Buprenorphine Update: Bupe is (still) "Butiful"

Author: Alec Feuerbach

Peer Reviewers: Trevor Cerbini, Nicole Anthony

Faculty Reviewer: Scott Kendall

Two years ago, Dr. Trevor Cerbini wrote an excellent post for this blog highlighting the basics – and beauty – of buprenorphine (bupe). He highlighted the staggering mortality of Opioid Use Disorder (OUD), explaining that 5.5% of patients treated for opioid overdose in the ED die within one year.[1] He made a strong argument for bupe based on its pharmacology and the current literature. A partial agonist at the mu-receptor, bupe saturates the opioid receptor, blocking withdrawal while also providing a ceiling effect for euphoria and respiratory depression. The number needed to treat to get one patient stable on medication-assisted treatment is two;[2,3] the number needed to treat to save a life after nonfatal overdose ranges from 30 to 55, depending on the study.[4,5] Finally, Dr. Cerbini described the standard method for completing buprenorphine induction in the ED:

1) Confirm withdrawal with a COWS score of ≥ 8

2) Give 4 to 8 mg

3) Reassess and give more if withdrawal persists (generally up to 16 mg total; though some suggest doses up to 32 mg as we will see)

4) Connect to outpatient care

In other words, Dr. Cerbini covered everything you need to know to use this drug safely and effectively in the ED. So why bring it up again?

For one, the opioid epidemic is getting worse. From April 2020 to April 2021, a record high of 75,673 people died from opioid overdose.[6] For comparison, 36,000 patients died in car crashes last year.[7] The COVID-19 pandemic has worsened the opioid epidemic by decimating medical services, straining personal finances, creating emotional stress, and isolating people from their support systems.[8] Now, more than ever, we need to refresh ourselves on how to use life-saving medications like buprenorphine to care for our patients struggling with opioid addiction. (In other words, re-read this earlier post now!)

And still, while the epidemic rages on, researchers, clinicians, and emergency medicine providers have pushed the boundaries of caring for people with OUD, expanding the use of buprenorphine in new and exciting ways. This brings us to the goal today: review some of the new literature about buprenorphine and highlight the directions that opioid treatment in the ED may be heading.

Expanding access

Because we are often the first point of contact for patients struggling with OUD, there have been calls to increase buprenorphine prescribing by emergency providers. In 2015, a robust, single-site, randomized-control trial by D’Onofrio et al. showed that ED-initiated buprenorphine decreased both self-reported opioid use and need for inpatient addiction services.[9] Following this landmark study, additional reports have shown successful implementation of ED-based buprenorphine programs.[10-12] Still, questions have remained about the feasibility and sustainability of widespread adoption of this practice.

For example, a mixed-method study in 2020 outlined perceived barriers to ED-initiated buprenorphine.[13] These included 1) perceived lack of education about and familiarity with buprenorphine, 2) concern that resources needed to care for critically ill patients would be inappropriately diverted to those with opioid withdrawal, 3) sense that starting long-term medications go beyond the scope of emergency medicine, 4) a lack of outpatient follow-up and resources, and 5) lack of leadership buy-in, dedicated resources, and protocolized care.

Despite such barriers, we have recently seen a surge in the successful implementation of ED-based buprenorphine programs nationwide. One such program is the California Bridge Program, funded by a federal grant from the Department of Health and Human Services’ Substance Abuse and Mental Health Services Administration. Starting in 2019, the California Bridge Program enrolled 52 hospitals across the state. representing a diverse range of practice types — urban and rural, teaching and non-teaching. All were successfully able to increase buprenorphine utilization to treat withdrawal; 45 hospitals were even using buprenorphine after naloxone reversal (more on that later).[14] Along with showing feasibility of ED buprenorphine programs, this study highlighted several key components of success – simple ED-based protocols, peer navigators to assist with motivational interviewing and harm reduction, and financial resources to support implementation (participating programs received a $125-260k grant).

Other studies have described similar efforts to improve the treatment of patients with OUD. Three hospitals in the University of Pennsylvania network increased their buprenorphine prescription rate in the ED or at discharge from 3% to 23% of opioid-related visits.[15] Among attendings who had managed at least 10 opioid-related patient encounters, they were able to increase the likelihood of prescribing buprenorphine from 7% to 70%. Contributing to their success were numerous interventions. One was the implementation of a system that automatically identified patients with OUD and alerted peer counselors of their presence. The authors also described an intentional effort to create a culture that encourages the use of medications to treat OUD and a financial incentive to attendings to complete X-Waiver training.

(Note: it is now possible to receive a limited prescribing waiver that allows physicians to prescribe buprenorphine for up to 30 patients at once without completing the eight hours of training that was previously required. To do so, submit an alternative notification of intent with the Substance Abuse and Mental Health Services Administration.)

Still, we have work to do. A recent, retrospective analysis of nearly one-third of ED visits nationwide showed that one month after ED discharge for opioid overdose, only 7.4% of patients received prescriptions for naloxone and only 8.5% for buprenorphine.[16] Clearly, we are missing opportunities to connect patients presenting with opioid overdose to these life-saving medications.

Giving higher doses

Another emerging trend in the use of buprenorphine is increasing comfort with escalating doses during the initial induction of the medication. Success with this strategy was described by Herring et al.[17] Existing guidelines from the Department of Health and Human Services generally limit the first 24-hour dose to 12 mg total, [18] and many ED-based algorithms limit the ED-administered dose to 16 mg on the first day. Herring et al. argue that for many individuals with significant OUD, higher doses are required to be effective. Indeed, when reviewing the opioid inductions completed during 2018 (n=579), the authors noted that 63.2% required doses greater than 12 mg to significantly curb withdrawal, and 23.8% required doses equal to, or greater than, 28 mg. Importantly, no patients requiring these high doses had abnormal alterations of their vital signs, a new requirement for supplemental oxygen, or the need for naloxone reversal.

Among all inductions reviewed, there were only five documented cases of precipitated withdrawal and only one of these five cases appeared to be related to high-dose initiation: the patient initially tolerated 8 mg before experiencing precipitated withdrawal after an additional dose of 24 mg. The other four cases occurred after the initial dose of 8 mg. Notably, in all of these other cases, the symptoms resolved after additional doses of 24 mg buprenorphine, and all patients were discharged in stable or improved condition. Although based on a small sample, this lends some support to the common belief that the treatment for precipitated withdrawal is more buprenorphine.

Herring et al. also argue that this strategy may be beneficial when considering the social determinants of health of patients presenting to the ED with OUD. Of the patients in this single-center study, one-quarter were undomiciled, almost half had comorbid psychiatric conditions, and nearly all were under- or uninsured. For this type of population, a high-dose initiation can crucially extend the patient’s withdrawal-free period, allowing them more time to navigate the outpatient addiction treatment network and connect with long-term treatment.

For those worried this type of high-dose algorithm would unreasonably burden the ED, the median length of stay for these patients was just over two hours.

Giving smaller doses

On the other end of the spectrum is very-low dose induction of buprenorphine. This method is sometimes referred to as “micro-dosing”; however, some experts in addiction medicine argue this term is pharmacologically inaccurate and potentially confusing given its lay association with the micro-dosing of hallucinogenic drugs.[19]

Micro-dosing involves the induction of buprenorphine with minuscule, gradually increasing, doses of buprenorphine while tapering the opioid the patient was previously using. The goal of this method is to start the patient on buprenorphine without any withdrawal period at all. As previously discussed, with standard induction methods, a patient has to be experiencing at least mild to moderate withdrawal prior to starting buprenorphine. Though not life-threatening, even mild withdrawal is uncomfortable and may be a barrier to buprenorphine initiation.

To bypass the necessary withdrawal period, various methods have been developed including bridging to therapy with a low dose buprenorphine patch or initiating very small doses of buprenorphine in what has been termed the “Bernese method”. One case study describes initiating a dose of 0.2 mg buprenorphine on days one and two, 0.8 mg on day three, and then slowly increasing to a total of 8 mg on day nine. Simultaneously, the patient decreased their daily street heroin use of 2.5 g by 0.5 g per day until they stopped using on day 6.[20]

Although this method offers hope for initiating buprenorphine without withdrawal — theoretically increasing the tolerability of, and thus compliance with, this process — it does present its own challenges. Permitting the continued use of street drugs will likely give some clinicians pause, though this method could also be used for transitioning from methadone. Other barriers include the fact that buprenorphine does not typically come packaged in the low doses desired for this strategy so medication films have to be modified either by a pharmacist or the patient themselves. Furthermore, a review of the literature describing this method showed that both very low-dose initiation and patch initiation still involved about 50% of patients experiencing some withdrawal symptoms.[21] More data about the efficacy and safety of very low-dose initiation should be forthcoming as there is an ongoing randomized controlled study comparing it to standard initiation.[22]

An obvious barrier for us is that this method typically draws out the induction of buprenorphine over days to a week rather than minutes to hours, seriously limiting its utility in the ED. Still, it is worth being aware of this method when consulting colleagues in addiction medicine and discussing with patients who may have had bad, past experiences initiating buprenorphine. For patients that hope to make the notoriously difficult transition from methadone (with its long half-life) to buprenorphine, this method may also offer some hope.

Starting after naloxone revival

Every year, there are almost 500,000 ED visits for opioid overdose in the US, nearly double the number of ED STEMI visits. As already established, these patients have a staggering one-year, all-cause mortality that can be reduced anywhere from 38% to 59% by connecting them to medical therapy.[23] Unfortunately, in one study, fewer than a third of patients were started on medication therapy in the year after a nonfatal overdose.[24] So if we can do it safely, why not start buprenorphine during a nonfatal overdose visit while the patient is still in front of us?

Although still a new practice, several reports have described successful examples of doing just that. Herring et al. have even published a proposed algorithm for what they call the ODNaloxoneBupe pathway (see Figure 1 below).[25] They suggest initiating buprenorphine in an otherwise healthy patient experiencing naloxone-induced withdrawal symptoms (as long as they have a normal mental status and report no other co-ingestion or methadone use). In their pathway, they initiate 4 mg buprenorphine and then continue with the pathway, as usual, paying close attention to respiratory depression and precipitated withdrawal. They suggest reversing buprenorphine, if needed, with high-dose naloxone (2-3 mg IV push) followed by a drip at 4 mg/hr. In this paper, the authors give examples of three patients that required naloxone for opioid overdose, were immediately started on buprenorphine, and then, most importantly, attended all follow-up appointments.

Figure 1 (from Herring et al. [25]) – ODNaloxoneBupe Pathway

In Camden, New Jersey, this practice has been taken one step further by protocolizing buprenorphine initiation by Emergency Medical Services for patients who refuse transport to the ED.[26] They argue for the need for such a practice considering that a large percentage (36% in 2019) of their opioid revival patients refuse transport to the ED. Their protocol differs slightly from the ODNaloxoneBupe pathway described above: rather than starting with 4 mg doses and up-titrating, they give a dose of 16 mg upfront. Theoretically, giving large doses upfront should rapidly and safely reverse withdrawal symptoms by capitalizing on buprenorphine’s ceiling effect which limits its impact on respiratory depression. In their initial report, they describe three “exemplary cases” of eighteen total cases. Though they refused transport to the ED, all three patients did well with buprenorphine after naloxone and attended their next day’s appointment. Two remained enrolled in the clinic 30 days later. They don’t describe the other fifteen cases but do note that “all had improvement in symptoms following buprenorphine treatment without any signs of precipitated withdrawal.”

Interestingly, though likely “not ready for prime time”, one study even looked at the possibility of bypassing naloxone entirely and giving intravenous buprenorphine to reverse methadone-induced respiratory depression.[27] The researchers found that patients with presumed methadone overdose who received buprenorphine were more likely to have complete reversal and less recurrence of respiratory depression than those that received naloxone. They were also less likely to develop withdrawal symptoms, require intubation, or develop ARDS.

Considering these results are from a pilot study with a relatively limited sample size (n=85), and other descriptions of using buprenorphine for reversal of opioid overdose come from case reports and anecdotes [28-30], this study should not yet change practice. If externally validated, however, this practice of using buprenorphine as the initial treatment for opioid overdose could potentially facilitate the transition to long-term medication treatment for OUD.

At the very least, this study is another demonstration of the potential power of this medication in our fight against the opioid epidemic.

In the words of Dr. Trevor Cerbini, Bupe is Butiful, and it’s a medication with which we should all be comfortable.