Buvidal/Brixadi – a long-acting injectable buprenorphine formulation for the treatment of opioid dependence

ABSTRACT

Long acting (or extended release) injectable buprenorphine formulations for the treatment of opioid dependence have been introduced in a number of countries in recent years. One such product, Buvidal, available as Weekly or Monthly subcutaneous injections, has been increasingly used in many European countries and Australia for several years, and has recently been registered under the brand name Brixadi in the United States. This review provides an overview of opioid dependence, examines the rationale for the development of Buvidal, its pharmacological properties, evidence of efficacy and safety, and key principles of clinical care in the treatment of opioid dependence. Particular attention is given to issues of pain management, pregnancy, and treatment in custodial settings. This long-acting injectable buprenorphine product is an important addition to the available options for the treatment of opioid dependence, providing a safe and effective alternative to treatment with medications requiring daily dosing.

Plain Language Summary

Buvidal (known as Brixadi in the USA) is available in a number of countries for the treatment of opioid dependence. Buvidal contains the opioid medication buprenorphine, taken either once-a-week or once-a-month as an injection under the skin. Compared to daily dosing with buprenorphine or methadone taken under the tongue (known as sublingual), the less frequent dosing makes treatment much more convenient for many patients (and service providers). Buprenorphine reduces opioid withdrawal symptoms, cravings, and the effects of additional opioid use. Buvidal has similar side effects and treatment outcomes to sublingual buprenorphine (e.g. on outcomes, such as reduced illicit opioid use and improved general health). Many patients report less stigma and higher satisfaction ratings with Buvidal, whereas others prefer daily dosing with either sublingual buprenorphine or methadone. Patients should have a range of treatment options available to them. Most patients can start treatment directly with Buvidal, or transfer from sublingual buprenorphine without difficulty. However, greater care is required for patients transferring from methadone in order to prevent precipitated withdrawal symptoms. Buvidal can be safely used by patients who also have other health conditions in addition to opioid dependence, such as chronic pain and in pregnancy. It is also being increasingly used in prison settings due to its simpler dosing requirements and reduced risk of diversion to others.

1. Introduction

1.1. Opioid dependence: an overview

Opioid dependence is a chronic-relapsing condition characterized by a pattern of persistent opioid use despite clinically significant impairment to the individual’s health and/or psychosocial functioning [1]. Opioid dependence has the following features: (i) impaired control over opioid use (e.g., inability to reduce or stop opioid use, relapse after cessation attempts, cravings); (ii) increasing precedence of opioid use over other aspects of life (e.g., health, relationships, daily activities, and responsibilities); and (iii) physiological features including tolerance to the effects of opioids and a withdrawal syndrome following discontinuation. Opioid dependence typically involves periods of exacerbation and remission, with stressful life events, relationship issues, and deteriorating physical (e.g., pain) or mental health that can increase the risk of relapse.

The Global Burden of Disease study estimated 40.5 million people were opioid dependent in 2017, at an age-standardized rate of 510 people per 100,000 population globally, with the highest prevalence rates reported in the United States, Middle East and North African countries [2].

Opioids may include synthetic opioids or naturally occurring opiates and may be prescribed or used illicitly. The profile of opioids used varies considerably by different regions and over time – with heroin dominating global markets for many decades [2]. There has been a marked increase in rates of pharmaceutical opioid dependence in North America and Australia in recent decades, corresponding to high rates of opioid prescribing [3]. The median risk of developing opioid dependence among people prescribed opioids for any pain condition is estimated at approximately 5% (range 0–31%), higher among people prescribed long-term opioids for chronic non-cancer pain [4,5]. The last decade has also seen a marked increase in the use of illicit synthetic opioids such as fentanyl and other high potency synthetic opioids (HPSOs) adulterating illicit drug markets in North America, with concerns that similar increases may occur elsewhere [3].

Opioid dependence is associated with a range of significant physical, economic, and social harms for individuals and their communities, accounting for 16.6 million disability-adjusted life-years in 2017 [2]. Specific harms include transmission of blood-borne viruses (BBV) (Human Immunodeficiency Virus (HIV), Hepatis C and B Viruses) through shared injecting equipment, other injecting related injuries and diseases, other health problems, increased criminal activity to acquire opioids, exposure to violence, homelessness, economic distress, impaired relationships, parenting, and employment. People with opioid dependence have significantly reduced life expectancies compared to the general population, with one cause of mortality, opioid overdose causing over 100,000 deaths worldwide annually [2].

People with opioid dependence also have higher rates of comorbid health problems than the general population – including higher rates of polysubstance use, mental illness (e.g., depression, anxiety, and trauma disorders) [6,7], and chronic pain (estimated as high as 44.0% [95% CI: 40.0–49.0] of patients in opioid dependence treatment) [8].

1.2. Clinical interventions for addressing opioid dependence

There are a number of effective treatments and harm reduction interventions for people with opioid dependence [2].

Harm reduction interventions aim to reduce the harms associated with the use of opioids – but not necessarily to reduce opioid use [9] – and include evidence-based interventions such as needle syringe programs (to reduce BBV transmission associated with shared injecting equipment), take-home naloxone programs (supply of naloxone and education to potential first responders), and drug consumption rooms (safer facilities for drug consumption to prevent overdoses). Harm reduction services can also serve as an entry point for people to engage with addiction treatment and other health services.

As a chronic relapsing-remitting disorder, opioid dependence usually requires long-term treatment tailored to the needs of individual patients over time. The aim of the treatment is to reduce or cease unsanctioned opioid use and to stabilize the physiological, psychological, and social harms associated with chronic opioid use. Treatment options and responses include:

• psychosocial interventions (e.g., case management, counseling, residential, or day-rehabilitation programs, life skills programs, housing, welfare, and vocational interventions),

• withdrawal services – short-term interventions designed to assist people to safely complete opioid withdrawal and to engage in ongoing care,

• medication-based treatments – combining the use of opioid medications with medical and psychosocial interventions, and can involve opioid agonists (e.g., oral methadone, and in some jurisdictions slow-release oral morphine, supervised injectable heroin, or hydromorphone programs), partial agonists (e.g., buprenorphine), or opioid antagonists (e.g., naltrexone).

The key elements of medication-based treatment of opioid dependence [10] include: (a) safe and effective use of medicine; (b) regular clinical reviews and monitoring; (c) participation in psychosocial interventions [11]; and (d) addressing medical, psychiatric, and social comorbidities. Opioid dependence treatment also provides the opportunity to engage patients to address other health and psychosocial issues.

For many decades, methadone was the main medication used for treating opioid dependence globally with a strong evidence base regarding its ability to reduce unsanctioned opioid use, mortality, HIV transmission, and crime and to improve health outcomes [2,12]. Methadone is a long-acting opioid that usually requires once-a-day dosing when treating opioid dependence. Despite being highly effective, a concern with opioid medications is their non-medical use by patients (e.g., unauthorized dose escalations, injecting medications designed for oral use) or diversion to others (resulting in overdose deaths in people with low opioid tolerance such as children). For this reason, most methadone programs require daily or frequent supervised dosing at a clinic or pharmacy, with ‘take-away’ (or unsupervised) doses available for patients assessed as low risk of non-medical use of their medication [10]. The requirement for many patients of daily or frequent attendance (e.g., several times a week) for dosing at a clinic or pharmacy adds considerably to the inconvenience, treatment burden, and costs for patients and service providers, and can often cause friction between patients and service providers regarding access to take-away doses.

Buprenorphine is a partial agonist at the mu opioid and opioid receptor-like-1 receptors, resulting in analgesia, reductions in opiate withdrawal and cravings, and opiate effects (e.g., respiratory depression, sedation) that are dose dependent within a limited range, above which higher doses do not produce corresponding increases in effect (i.e., ceiling effects) [13,14]. Thus, BPN exhibits an enhanced safety profile compared to full agonists, demonstrated in reduced mortality risk compared to the treatment of opioid dependence with methadone [15,16]. Buprenorphine also acts as an antagonist at Kappa and Delta opioid receptors, which may reduce adverse events such as constipation, dysphoria, and opioid hypersensitivity [13–15].

Buprenorphine has been licensed for the treatment of opioid dependence for over 20 years in many countries [17], in the form of transmucosal (sublingual and/or buccal) preparations – often administered as a once-a-day dose. Buprenorphine also has a history of non-medical use (e.g., diverted or injected doses) [18], albeit the safety concerns are less than for other opioids such as methadone. To discourage diversion and injecting of buprenorphine tablets, combination buprenorphine-naloxone tablet or film products (in a 4:1 ratio) were developed – causing uncomfortable naloxone (antagonist) effects if injected by an opioid-dependent person not in buprenorphine treatment [19].

The greater safety profile of buprenorphine has allowed less emphasis upon supervised dosing than methadone, and many countries have policies enabling patients to receive sublingual buprenorphine doses for up to one month at a time [17]. In other countries or treatment settings (e.g., prisons), concerns regarding non-medical use of buprenorphine have resulted in a supervised dosing framework similar to methadone, requiring patients to attend clinics or pharmacies either daily or several times a week to access their medication. The inconvenience, costs, stigma, and treatment interruptions (from poor medication adherence) associated with regular supervised buprenorphine treatment remain barriers for many patients engaging with treatment [20].

Long-acting buprenorphine injections (LAIB) were developed as a way of overcoming some of the concerns and treatment barriers associated with daily dosing of sublingual buprenorphine. Two formulations are licensed in many countries, including Buvidal or Brixadi, and Sublocade. This review focuses on the use of Buvidal/Brixadi. The potential advantages and disadvantages of using LAIB over SL formulations are summarized in Table 1.

Table 1.

Potential positive and negative aspects of Buvidal compared to sublingual buprenorphine treatment.

Potential positives	Potential negatives
Reduced frequency of clinic or pharmacy visits and greater convenience for patients	Some patients report loss of connection to community and the daily structure associated with daily dosing (e.g., at a methadone clinic)
Reduced total treatment costs for patients (e.g., transport, lost productivity of attendance for daily dosing)	Some patients report Buvidal interferes with desire to continue to use opioids (e.g., heroin) whilst in treatment
Less risk of non-medical use of medication, resulting in enhanced community safety and perceptions of treatment	Adverse events at injection sites can be problematic for some patients.
Expanding treatment in some settings (e.g., prisons, residential-rehabilitation programs)
Less stigma compared with other medications for opioid dependence
Potentially easier induction into treatment with Buvidal Weekly than SL BPN
The potential for improved adherence and outcomes for ‘hard to treat’ clients
The potential for less severe withdrawal symptoms on stopping LAIB

2. Clinical pharmacology of Buvidal/Brixadi

2.1. Formulations

Buvidal is a long-acting subcutaneous injectable formulation of buprenorphine designed for once-a-week (Buvidal Weekly) or once-a-month (Buvidal Monthly) administration [21–24]. Administration can be in upper arms, thighs, abdomen, or buttocks.

Buvidal Weekly is available in four buprenorphine dose strengths in prefilled syringes with a ½-inch, 23-gauge needle: 8 mg/0.16 mL, 16 mg/0.32 mL, 24 mg/0.48 mL, or 32 mg/0.64 mL.

Buvidal Monthly is available in four buprenorphine dose strengths in prefilled syringes with a ½-inch, 23-gauge needle: 64 mg/0.18 mL, 96 mg/0.27 mL, 128 mg/0.36 mL, or 160 mg/0.45 mL.

Buvidal contains buprenorphine in a delivery system based on FluidCrystal injection depot technology. After subcutaneous injection, the FluidCrystal formulation absorbs interstitial aqueous body fluid and transforms from liquid to highly viscous liquid crystal (or gel-like) phases in situ and resulting in a slow and consistent release of BPN over a week or a month, depending on the formulation [25–27]. There is a small amount of ethanol (the maximum level of ethanol in a Buvidal injection is less than 100 mg) – approximately one hundredth of a standard drink of alcohol and clinically unlikely to be of relevance.

2.2. Onset, elimination, and duration of effects

Buprenorphine effects commence within 1–2 hours after injection, with peak concentrations observed 6–10 hours after the Buvidal Monthly injection, and 16–24 hours after the Buvidal Weekly [25–27]. After the initial peak, the plasma BPN concentrations decrease slowly until the next dose is administered (see Figure 1).

Figure 1.

Modeling of buprenorphine plasma levels for Buvidal Weekly 24 mg, Buvidal Monthly 96 mg, and sublingual buprenorphine 16 mg daily.

From Lintzeris N., Dunlop A., Shultz M. Clinical Guidance for the use of Long-Acting Injectable Buprenorphine formulations in the treatment of opioid dependence. NSW Ministry of Health, Sydney. ISBN: 978-1-76023-854-4. https://www.health.nsw.gov.au/aod/Publications/laib.pdf.

BPN is largely metabolized (N-dealkylation) by cytochrome P450 (CYP3A4) to the active metabolite nor-buprenorphine, and both then undergo glucuronidation [21], and mainly excreted in urine and feces.

Buvidal Weekly has a terminal plasma half-life of between 3 and 5 days, and Buvidal Monthly has a half-life of 19–25 days. Plasma concentrations accumulate with successive doses at the outset of treatment, until steady state equilibrium is achieved – usually after three to five doses. The gradual release of BPN over time allows an extended duration of action and more stable plasma levels – with lower peak and comparable trough plasma levels, than experienced with daily sublingual dosing [21–25] (see Figure 1).

Simulation modeling and clinical experience suggest that BPN plasma concentrations decrease slowly over time after the last injection, with persistent BPN plasma levels persisting for 2–4 weeks after the last Buvidal Weekly dose, and 8–16 weeks after the last Buvidal Monthly dose [22].

2.3. Pharmacodynamic properties

Laboratory and clinical trials indicate that Buvidal effectively reduces opioid withdrawal symptoms and cravings for opioid use in opioid-dependent people [28,29]. ‘Opioid blockade’ - the inhibition of the physiological and subjective effects (i.e., drug-liking) of other opioids – is achieved by BPN due to its greater mu-opioid receptor affinity than most other opioids [14]. The blockade of subjective opioid effects has been demonstrated with laboratory hydromorphone challenge studies with Buvidal Weekly formulations [28,29], with higher Buvidal doses achieving greater blockade. Animal studies suggest that buprenorphine also blocks or reduces the effects of fentanyl [30] – suggesting it should also be effective in reducing fentanyl use in patients. Effects of LAIB upon pain outcomes are examined later.

The ability for buprenorphine to achieve reduction of opioid withdrawal symptoms, cravings and to block the effects of exogenous opioids show considerable interindividual variability – with some patients requiring higher doses of buprenorphine to achieve these effects [26], emphasizing the need to titrate and individualize doses for optimal treatment outcomes.

2.4. Safety profile

Adverse effects of Buvidal [21–24] include

• General or systemic adverse events common with BPN administered sublingually – most frequently headache, constipation, nausea, vomiting, and diarrhea (occurring in up to 10% of patients), usually following the initiation of BPN treatment and subsiding as tolerance develops; and

• Adverse events related to the subcutaneous Buvidal injection – most frequently pruritus, localized pain (5–10%), swelling, erythema (1–5%), bruising and cellulitis (<1%). The frequency of localized adverse events may be reduced by rotating injection sites

• Therapeutic doses of buprenorphine do not appear to be associated with clinically significant prolongation of QTc or increased risk of Torsades de Pointes (TdP) [31] and should be preferred to methadone in patients with underlying risk for TdP [32].

• A potential problem with initiation of buprenorphine treatment is the emergence of precipitated withdrawal [33,34] – caused by the displacement of full opioid agonists (e.g., methadone, heroin) from mu opioid receptors when buprenorphine is initiated due to its higher receptor affinity – however buprenorphine has lower intrinsic receptor activity (as a partial agonist) and this rapid reduction in opioid activity can be experienced as sudden onset of severe opiate withdrawal symptoms (including anxiety, agitation, abdominal cramps, nausea, sweating, dilated pupils, rhinorrhea, muscle cramps, joint aches and cravings to use opioids). This is mainly a concern for patients transferring from methadone to buprenorphine (and possibly in patients using fentanyl or other HPSOs) but rarely occurs when commencing buprenorphine in patients using heroin or other short acting opioids (e.g., standard release morphine, oxycodone). Strategies for initiating Buvidal treatment are described later.

Drug–drug interactions [20] of clinical relevance include (a) sedation, respiratory depression, and overdose – while considered quite safe when used in isolation, buprenorphine can contribute to sedation, respiratory depression, and overdose in combination with alcohol and other sedating drugs or medications (e.g., benzodiazepines, antipsychotic medications, gabapentinoids); and (b) serotonergic syndrome in vulnerable patients (e.g., concomitant use of relevant medications such as monoamine oxidase inhibitors, SSRIs, SNRIs, TCAs, bupropion, and triptans).

Moderate-to-severe liver disease is a potential precaution when considering long-acting buprenorphine formulations. Moderate-to-severe liver impairment can result in reduced clearance and accumulation of buprenorphine in patients [14], and transmucosal buprenorphine formulations should be prioritized, allowing easier dose adjustments and cessation of buprenorphine treatment if required.

3. Efficacy and effectiveness for Buvidal

Systematic reviews have examined the outcomes of the Buvidal/Brixadi treatment [35,36], usually pooling findings with studies using the alternative LAIB formulation (Sublocade). Two randomized controlled trials [37,38] (n = 547 participants) have compared Buvidal to conventional SL BPN treatment, reporting comparable treatment retention, reductions in unsanctioned opioid use and safety outcomes. An open-label RCT [38] identified superior patient-reported ratings of global satisfaction, effectiveness, and treatment convenience for Buvidal over SL BPN. An observational cohort study [39] identified high treatment retention rates (74%) at 48 weeks in n = 227 patients either initiating treatment or transferring from sublingual BPN treatment. Studies examining the outcomes of prison-based treatment are described later. A pilot study [40] identified the potential for Buvidal to be successfully used for patients with complex treatment needs and poor treatment adherence, although further research is required to identify whether certain patient groups differentially benefit from LAIB or conventional SL BPN treatment. Clinical trials have not directly compared the two LAIB products (Buvidal or Sublocade), nor directly compared Buvidal to other medications such as methadone or naltrexone, although a RCT [41] of the alternate LAIB (Sublocade) to standard of care with either methadone or sublingual buprenorphine demonstrated LAIB achieved greater abstinence from opioids, a comparable safety profile, and was less costly to deliver among participants with more severe opioid dependence.

Randomized trials, clinical experience, and qualitative studies [42,43] of patients in Buvidal treatment highlight that it increases convenience and reduces the burden of treatment engagement for many patients – particularly beneficial for those with social commitments such as employment or childcare, and for those wishing to avoid the stigma of regular dosing at clinics or pharmacies [44]. Buvidal treatment may also be beneficial for those patients who struggle to adhere to treatment with medications requiring daily dosing (e.g., due to homelessness, domestic violence, travel, comorbidities that impair mobility and/or cognition). However, there are also a group of patients for whom Buvidal treatment interferes with their desire to continue to use ‘illicit’ opioids (e.g., heroin) – and who may prefer treatment with medications administered daily (e.g., SL BPN, methadone, diamorphine treatment) [42,43]. For others, daily attendance at a clinic or pharmacy may be preferred – providing an opportunity for more frequent monitoring (e.g., for those with significant medical, psychiatric, or social comorbidities) and/or social engagement for socially isolated patients.

In summary, current evidence indicates that treatment with Buvidal achieves comparable treatment outcomes and favorable patient satisfaction ratings to SL BPN for most patients but does not identify whether SL or LAIB approaches achieve better outcomes for specific patient groups. While many patients prefer treatment with LAIB, some patients prefer alternative treatment approaches, highlighting the importance of (a) patient education regarding the potential benefits and disadvantages of different treatment approaches; (b) shared decision-making between treatment providers and patients in selecting medications that align with each patient’s circumstances and treatment goals and respects patient autonomy; and (c) the opportunity to trial different medications and tailor treatment according to the patient’s experience.

4. Clinical use of Buvidal in treatment of opioid dependence

4.1. Assessment, indications, contraindications

A comprehensive assessment is essential for safe and effective treatment, aiming to identify the patient’s pattern of substance use, prior treatment attempts, key medical, psychiatric, and social conditions, treatment goals, and preferences [10,22].

Buvidal is indicated for the treatment of opioid dependence [21–24]. Buvidal Weekly or Buvidal Monthly should not be administered to people who are hypersensitive to BPN (a very rare condition) or any of the excipients (phosphatidylcholine [soybean], glyceryl dioleate and ethanol [in Buvidal Weekly], and N-methyl-2-pyrrolidone [in Buvidal Monthly]).

4.2. Dosing recommendations

4.2.1. Transferring from sublingual buprenorphine to Buvidal treatment

Transferring from a sublingual BPN treatment is a relatively straightforward process whereby the daily SL BPN dose determines the size of the first Buvidal Weekly or Monthly dose as described in Table 2 [21,22], with clinical titration of subsequent doses. Patients should be reviewed before their next scheduled dose for assessment of the adequacy of the first dose, with supplemental 8 mg Buvidal Weekly doses indicated if the patient is experiencing withdrawal or cravings following the initial dose. In a trial of patients transferring from SL BPN to Buvidal treatment [38], 20 of 60 participants (33%) received a supplementary 8 mg Buvidal dose during the induction period.

Table 2.

Dose conversions between sublingual buprenorphine, Buvidal Weekly and Buvidal Monthly.

Daily SL BPN dose	Buvidal Weekly dose	Buvidal Monthly dose
2–6 mg	8 mg	No Monthly equivalent
8–10 mg	16 mg	64 mg
12–16 mg	24 mg	96 mg
18–24 mg	32 mg	128 mg
26–32 mg	No Weekly equivalent	160 mg

Patients transferring from sublingual buprenorphine can transition to Buvidal Weekly doses or can transition directly to Buvidal Monthly doses. Patients who are anxious about whether the Buvidal injection will ‘work’ or ‘hold them’ can be offered the Buvidal Weekly dose – representing less of a commitment than commencing with Monthly doses, and patients can then change to Monthly doses anytime thereafter

4.2.2. Commencing Buvidal for patients using short-acting opioids

For patients entering treatment with short acting opioids such as heroin, morphine, or oxycodone, treatment can be initiated either directly with Buvidal Weekly, or can commence with SL BPN for one or more doses and then transition to Buvidal Weekly or Buvidal Monthly.

Buvidal Weekly can be initiated directly without the need for a run-in period of SL BPN treatment [21–24]. Buvidal Weekly theoretically has a lower risk of initiating precipitated withdrawal than SL BPN due to the gradual increase in buprenorphine plasma levels with Buvidal Weekly (reaching peak plasma concentrations 16–24 hours after the first dose, compared to 60–90 minutes for SL BPN) [21–24]. This gradual increase in buprenorphine levels reduces the risk of precipitating withdrawal – which arises due to the displacement of opioid agonists from mu receptors by buprenorphine. Hence, whilst most clinical recommendations for initiating SL BPN require the patient to be experiencing mild opiate withdrawal symptoms prior to the first dose of SL buprenorphine being administered, or to use low ‘test doses’ of SL BPN (e.g., 4 mg spaced 1–2 hours apart), treatment with Buvidal Weekly can be commenced without the patient being in mild opiate withdrawal at the time of the first dose.

Initiation of Buvidal Weekly in a patient using heroin or other short-acting opioids involves the administration of a 16 mg Buvidal Weekly dose (or 24 mg in patients with high opioid tolerance), and review of the patient on subsequent days. Routinely, the next Buvidal dose should be administered at approximately 7 days after the first dose – with some flexibility in the timing of the Buvidal Weekly doses ±2 days either side of the 7-day interval (i.e., the next dose can be administered 5–9 days after the last Buvidal Weekly dose).

Patients commencing Buvidal treatment should be instructed that the first dose may ‘wear off’ before the proposed 7 days (often experienced as opioid withdrawal symptoms and/or cravings) or experience side effects (see section 2.4) [45]. Patients should have the option of attending earlier to receive their second dose (e.g., at day 5 or 6) if they are experiencing withdrawal symptoms or can access supplementary Buvidal Weekly 8 mg doses if required before day 5. Supplementary or ‘top up’ doses of 8 mg Buvidal Weekly can be administered – spaced at least 24 hours apart, up to 40 mg total Buvidal Weekly administered over the first 7 days.

Subsequent Buvidal doses should be tailored according to the needs of the patient – maintaining doses if the patient is comfortable, not in withdrawal experiencing cravings or using unsanctioned opioids; increasing the dose if the patient reports withdrawal, cravings or persistent opioid use; or reducing the dose if the patient reports over-sedation or other clinically important side effects (e.g., severe nausea, headaches).

Patients can continue Buvidal Weekly for one or more weeks – or can transition to Buvidal Monthly after the first Buvidal Weekly dose. A guide to transitioning between Buvidal Weekly and Buvidal Monthly doses is shown in Table 2.

Initiating treatment directly with Buvidal Weekly can simplify procedures for patients and service providers compared to commencing treatment with SL BPN, increasing the settings in which treatment can be delivered (e.g., emergency departments). There are nevertheless circumstances where treatment initiation with SL BPN should be considered: (a) the patient has a strong preference to commence SL BPN treatment, (b) the patient has never used buprenorphine before and may be sensitive to side effects (e.g., headache, nausea, sedation), or (c) there may be other safety concerns such as the potential for clinically relevant drug–drug interactions, severe underlying hepatic disease, or other complex medical comorbidities that may be easier to manage using short acting buprenorphine products [22].

4.2.3. Commencing Buvidal for patients using fentanyl or other high potency synthetic opioids

Initiation of buprenorphine treatment may be more complicated in patients using fentanyl or other HPSOs [46]. While fentanyl is a short-acting opioid, its high lipophilicity and mu receptor binding mean that chronic fentanyl use leads to accumulation in fat tissue and re-release back into systemic circulation, such that fentanyl remains present and active on opioid receptors in the brain long after it would normally be expected based on its short half-life (or ability to be detected in urine toxicology) [47,48]. This theoretically increases the potential for precipitated withdrawal when initiating buprenorphine treatment. The evidence remains unclear at this time – anecdotal reports suggest buprenorphine initiation in patients with chronic fentanyl use can cause precipitated withdrawal and complicate buprenorphine initiation. However, a prospective RCT comparing initiation with SL BPN (8–16 mg day 1) or Buvidal (24 mg Weekly dose) in 1200 opioid-dependent patients with recent fentanyl use, identified only 9 cases of precipitated withdrawal (< 1% incidence), with similar rates in both groups (5 in SL BPN arm, 4 in Buvidal arm), and comparable to reported rates among persons using heroin or prescription opioids [47]. A post hoc analysis of an RCT comparing sublingual buprenorphine to Buvidal examined outcomes for patients entering treatment using fentanyl, and identified that whilst generally positive outcomes were achieved in both groups, there were significantly more opioid negative urines in the Buvidal arm (75%) compared to the SL BPN arm (62%), suggesting Buvidal may be more effective in reducing fentanyl use [48], although further studies are required. Greater clinical monitoring and caution is warranted when initiating buprenorphine in patients using HSPOs until research establishes the risk of precipitated withdrawal in patients with chronic use of fentanyl or other HPSOs.

4.2.4. Transferring to Buvidal from methadone treatment

Patients transitioning from methadone to buprenorphine treatment are at greatest risk of experiencing precipitated withdrawal, with the risk greatest in patients attempting transfers from methadone doses greater than 30 mg [34,49]. This is most likely related to methadone’s extended duration of action, with persistent opioid receptor occupancy for days after last dosing.

Transfers from low-dose methadone treatment (< 30 mg) directly to Buvidal are relatively straightforward: stop methadone and delay the first dose of Buvidal Weekly 16 mg until the patient is experiencing at least mild opioid withdrawal symptoms (and at least 24 hours after the last methadone dose). The patient should be reviewed the following day, adding supplementary doses of Buvidal 8 mg Weekly (spaced at least 24 hours apart, to a total of 40 mg Buvidal in the first week) until the patient is comfortable. Subsequent Buvidal Weekly or Monthly doses should be clinically titrated.

For patients transitioning from higher methadone doses (>30 mg), it is recommended they transfer to SL buprenorphine prior to initiating Buvidal treatment. A number of strategies are described in the literature [21,34,49], including “conventional,” “microdosing,” or “bridging” transfers (a full description is beyond the scope of this review). At this time, the literature does not provide clear evidence of the superiority of any one approach, and further research regarding optimal transfer approaches is required.

It should also be noted that a significant minority of patients attempting transfer from methadone to buprenorphine will not remain in buprenorphine treatment for any extended period of time. Estimates suggest up to 20% of patients attempting methadone to buprenorphine transfer seek to return to methadone within the first month [34] – regardless of the transfer approach attempted, or whether patients experienced precipitated withdrawal. This suggests that methadone (a full Mu opioid agonist, N methyl-D-aspartate (NMDA) receptor antagonist and serotonin reuptake inhibitor [50]) is better suited to some patients and emphasizes the importance of allowing patients to return to methadone if buprenorphine does not suit them.

4.2.5. Maintenance doses of Buvidal

Most patients are maintained on Buvidal Monthly doses, administered every 4 weeks, with Buvidal Weekly doses infrequently used for long-term treatment. The four Monthly dose options (64 mg, 96 mg, 128 mg, 160 mg) provide the ability to tailor the dose to the needs of the individual patient. In Australia, the most commonly used doses of Buvidal Monthly are 96 mg and 128 mg doses [51]. Similarly, a study from the USA [52] identified that patients treated for prescription opioid dependence with Buvidal Weekly predominately used 32 mg or 24 mg doses (over 90% of Weekly doses), and almost 80% of Monthly doses were 128 mg or 96 mg doses.

Whilst doses are routinely scheduled to occur every seven (Buvidal Weekly) or 28 (Buvidal Monthly) days, it is recognized that some flexibility is required to accommodate missed appointments, work or travel commitments, appointment availability, etc. To avoid missed doses, the Weekly dose may be administered up to 2 days before or after the 7-day time point (days five to nine), and the Monthly dose may be administered up to 1 week before or after the monthly time point (weeks 3–5).

If a scheduled dose of Buvidal is missed, the next dose should be administered as soon as practically possible. If more than 10–14 days has occurred between doses of Buvidal Weekly, or more than 8 weeks between Buvidal Monthly doses has elapsed, re-induction may be required.

5. Discontinuing Buvidal treatment

Whilst long-term outcome studies of patients discontinuing Buvidal treatment are lacking, we can extrapolate from studies of patients discontinuing methadone or SL BPN treatment. Discontinuation of opioid dependence treatment is often associated with resumption of unsanctioned opioid use – with associated risks of opioid overdose (in the context of reduced tolerance to opioids following the cessation of buprenorphine), and of relapse to regular opioid use and dependence [53]. Consequently, the cessation of buprenorphine treatment should not be recommended for patients with a poor prognosis for relapse [10]. This includes (a) patients who have not achieved an extended period (more than 1 year) of abstinence from unsanctioned opioid use, who continue high-risk use of other substances (e.g., alcohol, cocaine, amphetamine-type stimulants)- and/or are in drug-using social environments, (b) patients with unstable social conditions (e.g., homelessness, domestic violence), (c) patients with unstable medical (e.g., chronic pain) or psychiatric conditions. Under such circumstances, patients should be encouraged to address these conditions before attempting cessation of opioid dependence treatment.

Studies have not identified the optimal approach for ceasing Buvidal treatment. Clinical experience and anecdotal reports suggest that cessation of Buvidal Monthly is associated with mild opiate withdrawal symptoms. A recent prospective case series [54] of patients stopping long-term Buvidal treatment in a residential rehabilitation unit reported mild and generally well-tolerated opioid withdrawal symptoms and cravings, peaking in severity between weeks 5 and 8 after a final dose of Buvidal Monthly 64 mg. The mild withdrawal syndrome is most likely due to the gradual release of buprenorphine from the Buvidal Monthly injection over this time frame.

The severity of withdrawal symptoms on stopping opioid medication is only one factor influencing resumption of unprescribed opioid use, and despite the likelihood that withdrawal severity from Buvidal is milder than withdrawal from SL BPN or methadone, clinicians and patients should prepare for relapse and have management plans to minimize resumption of substance use [10,22]. These include psychosocial support (e.g., relapse prevention counseling, peer-support programs) and provision of take-home naloxone for overdose prevention. Some patients may seek to use naltrexone medication to assist in their abstinence goals. Patients who relapse into unsanctioned opioid use should have the option of resuming Buvidal treatment as soon as possible.

6. Special populations: pain, pregnancy, prisons

6.1. Pregnancy

BPN and methadone treatment, provided with adequate antenatal care, are associated with improved retention in treatment, reduced maternal heroin/other opioid use, and improved antenatal outcomes (reduced fetal death, increased neonatal birth weight, and decreased premature delivery) [55–58]. Buprenorphine is associated with a reduced risk of neonatal withdrawal requiring treatment and improved birthweight and gestational age compared to methadone and is considered a safe and effective first-line treatment for opioid dependence in pregnancy [56–58].

There are limited data on the effectiveness of LAIB products during pregnancy [59]. Buvidal products have more stable blood levels than SL BPN, and the lower level of norbuprenorphine (active metabolite of buprenorphine) in LAIB may be associated with a reduced risk of neonatal withdrawal compared to SL BPN [60]. There are few published data on neonatal withdrawal from Buvidal during pregnancy. The investigators of a randomized trial comparing the effectiveness of sublingual BPN to Buvidal Weekly note that current protocols for managing pain and neonatal withdrawal during pregnancy appear adequate for pregnancies with long-acting buprenorphine exposure [61,62].

Excipients in Weekly and Monthly Buvidal are not of significant concern, although N-Methyl-2-pyrrolidone (NMP), which does cross the placental barrier, is found in monthly Buvidal, and is metabolized within 24 hours [62]. There is preclinical evidence of possible NMP toxicity at much higher doses than a patient would be exposed to using Buvidal products [63].

Individual risk–benefit assessments, including the mother and fetus, are recommended when assessing continuation of Buvidal during pregnancy. After discussion of risks and benefits of continuing or changing treatment, pregnant women treated with Buvidal may choose to transfer to SL BPN. However, the principle of not changing treatment for a stable patient should also be considered [58]. Buvidal treatment can be continued during pregnancy if the benefits for the mother and fetus outweigh the risks.

Switching from methadone to BPN is generally not recommended due to the risks of precipitated withdrawal and associated risk of early labor.

There is a general need to improve breastfeeding rates in women in medication assisted treatment of opioid dependence [64]. Buprenorphine and norbuprenorphine are found in breastmilk [65], in reduced quantities and with poor oral bioavailability, limiting neonatal exposure. Buprenorphine in breastmilk may reduce the likelihood of neonatal withdrawal [66]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Buvidal when breastfeeding. Buvidal should be used during breastfeeding if the potential benefits outweigh the potential risks to the mother and baby.

6.2. Pain management

Buprenorphine has analgesic properties, and certain ‘low dose’ buprenorphine formulations are licensed for the management of acute or chronic pain (e.g., sublingual tablets, topical patches) [67]. However, neither ‘high dose’ sublingual buprenorphine nor LAIB formulation is licensed nor indicated for the treatment of pain in the absence of an opioid use disorder. There are two clinical scenarios to be addressed when considering pain management in patients in Buvidal treatment.

6.2.1. Acute pain management

Patients in buprenorphine treatment for opioid dependence frequently encounter episodes of acute pain (e.g., dental pain, motor vehicle accidents, falls). Acute pain management can be complicated by buprenorphine treatment; nevertheless, safe and effective acute pain management approaches in patients in Buvidal are available [67].

Mild acute pain may be effectively managed using non-opioid medications (e.g., NSAIDs, paracetamol) and physical therapies (e.g., acupuncture [68], physiotherapy).

The management of moderate or severe acute pain (e.g., dental pain, acute trauma) may require the use of opioid analgesia if non-opioid approaches are ineffective. Reviews examining perioperative pain management in patients treated with SL BPN arrived at similar recommendations [69,70]. Extrapolating from these reviews, the following approaches can be used for Buvidal patients requiring management of moderate or severe acute pain:

1. continuation of Buvidal treatment (surgical excision of recent Buvidal injection sites is not recommended) or transfer to SL BPN if Buvidal unavailable. This is preferable to ceasing BPN due to the need for lower total opioid agonist doses, better pain management, and better coordination of ODT on release from hospital.

2. addition of full agonist opioid analgesics (e.g., oxycodone, hydromorphone, morphine) titrated to clinical effect – usually requiring higher than usual doses to achieve effective pan relief (due to opioid receptor blockade and opioid tolerance that occurs with chronic buprenorphine treatment, and/or opioid hyperalgesia in opioid dependent patients). Education of patient and hospital staff regarding the need for higher opioid doses can allay concerns that the patient is ‘drug-seeking.’

3. addition of multimodal pain strategies (e.g., non-opioid medications, physical and psychological therapies)

4. coordination with community ODT providers is essential for hospitalized patients to ensure a smooth transfer of care and pain management strategies.

Case studies demonstrate effective perioperative pain management using this approach [71,72] (albeit for the alternate LAIB formulation).

6.2.2. Chronic pain management in patients in Buvidal treatment

Chronic pain is common among patients in ODT – estimated at approximately 44% in a recent review [8] and may be managed or ‘masked’ by high doses of methadone or BPN. General principles of chronic pain management should be followed [73], and include

• patient education, self-management, and engagement in the treatment process,

• use of non-opioid medications (e.g., antidepressants, NSAIDs, paracetamol, gabapentinoids),

• psychological (e.g., Cognitive Behavioral Therapy) and physical therapy (e.g., exercise, physiotherapy) interventions

• coordination across service providers.

BPN itself is an opioid analgesic widely used in chronic pain management, with low doses (tablets and extended release 7-day topical patches) buprenorphine formulations indicated for the treatment of chronic pain in many countries [67]. There is an increasing experience in the use of high-dose buprenorphine products in patients with combined chronic pain and opioid dependence [74,75]. The potential benefits of high dose BPN in chronic pain treatment include the enhanced safety of BPN compared to other opioids (less respiratory depression, overdose, mortality, and fewer adverse effects), ability to use across a broad patient spectrum (drug clearance does not change with age, renal impairment, or mild hepatic impairment); BPN is associated with less opioid hyperalgesia compared to many other MOR agonists [67]. Concerns regarding the limited analgesic potential due to ‘ceiling effects’ of BPN have proven to be unfounded [76,77].

To date, the most experience in using BPN to treat patients with chronic pain and opioid dependence is with the use of high dose SL BPN formulations [78,79]. A systematic review identified rotation to high dose BPN from other opioids in pain patients resulted in comparable or improved pain outcomes c/w treatment with MOR full agonists, and considerably better outcomes than opioid taper and discontinuation [80]. Clinical experience suggests that most patients treated for combined chronic pain and opioid dependence require high SL BPN daily doses (e.g., commonly >16 mg daily) [81], and that pain outcomes may be improved with split daily dosing rather than single-day dosing.

To date, there is limited published evidence regarding LAIB products in chronic pain management, and no evidence directly comparing LAIB with other buprenorphine formulations or methadone in patients with chronic pain and opioid dependence. Nevertheless, the clinical experience of the authors suggests that some patients with both chronic pain and opioid dependence have better pain outcomes when treated with LAIB products than SL BPN – presumably due to the more stable plasma levels achieved with LAIB, the continuous release of LAIB over time compared to once- or twice-a-day doses of SL BPN, and the ‘behavioral disconnect’ between pain symptoms and medication use afforded by Buvidal. However, other patients report poor outcomes when transitioning from SL BPN to LAIB and prefer the ability to adjust their use of SL BPN in response to pain or other symptoms. Further research is required to establish the role of LAIB products in the management of patients with both chronic pain and dependence.

6.3. Custodial settings

Illicit opioid use is highly prevalent in some custodial settings, where access to healthcare including addiction treatment may be limited. Medication assisted treatment for opioid dependence reduces drug use, re-incarceration and is linked to improved treatment engagement post-release [82]. Extended-release formulations of buprenorphine have emerged as a promising treatment option in these settings.

Buvidal has been shown to be a safe and effective treatment in custodial settings [83–85], associated with reduced illicit/unsanctioned opioid use in prison (including reduced risk of diversion and non-medical use), good treatment retention, and high levels of satisfaction among patients [86] and staff [87] in custodial settings. Buvidal has as a subcutaneous injection. Buvidal has reduced healthcare and correctional costs compared to sublingual BPN or oral methadone in custodial settings [88,89] allowing more effective use of resources in custodial settings.

Assessment of patients in custodial settings must consider recent patterns of opioid use (type of opioid, dose, frequency, and route of use). Lower induction doses and/or the use of sublingual doses may be required for those assessed to have lower level of opioid tolerance [90].

Smooth transfer of treatment from correctional to community settings post-release is important. The protective effect of ongoing opioid assisted treatment on reducing opioid overdose risk requires an effective transfer of care between custodial and community settings [90]. There may be occasions where community service providers do not have access to Buvidal or where the patient would prefer SL BPN treatment, and in these situations transfer to other buprenorphine formulations can occur.

7. Future perspectives

The introduction of LAIB products is a significant advance in the delivery of effective opioid dependence treatment, enabling treatment models that require patient attendance only at monthly intervals. Together with advances in the delivery of medical and counseling services by telemedicine, we now have opportunities for more flexible service delivery models with the aim of increasing treatment access. It enables opioid dependence treatment to be scaled up in regional, rural, and remote areas [91], and in institutional settings in which treatment was previously difficult to implement, such as hospital and custodial settings. It also creates opportunities for the expansion of treatment in countries that may not have the infrastructure to establish widespread treatment services required for daily dosing. Buvidal (which does not require refrigeration) may also be useful in emergency situations where usual health services are disrupted by wars, conflicts, or environmental catastrophes (e.g., floods, fires).

As with any treatment innovation, however, establishing its effectiveness does not guarantee its uptake into routine usage. Implementation science methods [92] are required to enhance the uptake of LAIB in these populations and new treatment settings. Indeed, there has been marked variation between counties in the uptake of LAIB treatment to date. Some countries have seen marked uptake of LAIB (for example, it accounted for approximately a third of all opioid dependence treatment in Australia within 4 years of its introduction [51]), whereas there has been less uptake in other countries [93]. Implementation research examining the barriers and facilitators of innovation uptake will enable us to upscale new treatments more effectively in this area of medicine.

As with long-acting depot formulations in mental health settings, LAIB also has the potential to attract and retain patients with poor medication adherence – often due to social conditions (e.g., homelessness, domestic violence), polysubstance use, cognitive, physical, or mental health difficulties. On its introduction, many clinicians considered LAIB as a treatment option best suited to ‘stable’ patients who do not require frequent monitoring or review. However, there is increasing interest (based on mounting clinical experience) in examining the role of LAIB as a front-line treatment for hard-to-treat populations (e.g., patients with social risk factors, high-risk polysubstances, or severe mental health conditions [94]), and further systematic enquiry is warranted to better understand the role of LAIB in these populations.

There will be many patients for whom treatment with LAIB is not preferred or most effective, and patients should have the opportunity to access a range of treatment services that best meet their individual needs. Further research is required to establish whether different treatment options (e.g., methadone, SL BPN, LAIB, diamorphine, naltrexone) achieve better outcomes with certain patient groups, although in practice, patient preference and treatment availability often direct the choice of medication ahead of evidence from systematic reviews. In this regard, patients need access to culturally appropriate information regarding their treatment options, and codesign principles should be used to develop consumer information suited to local communities.

There remain a number of unknown questions or areas of interest regarding the use of LAIB in clinical practice. The potential for LAIB in treating patients with chronic non-cancer pain and opioid dependence is considerable, requiring further exploration. Many patients struggle to safely transfer from methadone to LAIB treatment, and further research is required to find simple and convenient approaches for patients to transfer from moderate or high methadone treatment (>40 mg). The cessation of LAIB dosing appears to be associated with mild opiate withdrawal syndrome and may prove to be a significant advance in assisting patients to successfully cease treatment. However, cessation of opioid treatment is historically associated with poor outcomes (including increased mortality and relapse to opioid use), and further research is required to better support patients seeking to successfully discontinue treatment.

8. Conclusion

Buvidal/Brixadi is a long-acting subcutaneous injection that allows for once-a-week or once-a-month dosing of buprenorphine for the treatment of opioid dependence. Clinical trials indicate Buvidal has comparable safety and efficacy compared to sublingual buprenorphine regarding the outcomes of illicit opioid use and treatment retention, and is superior for patient satisfaction outcomes. Doses should be titrated for individual patients, with four Weekly (8, 16, 24, 32 mg) and four Monthly (64, 96, 128, and 160 mg) dose options available, allowing flexibility in the frequency and size of doses.

Buvidal can be initiated directly in patients entering treatment using heroin, prescription opioid medications (e.g., oxycodone, morphine, hydromorphone), or high potency synthetic opioids (e.g., fentanyl, nitazenes). Caution is required when transferring patients from methadone, with a range of approaches available to minimize the risk of precipitated withdrawal. Patients may experience mild opioid withdrawal syndrome on stopping Buvidal.

Buvidal increases the range of treatment options available for opioid dependence and is particularly well suited to patients or settings (e.g., rural, prison settings) where regular attendance for dosing is difficult to sustain. Alongside medication, safe and effective treatment involves regular clinical review and monitoring and addressing comorbid health and social conditions using collaborative decision-making principles with patients.

Funding Statement

This paper was not funded.

Article highlights

• Buvidal/Brixadi is a long-acting injectable buprenorphine (LAIB) administered subcutaneously weekly or monthly, providing more stable plasma levels with lower peak-trough fluctuations compared to sublingual buprenorphine (SL BPN).

• RCTs show non-inferiority to SL BPN in treatment retention and reducing illicit opioid use, with superior patient satisfaction (convenience, effectiveness, and reduced stigma). Approximately 5–10% of patients experience local injection site side effects (transient pain, redness, swelling), alongside side effects common to other buprenorphine formulations.

• The clinical advantages of Buvidal include:

• Flexible initiation: Can commence treatment directly with Buvidal Weekly (16–24 mg doses) without the use of sublingual buprenorphine in people using short acting opioids (e.g., heroin, prescription opioids) with a lower risk of precipitated withdrawal. Patients using fentanyl or other high-potency synthetic opioids require cautious initiation of treatment with frequent monitoring. Transfer between buprenorphine formulations (e.g., sublingual buprenorphine) is simple. Some patients may experience precipitated withdrawal if transferring from methadone, and as such, direct transfer to Buvidal should only occur in patients transferring from low-dose methadone (≤30 mg) treatment.

• Simplified dosing: Most patients stabilize on Buvidal Monthly (64–160 mg), with doses every 4 ± 1 weeks, allowing some flexibility.

• Reduced treatment burden (fewer clinic visits) can lower barriers to treatment (e.g., employment, rural/remote access, stigma).

• Discontinuation: Most patients experience mild opiate withdrawal symptoms following cessation of treatment, peaking at 5–8 weeks post-last dose. Patients require ongoing care and relapse-prevention support when trying to discontinue treatment.

• Buvidal can be used in patients requiring pain management. For severe acute pain, full opioid agonists (e.g., oxycodone) can be added at higher doses; avoid discontinuing Buvidal. For chronic pain: LAIB may improve stability vs. SL BPN; further research is needed. Buvidal can be continued in pregnancy if the benefits of treatment outweigh the risks; stable levels may reduce neonatal withdrawal vs. SL BPN.

• Buvidal is being increasingly used in custodial settings: with reduced diversion risks, better treatment retention, and lower costs compared to daily-dosing therapies (e.g., methadone, SL buprenorphine).

• There is considerable potential for LAIB to enhance scalability in resource-limited regions and emergency settings. There is an urgent need for implementation research to address uptake disparities. Further research is required to examine the role of LAIB in patients with complex presentations (e.g., polysubstance use, social and health comorbidities).

• In conclusion, Buvidal/Brixadi expands opioid dependence treatment options with comparable efficacy to SL BPN, superior convenience, and applicability across diverse populations (e.g., pain, pregnancy, incarceration). Tailored dosing and shared decision-making are essential for optimizing outcomes.

Author contributions

N.L.: Conceptualization, Methodology, Writing (Original Draft, Review & Editing), Oversight, and leadership responsibility for research activity planning and execution; A.J.D.: Writing: Original Draft, Review & Editing.

Disclosure statement

N. Lintzeris has received honoraria from Camurus AB (manufacturer of Buvidal) and Indivior (manufacturer of a range of buprenorphine products) for providing professional education symposia and lectures at international and national conferences (but no funding support for travel or accommodation). The employer of N Lintzeris (South Eastern Sydney Local Health District) has received research funding from Camurus AB to undertake research trials using Buvidal. A. J. Dunlop: The employer of A. J. Dunlop (Hunter New England Local Health District) has received research funding from Camurus AB for undertaking research trials using Buvidal and from Indivior undertaking research trials using Sublocade. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

A reviewer on this manuscript has disclosed “I am a research advisor to Braeburn (markets Brixadi) in the US, I have received honorarium from Camurus for developing and giving a talk about LAI-buprenorphine, and my institution/University received research funding from Braeburn in the past to conduct a Phase 3 trial of Brixadi (I was PI of the grant – no personal fees received).” Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose