Initiating buprenorphine/naloxone for opioid use disorder in the emergency department

Opioid use disorder (OUD) is a public health crisis that continues to affect individuals across Canada, and requires a multifaceted approach to minimize its impact. Through the chronic consumption of opioids, many individuals can become dependent on opioids and develop OUD. Buprenorphine/naloxone is the recommended first-line treatment, whenever possible, for patients living with OUD. The Emergency Strategic Clinical Network™ within Alberta Health Services is targeting the crisis in emergency departments by implementing a provincially standardized program. The Buprenorphine/ Naloxone Initiations in Emergency Departments program includes identifying OUD, initiating treatment with the medication buprenorphine/naloxone, and providing rapid and reliable referrals to community clinics for titration and continued patient care. This paper provides an overview of opioids, OUD, opioid agonist treatments such as buprenorphine/naloxone, and details the program and protocol available in Alberta.

agonist treatment (OAT), buprenorphine/naloxone, emergency department (ED) Background T he opioid crisis continues to affect Canadians of various ages, genders, geographical locations, and socioeconomic statuses. From 2016 to 2019, there were over 13,900 deaths related to opioids in Canada (Government of Canada, 2019). In 2018 alone, there were 4,460 documented apparent opioid-related deaths, equating to one life lost an average of every 2 hours (Government of Canada, 2019). Multiple factors have contributed to the current crisis. From the late 1990s to the early 2000s, certain pharmaceutical companies encouraged healthcare providers to treat patients with opioids, suggesting that they were highly effective and non-addictive ( Jones et al., 2018). This resulted in a significant rise in the rate of opioid prescribing in Canada. Along with increasing prescribing rates, has come increasing rates of opioid misuse, abuse, and overdoses. In response, many healthcare providers have tried to reduce or stop prescribing opioids. When patients are no longer able to obtain prescribed opioids, many turn to illicit opioids to manage their pain and/or dependence. Over the last decade, a surge in illicit substances that contain synthetic opioids has further amplified the crisis. These illicit substances often contain unregulated levels of potent opioids, such as fentanyl, making them extremely dangerous. That is, they present a high risk of overdose.
In recent years, Canada has focused on implementing policies and strategies to address this public health crisis. These include legislative and regulatory changes to increase awareness and knowledge among healthcare professionals, increase access to treatment and harm reduction strategies, and increase availability and distribution of naloxone to the public for reversing overdoses (Health Canada, 2017. At the same time, there has been increasing efforts to enforce laws and regulations that focus on eliminating the manufacturing, distribution, and trafficking of illegal opioids into and within Canada (Health Canada, 2019). Despite these efforts, the rate and the number of overdoses in Canada continues to rise each year.
Many jurisdictions across the country have implemented local initiatives to respond to the opioid crisis. In Alberta, the Emergency Strategic Clinical Network™ (ESCN) within Alberta Health Services (AHS) has been leading the implementation of a province-wide strategy to help address the opioid crisis in emergency departments and urgent care centres (EDs) since March 2018. The ESCN is a group of healthcare professionals and patients working together across the province to improve emergency care and services in Alberta. The ESCN created a provincial expert working group that included physician experts, community/primary care services, and addictions and mental health experts. The team developed a province-wide initiative that starts treatment for individuals living with opioid use disorder (OUD) during an ED visit. The Buprenorphine/Naloxone Initiations in Emergency Departments program includes identifying OUD, initiating treatment with the medication buprenorphine/naloxone, and providing rapid and reliable referrals to community clinics for titration and continued patient care.

Opioids
Naturally found in the opium poppy (Papaver somniferum), opioids are manufactured as medications for pain management. Opioids are a class of substances that act on the central nervous system in the same way that endorphins operate through the activation of the opioid receptors mu, kappa and delta. Activation of these opioid receptors inhibits excitability and pain neurotransmission, which results in analgesic and possibly euphoric effects. These receptors also increase dopamine production and may influence the brain reward system. This natural reward system can cause individuals to repeat compulsive behaviours in order to replicate the dopamine release response. Chronic consumption of opioids may result in a chemical rewiring of the brain that leads to tolerance (needing to have higher doses to achieve the same effect), and physical dependence on opioids. Individuals who use opioids chronically may experience terrible physical and psychological craving and withdrawal symptoms when discontinued (National Institutes of Health, 2019).

Opioid Use Disorder
OUD is a chronic relapsing illness that involves a problematic pattern of opioid use. OUD includes the misuse of prescribed opioid medications, use of diverted prescription opioids, or use of illicitly manufactured opioids (Canadian Research Initiative on Substance Misuse (CRISM), 2018). The current Canadian national guideline recommends evidence-based long-term treatment of OUD using opioid agonist treatment (OAT) with or without psychosocial treatment (CRISM, 2018). The guideline also identifies buprenorphine/naloxone as the recommended first-line OAT for OUD wherever feasible.
OAT is significantly more effective than non-pharmacological treatments, and there is strong evidence that OAT effectively reduces morbidity, mortality, and the risk of HIV and hepatitis C infections among individuals that inject substances (CRISM, 2018). Withdrawal management alone without OAT will reduce a patient's level of opioid tolerance. This is not advisable due to the high rates of relapse that can lead to increased risk of morbidity and mortality (Bruneau et al., 2018;CRISM, 2018). Compared to other OAT medications such as methadone, buprenorphine/naloxone has many advantages. These include fewer side effects and lower risk of toxicity and drug-drug interactions (Bonhomme, Shim, Gooden, Tyus & Rust, 2012;Moody, 2013). Buprenorphine/naloxone allows for greater flexibility and patient autonomy, which results in increased treatment compliance, retention, and reduced substance use (CRISM, 2018;Holland et al., 2014).

Buprenorphine/Naloxone
Buprenorphine/naloxone is a 4:1 ratio combination medication generally taken once a day when patients are on stable maintenance doses. Buprenorphine is a long-acting partial opioid agonist that has a half-life of approximately 24-42 hours (CRISM, 2018). As a partial opioid agonist, buprenorphine provides little to no euphoric effects due to having lower intrinsic activity on opioid receptors than full opioid agonists (for example, fentanyl, morphine, heroin, etc.). When buprenorphine has fully saturated the receptors, it achieves a ceiling effect and additional doses will not increase its effectiveness. This ceiling effect reduces overdose and respiratory depression potential, making it a safer option. In addition to its high safety profile, buprenorphine has a high affinity for the receptor that will out-compete and can even displace other full agonist opioids (National Alliance of Advocates for Buprenorphine Treatment, 2019). Naloxone is an opioid antagonist that has poor bioavailability when administered sublingually or orally. It is included in the medication to lower its abuse potential (Drugbank, 2019). If the medication is diverted and injected, a sufficient dose of naloxone will be absorbed and induce withdrawal symptoms.

Buprenorphine/Naloxone in Emergency Departments
Buprenorphine/naloxone has been in Canada since 2007 but was typically only available in addiction medicine outpatient clinic settings. The ESCN recognized a potential opportunity to help patients by having the medication available in the ED. Due to the rising number of ED opioid-related presentations in Alberta, EDs provide an effective opportunity to intervene and initiate treatment that addresses the underlying condition of OUD, going beyond the extremely important practice of offering naloxone kits. Emergency departments are portals for identifying patients who live with OUD, who may present with an overdose, other concerns related to opioids, or issues not directly related to addictions (Winetsky, Weinrieb & Perrone, 2017). In 2018, 13% of individuals in Alberta with an apparent accidental death related to fentanyl had presented to an ED within 30 days before dying, highlighting the ED opportunity to intervene and the potential to prevent a catastrophic event (Government of Alberta, 2019). ED patients are more likely to continue engaging in treatment if they initiate buprenorphine/naloxone in the ED. In a key study, 78% (89/114) of ED patients randomized to buprenorphine/naloxone treatment remained in treatment 30 days later, compared to 37% (38/102) of patients who were referred to treatment without initiating buprenorphine/naloxone (D'Onofrio et al., 2015).
The Buprenorphine/Naloxone Initiations in Emergency Departments program was the first of its kind in Canada with a provincial scope. The ESCN supported the training and implementation of the standardized treatment protocol for patients who present with OUD in all adult EDs across Alberta. The ESCN team collaborated with multidisciplinary teams at each site, addressed various local needs and concerns, developed local champions, and provided expert front-line education and resources to more than two thousand emergency nurses, staff and physicians. Each local team typically included site and unit managers, emergency and primary care physicians, clinical nurse educators, pharmacists, social workers, and front-line emergency nurses. These local champions established program and protocol expertise, which they use to guide their colleagues on a day-to-day basis to ensure program sustainability over time.
There are programs in other jurisdictions across the country that offer buprenorphine/naloxone and each clinical pathway may vary in dosing, assessments, and treatment options. In the current AHS provincial ED program, there are three key steps ( Figure 1): 1. Identify OUD; 2. Initiate buprenorphine/naloxone for eligible patients in or out of the ED; and 3. Provide a rapid community clinic referral for medication titration and continued patient care.
Step 1: Identify opioid use Disorder To be eligible for buprenorphine/naloxone, patients should meet the American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) diagnostic criteria for OUD. In clinical practice, ED nurses can easily apply the "4 Cs" of addiction to help identify patients with addiction to any substance, including opioids. Problematic opioid use can be recognized by asking patients about craving, loss of control of amount or frequency of use, compulsion to use, and use despite consequences (Centre for Addiction and Mental Health, 2019). After the identification of OUD, patients may need encouragement and education from ED healthcare professionals to consider treatment. The ED nurse plays a vital role in establishing a safe and open environment where the patient feels respected and understood in a way that has the potential to motivate change. It is important to view every patient interaction as an opportunity to engage, educate, and offer supports. Some patients may not be ready to make challenging life changes during their ED visit and may need more time to make that decision.
Step 2: Initiate buprenorphine/Naloxone in or out of the emergency Department The next step is to initiate buprenorphine/naloxone in or out of the ED. There is absolute criteria listed in the protocol that patients need to meet (suspicion of OUD, willingness to engage in the medication, and no allergy to buprenorphine or naloxone) before safely receiving the medication. The protocol also identifies relative contraindications for specific patient populations that may benefit from expert consultation prior to initiation, such as pregnant or adolescent patients. If patients meet the absolute criteria, clinicians need also to consider the appropriate timing of initiation, where patients should be in a moderate level of withdrawal before receiving their first dose (Figure 2). Using the Clinical Opiate Withdrawal Scale (COWS) (Wesson & Ling, 2003) assessment tool, nurses are able to assess the patient's level of withdrawal quickly and objectively by finding the sum of 11 criteria (see Appendix A). If the score is 12 or greater, patients qualify for ED induction, receiving initial doses of buprenorphine/naloxone in the ED one hour apart, and is then discharged with additional doses to take at home along with patient teaching and a take home naloxone kit (see Appendix B).
If the score is less than 12, patients may still have another opioid on their receptors and would qualify for home induction. Due to the high affinity of buprenorphine, taking the medication too soon displaces the full opioid agonist and precipitates withdrawal symptoms, making the patient feel worse. In order to avoid precipitated withdrawal, patients are discharged with the instructions to take their doses at home once they start to experience moderate withdrawal symptoms and/or cravings. Home induction patients also receive teaching and a take home naloxone kit prior to discharge (see Appendix C).
Step 3: Provide Rapid Community Clinic Referral for Continued Patient Care Patients initiating buprenorphine/naloxone usually require titration over two to three days to reach a therapeutic dose. In this protocol, the ED completes day one of the titration, followed by a rapid referral to a community clinic and pharmacy that will follow up the next day for continued medication titration and patient care. Through collaboration with local community resources and pharmacies, there are several guaranteed next day walk-in referral options for patients, which include primary care, brick-and-mortar OUD treatment clinics, and virtual medicine options available across Alberta. As a system, these clinics ensure that Albertans anywhere in the province can receive OAT.

Future of the Opioid Crisis
At the time of publication, the ESCN has helped over 100 sites implement the protocol and is currently supporting the remaining sites to complete program implementation by early 2020 (see Appendix D). Identifying OUD and starting patients on buprenorphine/naloxone is not difficult or time intensive. The healthcare system as a whole in Alberta has made significant efforts to bring the medication to a variety of settings, such as correctional facilities, homeless shelters, and primary care. The province has also been working on improving accessibility and support for Indigenous patients and higher risk populations.
Although the future of the opioid crisis is unknown, it is predicted to continue over the coming years (Chen et al., 2019). While the crisis is complex and requires a multifaceted approach, providing patients with easy access to buprenorphine/naloxone can have significant effects in limiting the crisis across the country. Emergency nurses play a key role throughout every patient's visit, and influence each step of the OUD treatment protocol. ED nurses across Canada are encouraged to advocate for patients living with OUD and support the effective initiation and use of buprenorphine/naloxone. We should not overlook this valuable opportunity to prevent deaths related to OUD and to help our patients stabilize their lives, be safe and stay healthy.