Digital Features for this Adis Drug Q&A can be found at https://doi.org/10.6084/m9.figshare.25254046

FormalPara Adis evaluation of buprenorphine ER (Brixadi®) in opioid use disorder

Novel long-acting formulation using FluidCrystal® injection depot technology

Administered weekly or monthly as a subcutaneous injection

Non-inferior to sublingual buprenorphine/naloxone

Associated with high levels of treatment satisfaction

Generally well tolerated

What is the rationale for using buprenorphine extended-release (ER) in the management of opioid use disorder?

Opioids are a group of analgesic agents that are widely used in clinical practice, but can also be misused [1]. Opioid use disorder (OUD) is the chronic use of opioids that causes physical and psychological harm [1, 2]. OUD is an escalating global health problem [3] and is associated with high rates of mortality from overdose, respiratory depression, suicide, accidents, injuries, and infectious diseases such as HIV [2].

Treatment of OUD is based on individualized psychosocial support in combination with pharmacotherapy [1]. The American Society of Addiction Medicine (ASAM) national practice guidelines recommend the opioid agonists buprenorphine and methadone, as well as the opioid receptor antagonist naltrexone, for the pharmacological treatment of OUD [4]. Opioid agonists have been shown to reduce illicit opioid use, craving, and withdrawal symptoms, thereby improving the psychological consequences of OUD [1, 2]. Moreover, both methadone and buprenorphine reduce opioid overdose deaths and all-cause mortality by ≥ 50% [5].

As a partial opioid agonist, buprenorphine has a ‘ceiling effect’ and is less likely to cause respiratory depression than an overdose of a full opioid agonist such as methadone [2]. Various buprenorphine products have been developed for the treatment of OUD, including sublingual tablets and films, as well as three long-acting formulations: a subdermal implant and two depot formulations for subcutaneous injection [1, 2]. Limitations of sublingual buprenorphine include diversion, misuse, accidental pediatric exposure, poor retention, and non-adherence [2, 6, 7], which may diminish the effectiveness of buprenorphine and contribute to negative perceptions, stigma, and barriers to treatment [6, 7]. Long-acting formulations may address some of these limitations.

Brixadi® (CAM2038), a weekly or monthly subcutaneously administered extended-release (ER) formulation of buprenorphine (hereafter referred to as buprenorphine ER), is approved in the USA for the treatment of OUD (Tables 1 and 2) [8]. Because buprenorphine ER is intended for healthcare provider administration (Table 1), it may help to reduce the risk of abuse, misuse, diversion, and unintended pediatric exposure [7]. Consult local prescribing information for further details.

Table 1 Dosage and administration of buprenorphine extended-release injection (Brixadi®) in the management of opioid use disorder in the USA [8]
Full size table
Table 2 Warnings, precautions, and drug interactions associated with buprenorphine extended-release injection (Brixadi®) in the management of opioid use disorder in the USA [8]
Full size table

How does buprenorphine ER work?

Buprenorphine is a partial µ-opioid receptor agonist and a κ-opioid receptor antagonist [8]. Buprenorphine ER (Brixadi®) is formulated using FluidCrystal® injection depot technology, which allows for a low volume prefilled syringe [8,9,10]. Upon entry into the subcutaneous space, the injected solution spontaneously transforms into a highly viscous crystalline gel [8,9,10]. The gel depot encapsulates buprenorphine and gradually releases the drug at a controlled rate over a period of 1 week or 1 month [8, 9].

In a phase 2 study, buprenorphine ER produced immediate and sustained opioid blockade and suppression of opioid withdrawal in patients with moderate or severe OUD [9]. The subjective opioid drug liking effects of hydromorphone were blocked following subcutaneous injections of buprenorphine ER 24 mg or 32 mg weekly. Opioid withdrawal [assessed on the Clinical Opiate Withdrawal Scale (COWS)] was completely suppressed on day 1 after administration of buprenorphine ER and remained suppressed for the duration of the study [9]. The observed plateau for maximal response of drug liking was reached at buprenorphine plasma concentrations of ≈ 1.5–2 ng/mL [8].

Clinical studies demonstrated that buprenorphine ER at doses ranging from 7.5–32 mg weekly and 64–192 mg monthly was not associated with temperature elevations or clinically significant reductions in oxygen saturation [8].

What are the pharmacokinetic properties of buprenorphine ER?

Buprenorphine exposure increases dose-proportionally following single doses of weekly or monthly subcutaneous buprenorphine ER [8]. In phase 1 trials in healthy volunteers and patients with OUD, plasma concentrations of subcutaneous buprenorphine ER stayed between the maximum plasma concentration (Cmax) and the trough plasma concentration of equivalent doses of sublingual buprenorphine (i.e., within the therapeutic range) [11, 12]. The median time to Cmax is ≈ 24 h following weekly administration and 6–10 h following monthly administration of subcutaneous buprenorphine ER [8]. Steady state plasma concentrations are achieved after the fourth weekly or monthly dose. Plasma concentrations are ≈ 10% lower when buprenorphine ER is injected into the upper arm compared with other injection sites (Table 1) [8].

Buprenorphine is ≈ 96% bound to plasma proteins (mainly α- and β-globulin) [8]. Metabolism of buprenorphine involves N-dealkylation to form the major metabolite norbuprenorphine, with this pathway mediated predominantly by CYP3A4, and glucuronidation. Norbuprenorphine can undergo further glucuronidation. Following administration of a single radiolabeled dose of buprenorphine, 69% of the dose was recovered in the feces as unchanged drug, norbuprenorphine and two unidentified metabolites, with the remainder recovered in the urine. Following subcutaneous injection of buprenorphine ER, the apparent terminal plasma half-life of buprenorphine was 3–5 days (weekly) and 19–26 days (monthly) due to the slow release of drug from the depot [8].

Age, sex, and race have no clinically significant impact on buprenorphine ER pharmacokinetics [8]. There have been no formal studies assessing the effect of abnormal liver or kidney function on the pharmacokinetics of buprenorphine ER; however, use of buprenorphine ER is not recommended in patients with moderate or severe hepatic impairment (Table 1) [8].

What is the clinical efficacy of buprenorphine ER?

The efficacy of subcutaneous buprenorphine ER is non-inferior to that of sublingual buprenorphine/naloxone in patients with OUD, based on the results of a 24-week, randomized, double-blind, multicentre, phase 3 trial [13]. Participants were treatment-seeking patients aged 18–65 years with a diagnosis of moderate to severe OUD. They were considered to be good candidates for buprenorphine treatment based on their medical and psychosocial history. In a double-dummy design, patients were randomized 1:1 to receive subcutaneous buprenorphine ER plus daily sublingual placebo tablets (n = 213) or sublingual buprenorphine/naloxone tablets plus subcutaneous placebo injections (n = 215) for 24 weeks, followed by 4 weeks of follow-up with no study medication [13].

During the first week of treatment, the target dosage of subcutaneous buprenorphine ER was 24 mg weekly (achieved on day 4) and the target dosage of sublingual buprenorphine/naloxone was 16 mg/day (achieved on day 2) [13]. Subsequent dosages were flexible and were adjusted according to patient needs and clinical judgment. On days 5 to 7, the dosage of subcutaneous buprenorphine ER could be increased to 32 mg weekly, and the dosage of sublingual buprenorphine/naloxone could be increased to 24 mg/day. Study visits were weekly during phase 1 (weeks 1–11) and monthly during phase 2 (weeks 12–24). During the visits, subcutaneous buprenorphine ER or placebo injections were administered and a 1- or 4-week supply of sublingual buprenorphine/naloxone or placebo (as appropriate) was dispensed. The European Medicines Agency primary endpoint was the mean percentage of urine samples with test results negative for illicit opioids for weeks 1–24 and the US FDA primary endpoint was the response rate (see Table 3 for definition). The key secondary endpoint was the mean percentage of opioid-negative samples examined by a cumulative distribution function (CDF) for weeks 4–24 [13].

Table 3 Efficacy of buprenorphine extended-release injection in patients with opioid use disorder in a randomized, double-blind, phase 3 trial [13]
Full size table

Subcutaneous buprenorphine ER was non-inferior to sublingual buprenorphine/naloxone in terms of having a negative urine test for opioids or being a responder (Table 3) [13]. The mean percentage of opioid-negative urine samples during phase 2 (weeks 13–24) was significantly higher in the subcutaneous buprenorphine ER group than in the sublingual buprenorphine/naloxone group (34% vs 25%; p = 0.02). The CDF for subcutaneous buprenorphine ER was significantly superior to the CDF for sublingual buprenorphine/naloxone (27% vs 0%; p = 0.004). Among patients reporting intravenous drug use at baseline, the mean percentage of opioid-negative urine samples for weeks 4–24 was significantly higher with subcutaneous buprenorphine ER than with sublingual buprenorphine/naloxone (31% vs 15%; p < 0.001). Both formulations of buprenorphine were associated with immediate suppression of opioid craving [assessed by ‘need to use’ visual analog scale (VAS) scores] and withdrawal symptoms (assessed on the COWS). Counselling attendance at scheduled visits was high (84–100%) in both treatment groups [13].

Subcutaneous buprenorphine ER was associated with low levels of illicit opioid use in patients with OUD in a 48-week, open-label, multicentre, phase 3 trial [14]. Participants were aged 18–65 years with a current diagnosis of moderate or severe OUD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria or a past medical history of dependence. Patients new to buprenorphine treatment (n = 37) received a single 16 mg dose of subcutaneous buprenorphine ER on the first day of treatment, with additional 8 mg doses on days 4–7, if needed, to a maximum of 40 mg during week 1. Patients not new to buprenorphine treatment (n = 190) were switched directly to subcutaneous buprenorphine ER weekly or monthly at a dose corresponding to their current daily sublingual buprenorphine or buprenorphine/naloxone treatment. During the 48-week treatment period, the dose of buprenorphine ER could be adjusted, and patients could switch from weekly to monthly dosing or vice versa. The primary objective was to evaluate the safety and tolerability of buprenorphine ER; effectiveness was assessed as a secondary endpoint [14].

The percentage of the composite of illicit opioid-negative urine samples and self-reports increased from 0% to 63% in treatment-naïve patients, and increased from 78% to 83% in patients who switched from sublingual buprenorphine [14]. Patient self-reports of no illicit opioid use increased from 0% to 82% in treatment-naïve patients, and from 92% to 93% in patients who switched from sublingual buprenorphine. Subcutaneous buprenorphine ER also suppressed opioid craving (assessed by ‘need to use’ and ‘desire to use’ VAS scores) and withdrawal symptoms (assessed by COWS and Subjective Opioid Withdrawal Scale scores). Retention rates were high, with 74% of patients completing 48 weeks of treatment [14].

Real-world experience with buprenorphine ER supports the efficacy results observed during clinical trials [15,16,17,18]. Rapid and sustained clinical benefits including reduced opioid use, high rates of retention, and/or improvements in patient-reported outcomes (PROs) were reported across studies in the USA (n ≈ 800–1200) [15, 16], Germany (n = 109) [17], and Australia (n = 67) [18]. These studies included patients with OUD or opioid dependence who were treated with subcutaneous buprenorphine ER in emergency departments [15, 16], under routine care conditions [17], or in custodial settings [18].

Patient satisfaction

Patients receiving subcutaneous buprenorphine ER for opioid dependence reported high levels of satisfaction with treatment [14, 19,20,21]. In the previously discussed 48-week, open-label, phase 3 trial, 68% of patients who switched from sublingual buprenorphine indicated that subcutaneous buprenorphine ER was ‘much better’ than their previous treatment [14].

Patients receiving subcutaneous buprenorphine ER had improved treatment satisfaction compared with those receiving sublingual buprenorphine in a 24-week, randomized, open-label, multicentre trial (DEBUT) [20]. Outpatients aged ≥ 18 years who met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) criteria for opioid dependence were randomized to receive weekly or monthly subcutaneous buprenorphine ER (n = 60) or daily sublingual buprenorphine (n = 59) for 24 weeks. Doses of subcutaneous buprenorphine ER were established after initiation or switching from previous treatment with sublingual buprenorphine, to a maximum of 32 mg weekly or 160 mg monthly. The maximum dosage of sublingual buprenorphine was 32 mg/day. Patients treated with subcutaneous buprenorphine ER reported significantly higher and more sustained treatment satisfaction than those who continued to receive sublingual buprenorphine, as assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) at week 24 (primary endpoint; Table 4). In a post hoc analysis, 53% of patients receiving subcutaneous buprenorphine ER had a TSQM global satisfaction score of ≥ 80 at week 24, compared with 34% of patients receiving sublingual buprenorphine. The number needed to treat to achieve the threshold of ≥ 80 was 5.1. Subcutaneous buprenorphine ER was also associated with significantly greater improvements than sublingual buprenorphine in a number of other PROs (Table 4) [20].

Table 4 Patient satisfaction with buprenorphine extended-release injection in patients with opioid dependence in the randomized, open-label DEBUT trial [20]
Full size table

Real-world studies have also demonstrated high levels of satisfaction with buprenorphine ER in patients with opioid dependence [19, 21]. A quantitative survey of 28 patients receiving buprenorphine ER from an Australian drug and alcohol service found that most patients were satisfied with buprenorphine ER in reducing their cravings (100%), withdrawal symptoms (89%), and ongoing drug use (93%), in the flexibility to carry out daily and social activities (96%), in the flexibility of receiving treatment (89%), and in the travel time for treatment (89%) [19]. All patients were satisfied with their overall treatment experience and were satisfied that buprenorphine ER was the right choice for them compared with their previous treatment [19]. Qualitative interviews with 14 patients receiving buprenorphine ER from four treatment services in the UK also found a positive level of treatment satisfaction [21]. The majority of patients indicated a benefit of, or satisfaction with, buprenorphine ER in terms of effectiveness (77%), convenience (81%), and overall satisfaction (81%). Reported benefits of buprenorphine ER included a positive outlook on life (86%), reduced cravings (71%), improved self-care (71%), and improved relationships (64%) [21].

Patient perceptions and preferences

Real-world studies conducted in the USA [22], the UK [23,24,25], France [26], Italy [27], Spain [28], Sweden [29], Germany [30], and Australia [31, 32] have demonstrated a wide range of patient perceptions, views, and perspectives on buprenorphine ER, as well as varying treatment preferences.

In general, many patients were interested in buprenorphine ER [26] and were willing to receive it [22, 25, 28]. Most patients viewed buprenorphine ER as a good or valuable treatment option [23, 32] and believed it would improve quality of life and reduce stigma and discrimination [27]. Patients with a preference for buprenorphine ER or long-acting formulations cited reasons such as convenience, reduced medication burden, increased freedom, normality/stability, reduced stigma, perceived effectiveness, and administration by a healthcare professional [22,23,24,25, 29]. Patients who believed buprenorphine ER to be a good treatment option for them were more likely to be younger, female, previous heroin and methamphetamine users, and have < 10 years of school education [32]. This belief was also associated with shorter treatment episodes, fewer unsupervised doses, and longer travel distances [32].

Due to psychological factors, some patients did not perceive buprenorphine ER as an attractive treatment option [29]. Other patients preferred short-acting formulations for reasons including safety, reliability/effectiveness, ability to modify dosage, and frequent contact with support services [22, 24]. Some patients who switched from sublingual buprenorphine to buprenorphine ER experienced challenges during the first few weeks of the switching process, including injection-site reactions, illicit co-use, cravings, and withdrawal symptoms [30]. Motivations for discontinuing buprenorphine ER included withdrawal symptoms, inadequate efficacy, poor tolerability, feeling pressured into treatment, no longer requiring treatment, and wanting to use opioids again [29, 31].

What is the tolerability of buprenorphine ER?

Subcutaneous buprenorphine ER was generally well tolerated in clinical trials in patients with OUD, with a systemic safety profile similar to that of sublingual buprenorphine/naloxone [13, 14].

In the 24-week trial, the overall incidence of drug-related treatment-emergent adverse events (TEAEs) was 33% with subcutaneous buprenorphine ER and 30% with sublingual buprenorphine/naloxone [13]. The most common (incidence ≥ 5%) TEAEs were injection-site pain (9% with subcutaneous buprenorphine ER vs 8% with sublingual buprenorphine/naloxone), headache (8% vs 8%), constipation (8% vs 7%), nausea (7% vs 8%), injection-site pruritus (6% vs 6%), injection-site erythema (6% vs 6%), urinary tract infection (5% vs 5%), and insomnia (6% vs 3%). The majority of TEAEs were mild or moderate in severity. All injection-site adverse events were mild (74%) or moderate (26%) in intensity. The incidence of non-fatal serious TEAEs was 2% with subcutaneous buprenorphine ER and 6% with sublingual buprenorphine/naloxone. Five non-fatal drug overdoses were reported, all of which were in the sublingual buprenorphine/naloxone group. TEAEs leading to discontinuation of treatment occurred in 3% of subcutaneous buprenorphine ER recipients and 1% of sublingual buprenorphine/naloxone recipients [13].

In the 48-week long-term safety trial, the overall incidence of TEAEs was 63% (69% in patients who switched from sublingual buprenorphine and 32% in treatment-naïve patients) [14]. The most common (incidence ≥ 5%) TEAEs were injection-site pain (15%), injection-site swelling (12%), injection-site erythema (9%), headache (8%), nasopharyngitis (8%), nausea (7%), urinary tract infection (5%), and vomiting (5%). Most TEAEs were mild or moderate in intensity. Drug-related TEAEs occurred in 26% of patients (31% in patients who switched from sublingual buprenorphine and 5% in treatment-naïve patients). Most drug-related TEAEs were injection-site reactions, and most injection-site reactions were reported as mild to moderate. Serious TEAEs occurred in 5% of patients, two of which were injection-site-related and none of which were drug-related. Two percent of patients discontinued treatment due to TEAEs [14].

Post-marketing surveillance has identified cases of injection-site abscess, ulceration, and necrosis following initiation of buprenorphine ER, some of which have required debridement and antibacterial treatment [8]. Serious injection-site reactions like these are more likely to occur following inadvertent intramuscular or intradermal administration of buprenorphine ER (Table 1) [8].

What is the current clinical position of buprenorphine ER?

Weekly or monthly subcutaneous buprenorphine ER (Brixadi®) is a useful addition to the treatment options for OUD. In a pivotal phase 3 trial, buprenorphine ER met the primary endpoint of non-inferiority for the proportion of opioid-negative urine samples, and responder rate versus daily sublingual buprenorphine/naloxone. Buprenorphine ER was generally well tolerated, with a systemic safety profile similar to that of sublingual buprenorphine/naloxone.

In the DEBUT study, patients who received subcutaneous buprenorphine ER reported higher and more sustained treatment satisfaction than those who continued to receive sublingual buprenorphine. The greater treatment satisfaction experienced by patients receiving buprenorphine ER suggests that long-acting formulations may improve long-term treatment retention [33, 34], thereby reducing mortality associated with OUD [34]. This highlights the importance of considering PROs such as global treatment satisfaction as alternative endpoints in clinical trials [20, 33, 34]. As the open-label study was conducted under naturalistic conditions with few exclusion criteria, the results are likely to be generalizable [20, 34]. Indeed, real-world studies have also demonstrated high levels of satisfaction with buprenorphine ER in patients with opioid dependence.

Studies conducted in the real-world setting have shown that patients’ opinions and perceptions of buprenorphine ER differ greatly, as do their treatment preferences. As such, it is important to view buprenorphine ER as one option in a range of potential treatments [33]. While some patients preferred short-acting formulations (i.e., buprenorphine ± naloxone sublingual film or tablets), most expressed a preference for long-acting formulations. Further research is required to establish the place of long-acting buprenorphine formulations and who is most likely to benefit from them [10]. However, current evidence suggests that long-acting buprenorphine formulations are likely to benefit patients with OUD who [13, 34]:

  • Are at risk for unintended treatment interruption and/or loss of opioid tolerance;

  • Are at risk of diverting, abusing, or injecting their medication;

  • Have trouble taking daily medication;

  • Are averse to taking daily medication;

  • Cannot store their medication safely;

  • Are worried about having their medication stolen;

  • Have privacy concerns;

  • Have difficulty accessing consistent care (e.g., justice settings, homeless, rural communities).

Two long-acting buprenorphine formulations are currently approved for the treatment of OUD, with weekly or monthly subcutaneous buprenorphine ER (Brixadi®) having several potential advantages over monthly subcutaneous buprenorphine ER (Sublocade®) [35]. While Sublocade® requires refrigeration and can only be administered monthly and only in the abdominal area, Brixadi® has no refrigeration requirements, offers more dosing options (four doses for the weekly formulation and three doses for the monthly formulation), and may be injected in the upper arm, abdomen, buttock, or thigh (Table 1) [1]. Brixadi® also has a thinner, shorter needle and a smaller injection volume than Sublocade® [8, 35].

The availability of both weekly and monthly formulations of buprenorphine ER in doses that equate to those currently available for sublingual buprenorphine products (Table 1) aligns with the current treatment paradigm and clinical guidelines for OUD, which recommend individualized dosing and visit frequency during induction, stabilization, and maintenance [4, 36]. The ASAM guidelines also recommend psychosocial treatment based on individual patient needs, with the proviso that pharmacotherapy should not be hindered or delayed by a patient’s choice to forego psychosocial treatment or by the lack of available psychosocial treatment [4]. In addition, the guidelines recommend that all FDA-approved medications for OUD (i.e. methadone, buprenorphine, and naltrexone) be available to all patients. However, they also note that methadone can only be provided in opioid treatment programs and acute care settings, while buprenorphine and naltrexone can be prescribed in any setting [4].

An open-label US trial is comparing the cognitive effects of buprenorphine ER and naltrexone ER in patients with OUD [37]. The study will use functional magnetic resonance imaging to measure domain-specific brain activity induced by various cognitive tasks [37]. A pragmatic, randomized, open-label, phase 3 trial (MOMs) is also underway to compare the effects of buprenorphine ER and sublingual buprenorphine on mother and infant outcomes in pregnant women with OUD [38, 39]. Results of these trials are awaited with interest.

OUD is associated with a significant economic burden [2], particularly in terms of mortality, morbidity, lost productivity, and costs to the criminal justice system [40]. In two US cost-effectiveness analyses, buprenorphine ER was not cost effective compared with sublingual buprenorphine ± naloxone [41, 42] or oral methadone [41]. However, in other cost estimation and budget impact analyses conducted in the UK [43, 44] and Australia [45], buprenorphine ER was associated with lower costs than sublingual buprenorphine [43, 45] and oral methadone [43,44,45]. It should be noted that, in the context of escalating drug costs, it can be difficult to accurately assess the value of new therapies [46]. This is particularly true for injectable medications such as buprenorphine ER, which is part of a holistic approach to OUD and has a number of intangible benefits (e.g. reduced stigma, improved treatment compliance and retention) [46]. Further robust pharmacoeconomic analyses would be useful.