Early emergency department experience with 7‐day extended‐release injectable buprenorphine for opioid use disorder

As the opioid overdose epidemic escalates, there is an urgent need for treatment innovations to address both patient and clinician barriers when initiating buprenorphine in the emergency department (ED). These include insurance status, logistical challenges such as the ability to fill a prescription and transportation, concerns regarding diversion, and availability of urgent referral sites. Extended‐release buprenorphine (XR‐BUP) preparations such as a new 7‐day injectable could potentially solve some of these issues. We describe the pharmacokinetics of a new 7‐day XR‐BUP formulation and the feasibility of its use in the ED setting. We report our early experiences with this medication (investigational drug CAM2038), in the context of an ongoing clinical trial entitled Emergency Department‐Initiated BUP VAlidaTION (ED INNOVATION), to inform emergency clinicians as they consider incorporating this medication into their practice. The medication was approved by the European Medicines Agency in 2018 and the U.S. Food and Drug Administration in 2023 for those 18 years or older for the treatment of moderate to severe opioid use disorder (OUD). We report our experience with approximately 800 ED patients with OUD who received the 7‐day XR‐BUP preparation in the ED between June 2020 and July 2023.


INTRODUC TI ON
2][3] The year 2022 was the deadliest to date, with over 109,680 people dying from a drug overdose in the 12 months prior to December 2022.Among those, 79,770 deaths were attributed to opioids, largely driven by the potent synthetic opioid fentanyl and its derivatives. 4om 2016 to 2017 alone, the emergency department (ED) visits for opioid overdose have increased by nearly 30%. 5Evidence demonstrates that after an ED visit for a nonfatal opioid overdose, patients have a 5% mortality rate within the first year, with a high proportion dying within a month of their ED discharge.If treated with buprenorphine or methadone the mortality rate was decreased more than 50%. 6,7ED-initiated buprenorphine (BUP) has been shown to be effective in rapidly reducing withdrawal and engaging patients in formal addiction treatment. 8ED BUP prescribing increased from 12.3 per 100,000 ED visits in 2002-2003 to 42.8 per 100,000 ED visits in 2016-2017 (odds ratio for linear trend 3.31, 95% CI 1.04-10.5), 9with a recent report citing a 300% increase in the number of emergency physician BUP prescribers from 2016 to 2021. 10 Unfortunately, this increase in number of prescribers was not accompanied by an increase in the number of BUP prescriptions, leading to the conclusion that widespread adoption has lagged.2][13][14] While very recent federal policies reduced (2021) 15 or removed (2023) 16 the DATA 2000 X-waiver requirements for any DEA-licensed practitioner to prescribe, substantial increases in BUP access have as yet not been documented. 10,17e ability to administer an extended-release (XR) preparation of BUP potentially addresses many of these challenges, allowing more time to access follow-up care while providing continued medication for a longer duration.XR preparations assure continuation of treatment due to their long duration of action, even if unpleasant or bothersome symptoms occur during induction that can sometimes discourage adherence to daily transmucosal BUP therapy.
One FDA-approved and marketed XR-BUP preparation (Sublocade) provides the equivalent to 1 month of medication with a single injection.A second XR preparation, available as weekly and monthly formulations of XR-BUP, received approval as of May 23, 2023, and will be marketed (Brixadi) in the United States for individuals 18 years or old with OUD. 18It is already approved for use in OUD for patients 16 years or older in Europe and Australia. 19

PHARM ACO KIN E TIC S OF BUP
BUP is a semisynthetic, highly lipophilic, partial opioid agonist with very high affinity at the mu-opioid receptor.It is primarily available as a transmucosal film or tablet preparation with or without naloxone for treatment of OUD.SL-BUP is readily and rapidly absorbed through oral mucosal membranes. 21Patients are advised to keep the SL tablet or the film under the tongue for approximately 2-6 min for complete absorption.Despite rapid absorption, SL-BUP has low bioavailability (40%), which is why relatively large doses are needed to achieve therapeutic plasma concentrations. 22Once in plasma and bound to the mu-opioid receptor, BUP has a slow rate of dissociation producing a prolonged duration of action compared to other opioids. 23It has a large volume of distribution and high protein binding and reaches its peak plasma concentration in ~60 min after administration, yet there is wide interindividual variation in both rate of absorption and peak plasma concentrations. 22After 60 min, plasma concentrations drop quickly but with a 32-h terminal half-life, BUP remains available for binding to the mu-receptor for a prolonged period, albeit at decreasing concentrations 24 (Figure 1).
Long-acting injectable formulations of BUP potentially offer advantages over daily preparations when initiating BUP in ED patients and for improving retention in treatment.Sublocade, a 30-day XR formulation, is available in 100-and 300-mg doses and could potentially have ED applications.However, it is approved by the FDA for administration only after a 7-day lead-in with SL-BUP making its use in the ED impractical.Its rapid rise in blood plasma levels also precludes use in low levels of withdrawal.Off-label rapid Sublocade initiations have been described in case series only. 25A 7-day XR-BUP preparation that does not require a SL-BUP lead-in period may be very advantageous in an acute care setting.The assured 7 days of medication (with the weekly product) after injection addresses the typically fragmented care hand-off faced by ED patients and the for the treatment of moderate to severe opioid use disorder (OUD).We report our experience with approximately 800 ED patients with OUD who received the 7-day XR-BUP preparation in the ED between June 2020 and July 2023.

K E Y W O R D S
injectable buprenorphine, medications for opioid use disorder, opioid use disorder treatment previously mentioned barriers to successful full induction.While an XR formulation in the high-risk period after an ED visit is of potential clinical value, the long-term outcomes require further study.A previous study of a commercially insured cohort did not find advantages in retention of individuals receiving XR medications for OUD, though few patients received XR-BUP and follow-up was limited. 26e XR product used in ED-INNOVATION is a 7-day subcutaneous injectable extended preparation of BUP.The 7-day XR-BUP product is available in 8-, 16-, 24-, and 32-mg prefilled syringes, which produce plasma concentrations roughly equivalent to daily doses of SL-BUP of ≤6, 8-10, 12-26, and 18-24 mg, respectively. 27ter subcutaneous injection of 24 mg, plasma concentrations achieve 1.63 ng/mL within 4 h and 2.35 ng/mL at 6 h (figure 1).[30] The bioavailability of this product is six to eight times higher than that of SL-BUP, meaning a lower total dose is needed to achieve equivalent plasma concentrations. 31The terminal half-life is between 70 and 107 h, making it suitable for weekly dosing. 32The safety profile of the 7-day XR-BUP product is similar to that of SL-BUP with the exception of mild-to-moderate injection site pain that has been reported in a small number of patients receiving the injection. 25,26 I G U R E 2 Brixadi injection instructions. 37D discharge dosing of 16 mg of SL-BUP daily with a week-long prescription.

INITIAL CLINIC AL TRIAL S OF C AM2 03 8
Clinical trials of the CAM2038 product have demonstrated noninferiority to SL-BUP for multiple outcomes.In the clinical trial reported in the FDA application for CAM2038, the response rate, defined as no evidence of illicit opioid use at several prespecified time points, was found to be noninferior to SL-BUP. 33In the same study, CAM2038 was found to be superior to SL-BUP on the mean percentage of opioid-negative urine samples for weeks 4-24 of outpatient treatment. 31Retention in treatment, desire to use opioids, and severity of opioid withdrawal signs and symptoms as measured using the Clinical Opiate Withdrawal Scale (COWS) were similar between the CAM2038 and SL-BUP groups. 31A subsequent Phase 3, open-label, multicenter observational study demonstrated that rates of retention in care among patients receiving the CAM2038 product was high, 73.6% at 48 weeks, and the majority (68% [91/133]) of study participants rated CAM2038 as much better than their previous SL-BUP treatment.Only four of 133 (3%) indicated it was worse. 25The FDA initially approved CAM2038 based on safety and efficacy but did not allow the manufacturer to bring the medication to market due to an exclusivity clause delay allowed by another manufacturer of a monthly injectable BUP product 34 until May 2023. 18

ONGOING ED CLINIC AL TRIAL OF 7-DAY INJEC TAB LE XR-BUP PREPAR ATION
ED INNOVATION is an ongoing multisite study funded as part of the NIH HEAL Initiative effort to increase access to medications for OUD in general medical settings and to rapidly expand access to EDinitiated BUP.We describe this trial so that the context in which we are administering and the experience with this new 7-day XR-BUP preparation can be understood.A total of 28 diverse EDs (Figure 3)

Feasibility of implementation and training of ED staff on XR-BUP
ED nurses in all 28 sites were trained to administer XR-BUP with minimal added instructions as the syringe is similar to other prefilled injectables (e.g., enoxaparin) used in ED care.Importantly, it does not require refrigeration, making it feasible to store in the ED rather than a central pharmacy.There are a few specific caveats: 1) the first subcutaneous injection should not be given in the arm but can be administered in the upper gluteal area, thigh, or abdomen and 2) the injection site should not be rubbed postinjection (Figure 2).The upper arm site should only be used after steady state (four consecutive doses) as this site was associated with approximately 10% lower plasma levels than other sites. 37Few patients refuse the injection.The nursing staff assist in overcoming any hesitancy regarding the injection by reassurance of the small size of the injection needle (23-gauge) and the small volume of fluid (<1 mL).

Patient experience
While we are not presenting formal qualitative data from participants receiving XR-BUP at this time, the investigators did receive patient feedback during follow-up clinical interactions.Patients articulated that receiving XR-BUP in the ED was a welcome new option.Both ED clinicians and referral clinicians report a high level of enthusiasm for the 7-day XR-BUP formulation.(Table 1) One patient was incarcerated briefly during the following week and expressed gratitude for not facing withdrawal symptoms while in jail.Thus, having the extended duration of medication afforded by the injectable depot formulation for the first week of outpatient treatment seemed to be a stabilizing force, potentially mitigating early treatment ambivalence about taking daily BUP and other barriers (e.g., pharmacy access). 38

Precipitated withdrawal
As there has been mounting concern about precipitating opioid withdrawal during BUP initiation in the era of fentanyl, we briefly discuss our experience to reassure ED clinicians. 39,40BUP precipitated withdrawal (PW), in contrast to worsening withdrawal that emerges more gradually over time, has been described as the sudden onset of severe withdrawal signs and symptoms, usually within 1 h of administration of SL-BUP, 41,42 similar to what happens when a patient with opioid physical dependence receives a large dose of the opioid receptor full antagonist naloxone.Assessment of PW is based on the rapidity of onset of severe withdrawal symptoms, often with substantial increases in COWS scores (≥5) necessitating treatment with additional BUP and ancillary medications.
Based on our experiences with all forms of BUP, the concerns over PW with fentanyl use appear to be overstated, as the incidence of PW was <1%. 43Only four patients who received XR-BUP experienced PW (<0.5%).There were no clear "I definitely want to get that follow-up shot.I love how I have been feeling with this shot and not having to worry about anything now.I am so glad I came to the hospital that day and got a chance to take the shot.I am excited to have started this journey and taking my freedom back 1 day at a time." "Took away the ritual of still taking a pill everyday which was triggering for me." "I heard about the shot I want it.I came here just for the chance to get the shot." "It was the most amazing medication I've ever taken before because it saved my life.""I did not feel a thing (from injection)." Referred treatment clinician experience "Thank you, your team enrolled one of my toughest to engage patients." "Thank you for allowing us to do what's best for the patient." Abbreviation: XR-BUP, extended-release buprenorphine.

TA B L E 1 Illustrative quotations:
ED and referral clinicians, and patients receiving XR-BUP (CAM2038).
patient characteristics predictive of PW.All had fentanyl in their point of care urine testing, as did ~76% of the overall sample.
The time since last opioid use varied, as did the route of opioid administration. 43e treatment of PW does not differ based on the preparation of BUP received.Worsening withdrawal, defined as no improvement in withdrawal symptoms or any increase in COWS, is treated with additional SL-BUP, followed by symptomatic treatment with ancillary medications, such as acetaminophen and nonsteroidal anti-inflammatory agents for myalgias and pains; dicyclomine for abdominal pain; loperamide for diarrhea; ondansetron, prochlorperazine, or promethazine for nausea; and clonidine for elevated blood pressure, heart rate, or restlessness.Treatment of nausea and vomiting with sedating antiemetics such as promethazine, may have dual benefit in patients who might be agitated.When PW occurs, it is treated with high-dose BUP (SL-BUP up to 16-24 mg, with additional dosing as needed) 44,45 Small doses of benzodiazepines, such as 2 mg of lorazepam, may be used if anxiety is a prominent symptom.Large doses of benzodiazepines in combination with BUP could potentially result in excessive sedation and requires close clinical observation.A recent retrospective cohort study of high-dose BUP found the practice to be safe and well tolerated in uncomplicated patients with OUD. 46Oral medications, including additional SL-BUP, can be challenging to deliver in patients with PW due to vomiting or reluctance by the participant to receive further dosing.Intravenous (IV) access may be beneficial so that medications are more easily administered, titratable, and more rapidly therapeutic.Early use of IV fluids in patients with multiple episodes of vomiting and diarrhea can help mitigate fluid loss and prevent dehydration contributing to headache, malaise, and nausea. 41tamine, an NMDA receptor antagonist, has also been more recently used as an adjunct in the treatment of PW by the authors 44 but has yet to been studied vigorously.

Referral to community providers or treatment program
All patients should be referred to community providers or opioid treatment programs for follow-up with a specific scheduled appointment.The clinicians and programs should be alerted to information regarding the duration of XR-BUP and the patient needs to be discharged with instructions denoting the XR-BUP administration and communication to the referral clinician to resume or initiate BUP in some formulation ideally before Day 8.While it is possible that some individuals who receive XR-BUP may need additional SL-BUP to fully manage their withdrawal symptoms after discharge, we do not routinely recommend prescribing additional SL-BUP, as we are using the equivalent to 16 mg per day dosing.As with most medications, treatment response is variable and some patients may experience symptom control for longer than 7 days, others substantially shorter.
Additional dosing of BUP should be based on clinical assessment by the referral clinician.

DISCUSS ION
The vast majority of individuals in this trial tolerated 7-day XR-BUP injectable, even at low levels of withdrawal (COWS scores of 4), allowing for initiation of BUP early in an ED visit.Despite reports suggesting that fentanyl is a major risk factor for PW, we did not see this in our ED study population. 43It is plausible that the ED environment allows the clinicians to initiate BUP without major hesitation as the resources for treating PW are readily available.
We share our experiences with this new 7-day XR-BUP formulation to assist other clinicians treating OUD as medication will be available in the near future.XR-BUP should be of great interest to emergency clinicians as a tool to provide flexibility in addressing both clinician concerns and patient barriers during the crucial early period in BUP initiation.
The following are lessons and pearls from patients and clinicians.being unable to continue in short-term jail stays; or experiencing pressure to share, sell, divert, or misuse their medications.Finally, the protective effects of an XR-BUP preparation may be more and more important as the proliferation of fentanyl increases the risk of overdose dramatically even with a brief reoccurrence of use.
Initiating BUP treatment by providing full induction dosing and maintenance for 7 days has the potential to improve engagement in ongoing care along the cascade of care, including initiation and retention at 6 months. 47It has recently been reported that engagement in care is a threshold process.Williams and colleagues 48 studied over 19,000 patients with a new BUP initiation episode in primary care.They reported that attainment of the definition of Health Effectiveness and Data Information Set (HEDIS) quality measures for substance use disorders engagement, namely, two professional visits within 34 days from an initiation visit for medications for OUD, was met in almost half of patients retained at 6 months.
Perhaps even more importantly, only 2.9% who did not meet these criteria were engaged in care at 6 months.Thus, it is conceivable that a 7-day XR-BUP preparation with a direct referral may be a first step to meeting this critical threshold along the treatment pathway, by stabilizing patients early.To date, robust data evaluating any form of XR-BUP are quite limited, and we await further trial completions.
Our objective was to report our early experiences with this first U.S.-available 7-day XR-BUP preparation (previously known as investigational drug CAM2038) in the context of an ongoing ED research protocol entitled, "Emergency Department-INitiated bupreNOrphine VAlidaTION"; ED INNOVATION. 20This randomized clinical trial is currently enrolling individuals with OUD comparing traditional sublingual BUP initiation with the 7-day XR-BUP injectable on outcomes of engagement in treatment at 7 and 30 days.

Figure 2
Figure 2 depicts the 7-day XR-BUP syringe.Upon injection XR-BUP forms into a viscous liquid crystalline gel that encapsulates the BUP solution.Over time, the gel biodegrades, releasing BUP at a steady rate over a 1-week period, thus producing a sustained, circulating blood concentration of BUP-avoiding the daily peaks and troughs inherent to daily dosing.The prefilled syringes come in different doses, all in small volumes (<1 mL).In ED INNOVATION we administer a single 24-mg weekly injection dose (without a SL-BUP prescription upon ED discharge), equivalent to the standard both type (academic/community) and location (urban/suburban) throughout the United States have or are continuing to enroll in ED INNOVATION comparing different preparations of BUP.To date, approximately 1600 patients have been enrolled, half of which received the XR-BUP preparation.All patients are 18 years or older with untreated OUD and are English speaking.They must be in at least mild withdrawal with a COWS 35 score of 4 or greater to receive the injection. 36In the overall trial thus far, only 3% of the eligible individuals refused randomization.Patients are observed in the ED for 2 h after receiving XR-BUP and discharged with a follow-up appointment for comprehensive addiction treatment within 7 days.It is expected that referral clinicians discuss options that include continuing BUP, including 30-day injectable XR-BUP preparations, depending on patient preference and insurance.One investigator (AH) has successfully transitioned approximately 50 participants to long-acting, 30-day, XR-BUP (A.Herring, personal communication, May 01, 2023).Follow-up discussion with patients who received the injection have been positive, pointing toward the potential of F I G U R E 3 Geographic location of 28 RCT sites.RCT, randomized controlled trial.ED-administered 7-day XR-BUP to motivate continued maintenance and treatment engagement, including long-acting 30-day XR-BUP preparations.
m all set with how to give this injection, it very similar to XXX which we give all the time.""This (injection) is actually really nice, easy to administer."Patient experience "Dr … you treated me with a shot in my stomach, I'm still doing great.I praise you for helping me restore normalcy back in my life.I referred another person to you for help with opioid addiction."

First
and foremost, despite a high prevalence of fentanyl use, PW was rare in our experience and the ED length of stay postinjection was short, only 2 h.Early observations suggest relatively rapid onset and sustained positive clinical effects that are not dependent on successful attainment of a dispensed prescription of additional SL-BUP in the week following their injection.If the patient presents in severe withdrawal, it is likely that a rescue dose of SL-BUP may be required in the ED along with the injection.A smooth transition to a monthly XR-BUP injectable has been reported in multiple patients and offers potential for increased retention in treatment and several other potential benefits.It is possible that consistent blood levels without peaks and troughs are beneficial to sustain treatment and decrease craving.Patients may also benefit from not having to make daily decisions regarding taking their medication or other circumstances such as having their medication lost, stolen, or confiscated;