 207 million in 2013.⁴

 

The increased use of opioid prescriptions to treat chronic pain has resulted in the rise of opioid use disorder, addiction, and abuse. In 2013, 1.9 million people in the United States met the criteria for opioid analgesic abuse or dependence, according to the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition.⁵ Patients at increased risk for opioid misuse and/or opioid use disorder include those with a history of behaviors such as seeking early refills and “doctor shopping,” a personal and family history of substance abuse, a history of sexual abuse during preadolescence, or comorbid psychiatric disorders.³ The nonmedical use of opioid analgesics and the reduction strategies instituted to eliminate the overprescribing of these agents has led to an increase in heroin abuse. Most current heroin users were introduced to opioids as prescribed medications. Also, a major change has occurred in the demographic profile of persons with heroin addiction, who now comprise a populace that is older, more rural, and more gender equal, with fewer members of racial and social minorities.⁵

Paralleling the increase in the availability of opioid analgesics, opioid use disorder, and heroin use has been a rise in the number of deaths from prescription opioid overdose. Unintentional opioid analgesic overdose is a leading cause of accidental death in the United States.⁶ More than 16,000 deaths in the United States yearly are ascribed to prescription opioids.⁷ This is more than twice the number related to heroin use in 2013.⁸ As early as 2006, opioid drug poisoning deaths had surpassed the number of deaths related to heroin, cocaine, and psychostimulants collectively.⁴ Known contributing factors to opioid overdose include overprescribing by clinicians for the management of chronic pain, solicitation by patients from multiple providers or from profit-driven, high-volume pain management clinics (“pill mills”), and the nonmedical use of opioids by patients (ie, selling, sharing, and/or recreational use).9 As the dose of opioids increases, so does the death rate.⁵

Which of the following statements do you most agree with?

A public health crisis

Opioid overdose has become a major public health crisis in the United States. It has also contributed to a substantial financial burden. The annual medical costs of opioid poisoning total $72 billion.^9,10 Patients at increased risk for overdose are those with medical comorbidities that have the potential to cause respiratory depression or failure (eg, sleep apnea, lung disease, heart failure); those receiving benzodiazepines or sedative-hypnotics; those with psychiatric comorbidities (eg, depression, anxiety); and those with problematic alcohol use^.3 Opioid morbidity and mortality may be prevented through the early administration of an antidote.⁷ The administration of naloxone, an opioid antidote, by laypersons or nonmedical witnesses of an opioid emergency provides a quick, lifesaving intervention to someone who may die before emergency services arrive, especially in rural locations or in situations in which witnesses are afraid to call emergency services.⁹

The management of chronic pain is necessary and unavoidable in primary care, especially in rural or remote areas of the country where the number of pain specialists to whom patients can be referred is limited. Chronic pain is often managed in primary care. Thus, it is necessary for primary care providers to meet the needs of patients at high risk for opioid overdose by co-prescribing naloxone.

Naloxone

Naloxone is a 40-year-old drug that the US Food and Drug Administration (FDA) approved in 2015 for the rapid reversal of respiratory depression induced by heroin or prescription opioid overdose.¹¹ Naloxone is a high-affinity, short-acting opioid mu-receptor antagonist. It produces a discernible pharmacologic action only if opioid agonists are present. In the United States, a prescription is required to distribute a sterile solution of naloxone for parenteral (injected or intranasal) administration.^4,12 The recommended dose of naloxone is 0.4 mg, which may be repeated in 2 to 3 minutes if arousal is unsatisfactory after first administration.^2,13

In July 2014, Kaleo launched Evzio®, a 1-mg/mL naloxone hydrochloride auto-injector. This drug and device combination product has an electronic audio system that voices step-by-step instructions on how to administer an intramuscular or subcutaneous tissue injection. A carton contains two 0.4-mg/0.4 mL auto-injectors and a reusable trainer device.¹⁴ Adapt Pharma has acquired the right to use the brand name for naloxone, Narcan®, for its naloxone nasal spray, which has received FDA approval for safety and efficacy.^11,14

Clinicians have not widely adopted the co-prescription of naloxone with opioids or the distribution of naloxone kits and education to laypersons in the past for fear of legal ramifications. As of July 2016, there were 46 states with a naloxone access law. Prescribers have immunity from criminal action for prescribing, dispensing, or distributing naloxone to a layperson in 32 states and immunity from civil liability in 36 states. In 41 states, third-party individuals who may have the ability to respond quickly to an overdose are authorized to prescribe naloxone, and 40 states have legalized standing orders for naloxone to pharmacies and community-based naloxone dispensing programs. Laypersons are protected by Good Samaritan laws from criminal liability in 32 states and from civil liability in 40 states. In 14 states, there is no criminal liability if someone is discovered to be in possession of naloxone.¹⁵

As legal restrictions have decreased, financial restrictions have increased.^14,16 A carton of Kaleo auto-injectors has been priced at four times the invoice price of a box of same-strength 2-mL naloxone syringes. Also, the cost of Amphastar Pharmaceuticals’ 10-pack container of 2-mL naloxone syringes has increased by 60%, whereas the price of Hospira’s 10-pack container of 1-mL vials (0.4 mg/mL) is half the Amphastar price. A 2-mL naloxone syringe that fits an atomizer for intranasal administration is priced at $50.¹⁴ Kits containing a single intramuscular dose of naloxone have cost the health department of Baltimore, Maryland, $40 each.¹⁶

As legislation expands, so does FDA approval of naloxone, and because research supports the use of naloxone for at-risk patients undergoing pain management with opioids, there is a push to allow over-the-counter (OTC) access to naloxone with brief education or written instructions.¹² To make naloxone even more accessible, Dr. Karen Mahoney in 2016 released the FDA opioid action plan initiative to identify ways to aid manufacturers in acquiring approval for an OTC version of naloxone.¹⁷ A consumer-friendly Drug Fact Label (DFL) is required. The FDA has developed a DFL model with simple icons that correspond to the label directions; these provide consumers with the information needed to use naloxone safely.

As of December 2016, press releases by two popular US pharmacies, Walgreens and CVS, had announced the OTC distribution of naloxone in 24 and 30 states, respectively.^18,19 The term OTC as used in the press releases is misleading, however. An individual wishing to purchase naloxone does not need a prescription in hand from a prescriber, but the participating pharmacies do, through a standing order or collaborative practice agreement.²⁰ 

Naloxone use in the community

For more than 30 years, paramedics have used naloxone to reverse respiratory depression resulting from opioid overdose. It has proved to be effective and safe in the field.^21,22 Opioid overdose and naloxone distribution (OEND) programs were first established in 1996, and their numbers have increased dramatically since then, with approximately 140 organizations known to provide naloxone kits to individuals at 644 sites in the United States in 2014.^21,22 Evidence shows that laypersons who observe an overdose and have received appropriate education can and do use naloxone to reverse the effects of opioid overdoses.²¹

In one OEND program, the Baltimore Student Harm Reduction Coalition, it was found that the distribution of naloxone, together with training in intramuscular administration and the recognition of overdose risk factors and signs, successfully increased self-efficacy for overdose prevention and response. This self-efficacy persisted at 8 to 12 months after the completion of training.²¹ In a literature review, McDonald and Strang evaluated the association between take-home naloxone programs and overdose survival.²² The association was found to be strong, with a successful overdose reversal rate of 96.3% in 2336 cases in which take-home naloxone was administered.

Coffin et al⁶ conducted a 2-year study of naloxone and opioid co-prescribing for high-risk primary care patients receiving long-term opioid pain therapy in San Francisco, California. The numbers of opioid-related emergency department visits at 6 months and 1 year were found to be lower among the patients who received naloxone than in the patients who did not receive naloxone. At the US Army military installation at Fort Bragg, North Carolina, the number of emergency department visits for opioid overdose declined from eight to zero per month after naloxone co-prescribing started.^6,23 In North Carolina, Project Lazarus partnered a community-based prevention program with local clinicians in which naloxone was offered to suspected opioid abusers and to patients undergoing opioid treatment for pain who were considered to be at high risk for opioid overdose as part of their regular medical care. As a result of the co-prescribing and enhanced education for prescribers and laypersons, the number of opioid-associated deaths decreased by 50% in a single year.^4,23 Therefore, researchers recommend that naloxone be co-prescribed to primary care patients being treated with opioids for pain, with emphasis placed on those who have established risk factors, including receiving higher doses of opioids and having a record of opioid-related emergency department visits in the past.⁶

The number of community-based organizations providing naloxone kits to individuals is increasing. Nonetheless, in 2013, there were 20 states that did not have an organization providing naloxone kits to laypersons, and nine states had fewer than one layperson per 100,000 who had received a naloxone kit. Of the 29 states with marginal or no layperson access to overdose rescue kits, 11 had overdose death rates higher than the national median, underscoring the need for naloxone and opioid co-prescribing in primary care clinics.⁸

In response to the idea that clinicians’ fear of offending patients creates a barrier to naloxone prescribing in primary care, Behar et al evaluated the experience of patients undergoing opioid treatment for chronic pain with naloxone and their reactions to the offer of a naloxone prescription.²³ Overall, offers of naloxone prescriptions were acceptable to primary care patients receiving opioids. Most responded positively and believed that naloxone was appropriate. Furthermore, 60% of the patients had never heard of naloxone before the intervention, and more than one-third noted positive behavioral changes after receiving naloxone, with no negative behavioral changes. Behar et al propose that primary care clinicians may serve a population that community naloxone distribution does not reach, thus aiding a reduction in the morbidity and mortality of opioid poisoning.

Following the recommendations of the US Substance Abuse and Mental Health Services Administration, the American College of Emergency Physicians (ACEP) has issued guidelines for prescribing naloxone as an early antidote to at-risk patients in the following situations⁷:

• Discharged from an emergency department after opioid overdose
• Prescribed high-dose opioids or receiving chronic pain management
• Prescribed a rotating opioid medication regimen
• Having a history of substance abuse
• Receiving an extended-release/long-acting opioid preparation
• Undergoing a court-ordered opioid detoxification or abstinence program 
• Newly released from prison and with a history of opioid abuse

Proposal for co-prescribing in primary care

Primary care providers who care for patients with chronic pain must work to reduce opioid-related risks by using routine urine drug testing, assessing state prescription monitoring programs, implementing pill counts, practicing more cautious and constrained prescribing, and referring patients to substance abuse specialists after an assessment indicates deviant drug use behavior.⁴ The primary care provider must also protect high-risk patients whose pain is being managed with opioids against the potential for overdose. Offering naloxone kits to at-risk patients reduces overdose deaths, and the practice is safe and cost-effective. International and US health organizations consider that providing naloxone kits in primary care to individuals who may witness an opioid overdose, to patients in substance use treatment programs, and to persons being released from prison and jail is a component of responsible opioid prescribing.⁸

Naloxone and opioid co-prescribing is not necessary for all patients whose chronic pain is being managed in primary care; it is recommended only for patients at high risk for opioid overdose. Patients with any of the following factors are considered to be at high risk⁴:

• History or diagnosis of substance abuse, including alcohol abuse
• Need for high doses of opioids
• Being introduced to and/or continuing methadone; methadone has a long-half life, so the risk for toxic accrual is increased during therapy initiation
• Polypharmacy, especially co-administration of benzodiazepines
• Comorbid psychiatric disorders, especially an increased risk for suicide
• Impairments of cognitive function that could result in the ingestion of excessive amounts of opioids

The Centers for Disease Control and Prevention also recommends that a history of overdose be considered a risk factor and defines a high opioid dose as one equal to or greater than 50 MME (morphine milligram equivalents) per day.² The World Health Organization released guidelines for the community management of opioid overdose in 2014, adding to its list of high-risk opioid users those with other significant medical conditions (HIV infection, liver or lung disease) and members of the households of people taking high-dose opioids.¹³

Education is an essential component of the training of primary care providers who are co-prescribing naloxone while treating high-risk patients with chronic pain. Training must be provided not only to the patient with chronic pain who is receiving the opioid and naloxone co-prescription but also to the laypersons who may be close to them (ie, family members, household members, friends). The training provided to potential overdose witnesses differs from the training given to the individuals who disclose opioid use. First, these persons do not use opioids themselves and may not be acquainted with substance use and signs of overdose. Thus, an opportunity to offer education regarding substance use and addiction to reduce stigma is recommended. Also, such training may encourage the third party to talk with the individual at risk for overdose about substance use and overdose. Therefore, training can be beneficial in teaching the third party to provide support beyond the administration of naloxone.²¹

Naloxone education should include how to identify an overdose, call emergency services, and administer naloxone.⁴ Evidence has shown that education can be provided briefly as well as at length.^4,12 It can be provided by a clinician directly, sent to the patient’s home in written form, or recorded and delivered by a rescue device.⁴

Screening tools to identify at-risk patients, standardized prescribing guidelines to help providers prescribe naloxone appropriately, and patient education resources are available at PrescribeToPrevent.

Conclusion

Overdose is a risk in the management of chronic pain with opioids in primary care. Because clinicians are on the front lines in the care of patients with chronic pain in rural and remote areas, it is essential that these clinicians institute the practice of providing prescriptions for naloxone along with opioids in their protocols for the treatment of patients at high risk for opioid poisoning. Further research on the use of naloxone co-prescribing in primary care is encouraged in the realm of nursing because few data are currently available in primary care medicine or nursing. Furthermore, it is essential that clinicians in primary care lobby for broader naloxone access. 

Lesley Cooper, DNP, FNP-C, is a nurse practitioner currently working in Bahrain.

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References

1. American Academy of Pain Medicine. AAPM facts and figures on pain. Accessed September 15, 2017.
2. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49. doi: 10.15585/mmwr.rr6501e1
3. Lembke A, Humphreys K, Newmark J. Weighing the risks and benefits of chronic opioid therapy. Am Fam Physician. 2016;93:982-990.
4. Coe MA, Walsh SL. Distribution of naloxone for overdose prevention to chronic pain patients. Prev Med. 2015;80:41-43.
5. Compton WM, Boyle M, Wargo E. Prescription opioid abuse: problems and responses. Prev Med. 2015;80:5-9.
6. 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. Ann Intern Med. 2016;165:245-252.
7. American College of Emergency Physicians. Naloxone prescriptions by emergency physicians. Ann Emerg Med. 2016;67:149-150.
8. Wheeler E, Jones S, Gilbert MK, Davidson PJ; Centers for Disease Control and Prevention (CDC). Opioid overdose prevention programs providing naloxone to laypersons – United States, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:631-635. 
9. Mitchell KD, Higgins LJ. Combating opioid overdose with public access to naloxone. J Addictions Nurs. 2016;27(3):160-179.
10. US Department of Health and Human Services. Addressing prescription drug abuse in the United States: current activities and future opportunities. Accessed September 15, 2017.
11. FDA moves quickly to approve easy-to-use nasal spray to treat opioid overdose. US Food and Drug Administration. Published November 18, 2015. Accessed September 15, 2017.
12. Behar E, Santos G, Wheeler E, Rower C, Coffin PO. Brief overdose education is sufficient for naloxone distribution to opioid users. Drug Alcohol Depend. 2015;148:209-212.
13. Community management of opioid overdose. World Health Organization. Published 2014. Accessed Septembe 15, 2017.
14. Thompson CA. Naloxone access increases, as does price. Am J Health Syst Pharm. 2015;72:1426-1427.
15. Naloxone overdose prevention laws. The Policy Surveillance Program: A LawAtlas Project. Accessed September 15, 2017.
16. Johnson, SR. Price hikes hamper use of naloxone against opioids. Modern Healthcare. Published September 3, 2016. Accessed September 15, 2017.
17. Mahoney K. FDA supports greater access to naloxone to help reduce opioid overdose deaths. US Food and Drug Administration. Published August 10, 2016. Accessed September 15, 2017.
18. Walgreens enables no-Rx access to naloxone in Louisiana. Chain Drug Review. Published November 23, 2016. Accessed September 15, 2017.
19. CVS Health makes overdose-reversal drug naloxone available without a prescription in Idaho. CVS Health. Published August 12, 2016. Accessed September 15, 2017.
20. Davis C. “Over the counter” naloxone access, explained. The Network for Public Health Law. Published March 1, 2016. Accessed September 15, 2017.
21. Lewis DA, Park JN, Vail L, Sine M, Welsh C, Sherman SG. Evaluation of the overdose education and naloxone distribution program of the Baltimore Student Harm Reduction Coalition. Am J Public Health. 2016;106:1243-1246.
22. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction. 2016;111:1177-1187.
23. Behar E, Rowe C, Santos G, Murphy S, Coffin PO. Primary care patient experience with naloxone prescription. Ann Fam Med. 2016;14:431-436.

This article originally appeared on Clinical Advisor