Compared implementation of the long-acting buprenorphine treatment buvidal in four European countries

ABSTRACT

Background

Buvidal is the only depot buprenorphine currently available in Europe. Buvidal offers a new treatment paradigm, which may require some adjustment in the national regulatory frameworks for opioid agonist treatments (OATs), as well as the national care systems.

Research design and methods

Data on the national dissemination of Buvidal, types of populations treated, and the national regulatory framework and care organization system through which Buvidal has been implemented were compared between the UK, Finland, Spain, and France, using a qualitative survey.

Results

In 2022, the proportion of people on OAT who received Buvidal was 2.1% in the UK, 60–65% in Finland, 1% in Spain, and 0.3% in France. In both Finland and the UK, the cost of the medication is covered by the national health system, whereas, in Spain and France, Buvidal is accessible only in specialized centers, which must carry its cost. Other national features may explain the gaps in Buvidal use, including the baseline level of OAT coverage, which was high in both France and Spain

Conclusions

Important national discrepancies are found regarding Buvidal dissemination among people on OAT

KEYWORDS:

• Buprenorphine
• buvidal
• UK
• Finland
• Spain
• France

1. Introduction

Opioid use disorder (OUD) is a severe behavioral disorder, associated with difficulty to control opioid use, thus progressively leading to severe health and social consequences [1]. Buprenorphine and methadone are the most common medicines used for OUD [1,2]. They belong to the category of opioid agonist treatments (OATs), which are classically used as a safer replacement of the opioid causing OUD [1,2]. Other pharmacological options exist, including opioid antagonists such as naltrexone, which is used in a very different way, as it is has an antagonist action on opioid mu receptors so it requires that the patient be detoxified for opioids before being used [1,2]. By contrast, OATs activate opioid receptors, thus reducing withdrawal and craving, as well as the need to obtain drugs on the illicit market [1,2].

While OATs have classically been based in oral or sublingual forms, which are commonly taken on a daily basis, new long-acting formulations of buprenorphine have been commercialized for a few years. These formulations consist of either implant or depot forms, which are pharmacologically effective for periods of time ranging from one week to six months [3]. Among them, Buvidal is the first depot formulation of buprenorphine that has received a centralized European labeling [3]. The encapsulation of buprenorphine in Buvidal is performed using a lipid-based liquid named FluidCrystal® (soybean phosphatidylcholine and glycerol dioleate), and the depot form spontaneously and gradually dissolves into the body, thus releasing buprenorphine steadily, and with no removal procedure [3].

While Buvidal was progressively marketed in different European countries, surveys among opioid users [4–6], as well as expert guidance publications [3,7,8], led toward a set of preferred populations, in whom the features of a long-acting OATs may be more suitable and effective. Overall, these preferred populations consist of: (1) opioid users living in regions with lower medical coverage; (2) those leaving highly supervised facilities (e.g. hospital, or prison), who can thus be exposed to the risk of both overdose and withdrawal; (3) opioid users who divert or misuse sublingual forms of buprenorphine or methadone; and (4) former opioid users with a protracted period of cessation of opioid use (on opioid agonist treatment), and who no longer wish to take a daily treatment.

This selection of preferred populations was not specific to Buvidal, as it could perfectly apply to the other depot form of buprenorphine, i.e. Sublocade (Indivior), or, to some extent, to the implant form Sixmo (Titan). In practice, however, Sublocade has not been approved at this stage by the European Medicines Agency. Moreover, while Sixmo is approved in Europe, some specificities of the European approval clearly limit its utilization, in particular, the fact that it should not be used more than one year [9]. This imposes a step backward and a return into the sublingual form, which is hardly acceptable by opioid users. All put together, Buvidal remains at this stage the most widespread long-acting buprenorphine treatment across Europe.

A few years after Buvidal was progressively available across Europe, we wanted to explore how this new formulation of buprenorphine has been implemented in practice and in which type of patient groups it has been used. We performed a compared approach in four European countries, i.e. the UK, Spain, Finland, and France, respectively.

2. Methods

There was no patient involvement in this study, which was a qualitative survey consisting of gathering a series of data and organizational features from four European countries, i.e. the UK, Finland, Spain, and France, respectively. These four countries were identified with the objective to cover different areas within Europe, including Northern and Southern countries, as well as countries in and out of the European Union. The experts who participated in the study were Catriona Matheson for the UK, Carlos Roncero for Spain, Ari Kaski for Finland, and Florence Vorspan for France, respectively. All experts were chosen due to their knowledge on their national system on OST provision. They were contacted on 2 March 2023, with responses due for 1 May 2023. The specific questions were asked in English to the experts. They are listed in Table 1. For every answer provided by each national expert, the first author wrote a synthesis which was subsequently verified, corrected, and validated, by the expert. The four experts also participated in the final discussion of the results.

Table 1. Questions asked to the four different experts, representing four different European countries, about Buvidal and its implementation in their country.

What is the overall percentage of Buvidal in all OUD treatment and all types of buprenorphine in the past 3 years?
(2) Can you describe the medication circuit of Buvidal in your country (who can prescribe and deliver it? How is it reimbursed? Are there obstacles in the medication circuit that restrains the access to Buvidal®?)
(3) Compared to how methadone and sublingual buprenorphine are prescribed and dispensed in your country has the arrival of Buvidal on the national market changed the way patients access treatment?
(4) Apart from the 4 above-mentioned expected conditions addressed (first treatment access, leaving prison or inpatient detoxification, unstable patients diverting a previous OAT, stable patients tired of every day treatment use) have you prescribed Buvidal for other clinical situations?
(5) Are other types of patients receiving Buvidal?
(6) What future challenges do you identify regarding the implementation of Buvidal in your country ?

Ethical approval to conduct this survey was not required. The only data collected were aggregated national sale data, which did not require the agreement of the treated patients.

3. Results

Responses were provided by experts between April and August 2023. The completed sheets provided by the experts are available on demand. The key features of each country are displayed below. The main results regarding the situation of Buvidal in the four countries are displayed in Table 2.

Table 2. Synthesis of the main results regarding the situation of Buvidal in the United Kingdom, Finland, Spain, and France, respectively.

	United Kingdom	Finland	Spain	France
Proportion of people on OAT treated with Buvidal. In 2022	~2.1%	~60–65%	~1%	0.3%
Reimbursement of Buvidal by the national health insurance system	Yes	Yes	No	No
Buvidal prescribers	Any physicians, and non medical prescribers (nurses, pharmacists) with additional training	Specialized health care units	Specialized health care units	Specialized health care units
Dispensation of Buvidal in community pharmacies	Yes	No	No	No
Impact of Buvidal marketing on access to treatment	Reduction in the attendance of dispensation centers	Increase in the accessibility of OAT	No real impact	No real impact
Main categories of public concerned by Buvidal	All public with OUD	Buvidal is now the first-line OAT in the country	Incarcerated patients, those with limited compliance	Incarcerated patients, OAT diversion, stable patients
Future challenges about Buvidal in the country	Increasing drug storage facilities in clinics and pharmacies	No real challenge	Lifting regulatory barriers that restrain the access to Buvidal	Lifting regulatory barriers that restrain the access to Buvidal

OAT: opioid agonist treatment.

OUD: opioid use disorder.

3.1. United Kingdom

3.1.1. Proportion of people treated with Buvidal in the UK

Regarding the proportion of people treated with opioid agonist treatments who received Buvidal in the UK, no data was available for 2020 because it was the year of introduction of the formulation in the country. Among all patients treated with an opioid agonist treatment in the UK, people on Buvidal represented 0.9% in 2021, and 2.09% in 2022 [10–13]. Nevertheless, these figures represented an average number, while there were important discrepancies between the different British states. For example, proportions ranged from 0.04% of all patients treated with opioid agonist treatments in Northern Ireland in 2022, to 5.42% of the same type of patients in Scotland (for complete data, see supplemental materials). Regarding the proportion of people treated only with buprenorphine, the average percentage of patients who have received Buvidal was 3.30% in 2021, and 7.33% in 2022. Here also, important geographical gaps have been found, as only 0.08% of people treated with buprenorphine in Northern Ireland in 2022 received Buvidal, vs. 20.75% of the same population in Scotland.

3.1.2. Medication circuit of Buvidal in the UK

In the UK, the cost of treatment is covered by the NHS although there may be private clinics in which individuals bear the cost, but these are few. Buvidal can be prescribed by both medical and non-medical prescribers, that is, pharmacists and nurses. In this model non-medical prescribers prescribe under what is called a ‘patient care directive’ which is issued by a clinician and allows a qualified prescriber to prescribe under restricted conditions. Pharmacists are more often independent prescribers in which they make clinical decisions and prescribe accordingly in their specialist clinical area. The administration of Buvidal takes place either in a clinic linked to a specialist drug services or, more rarely but increasingly, in a community pharmacy. In theory, GPs can prescribe and administer Buvidal, or get a practicing nurse to administer it, but, in practice, that is currently rare. The majority of the population treated is prescribed in specialist drug services, and it is , usually, a nurse or specialist pharmacist who administers it. Buvidal is stored on site in a controlled drugs cabinet which requires a UK government Home Office license. Community pharmacies hold these licenses for storage of all ‘controlled opioid drugs dispensed in the community.

3.1.3. Impact of Buvidal marketing on access to treatment

Buvidal has changed access to treatment in the sense that the vast majority of methadone and sublingual buprenorphine was previously dispensed via a community pharmacy, and often taken under the direct supervision of the pharmacist. Now some people do not need to attend the pharmacy at all, or certainly not as often, even if they may still need to collect other medication. Buvidal is thus largely administered in specialized drug centers although there is a small but increasing number of pharmacies who have developed administration schemes happening, particularly in Scotland [14], or initially in the Essex [15].

3.1.4. Main categories of public concerned by Buvidal

Buvidal is used for OUD which is largely related to illicit drug use. However, anecdotal discussions between clinicians indicate there are some patients seen through addiction services who had OUD via an opioid analgesic route that have received Buvidal. There is no specific, defined pathway for using Buvidal for opioid analgesic use disorder yet, but this is an area under discussion for expansion.

Buvidal is also used in prison. One early adopter of Buvidal was the prison service in Scotland [14]. This was accelerated during the pandemic to minimize prisoner queuing and contact during Covid 19. An evaluation has been conducted which reported good patient satisfaction [16]. Another area of interest is using Buvidal in the homeless population. This has been explored in a study covering Wales (as early adopters), England and Scotland [17].

3.1.5. Future challenges about Buvidal in UK

The main challenge in the UK is for storage of Buvidal in drug services who do not have appropriate storage facilities (i.e. controlled drugs cabinets). Drug storage of controlled drugs requires a license from the UK Government Home Office, which takes time and costs money. For this reason, many drug services do not have this license. A way around this is to prescribe and ask a community pharmacy to store in their controlled drugs cabinet on a named patient basis, until required. There are also other long-acting buprenorphine injections coming to market now (Sixmo and Sublocade). Whilst Buvidal is now included on local formularies and can therefore be prescribed under the NHS, these other products will take longer or might not get approval in all areas. These decisions are made locally and based on cost-effectiveness information.

3.2. Finland

3.2.1. Proportion of people treated with Buvidal in Finland

The last official Finnish data is from year 2019. At that time, it was estimated that there were 4,729 patients on OAT in total. Of them, 12% were on buprenorphine depot-injection (only Buvidal, as no other options were available), while 52% of them were on buprenorphine-naloxone and 35% on methadone [18]. No yearly data after that form is available, but it is likely that the proportion of patients on Buvidal has increased since then, since recent documents provided by Camurus estimated that even up to 60–65% of all patients treated with OAT in Finland were receiving Buvidal.

3.2.2. Medication circuit of Buvidal in Finland

According to the Finnish legislation, an OAT can be provided only in units with qualified medical staff and facilities [19]. Licenses to dispense OAT are provided and regulated by regional state administrative agencies. The treatment costs are covered by wellbeing services counties, either they provide the service by themselves or buy some or all from private healthcare. The wellbeing services counties are financed by the state. The only exception is the buprenorphine-naloxone delivered by community pharmacies. In these cases, the patient must pay part of the medicine costs themselves, the rest is covered by national healthcare insurance. As any other OAT, Buvidal may be administered by licensed health care units. The medication is provided to patients with no costs, as the expenses are covered by wellbeing services counties, which are responsible for health care services regionally. In Finland, OATs are usually initiated in addiction services or other special health care, but also in primary health care by a qualified physician and medical staff. Usually, with sublingual buprenorphine or methadone, the treatment begins with daily supervised dosing, and take-home dosing is possible only after a period of time after induction, usually from weeks to months, depending on the center. In many clinics, the cessation of substance abuse is necessary for take home-dosing, and this is controlled by regular urine drug screens. Buprenorphine can also be delivered by community pharmacies.

3.2.3. Impact of Buvidal marketing on access to treatment

The arrival of Buvidal has vicariously increased the accessibility of OAT, by making the treatment less binding by longer dosing intervals compared to sublingual buprenorphine, thus possibly making the treatment more desirable.

3.2.4. Main categories of public concerned by Buvidal

Healthcare services in prison use Buvidal routinely for people with OUD in Finland [20]. Moreover, Buvidal is a frequent option for patients diverting methadone or buprenorphine. A specific feature of Finland is that the main cause of OUD is buprenorphine misuse [21]. An initiation of OAT thus very frequently results from a misuse of buprenorphine purchased on the black market. Last, Buvidal is also a frequent option for stable patients who prefer receiving a monthly dosing.

3.2.5. Future challenges about Buvidal in Finland

There is no real challenge about Buvidal in Finland, as long-acting formulations of buprenorphine are widely used in Finland, and even considered as a first-line option of OAT since it is considered safer and less binding than other OATs. Most of the time, sublingual buprenorphine is now used only in case of contraindication for long-acting formulations of buprenorphine or tolerability or adherence issues.

3.3. Spain

3.3.1. Proportion of people treated with Buvidal in Spain

Buvidal was approved in Spain in November 2020. According to Camurus national data, the percentage of people on OAT treated with Buvidal was estimated to reach 0.5% in 2021, and 1% in 2022.

3.3.2. Medication circuit of Buvidal in Spain

Buvidal prescription can be performed by any psychiatrist or any physician from an addition center or a prison healthcare service. Buvidal dispensing is provided only in hospital pharmacies or equivalent [22]. Before Buvidal initiation, patients should receive sublingual buprenorphine/naloxone [22], as no buprenorphine alone is labeled in Spain. Buvidal is free for patients [23].

3.3.3. Impact of Buvidal marketing on access to treatment

The arrival of Buvidal has not radically changed the conditions of access to OAT in Spain, in the sense that initiating Buvidal must fulfill the same circuit than other OATs. Moreover, the fact that the dispensation must be performed only by a hospital pharmacy, as well as the costs of the medication, which falls under the hospital budget, are major brakes to the initiation of long-acting forms of buprenorphine.

3.3.4. Main categories of public concerned by Buvidal

Healthcare services in prison are the main categories of facilities which have shown an interest in Buvidal. The other populations concerned are those who exhibit insufficient compliance and/or insufficient stability on sublingual buprenorphine. There are not so many reflections at the national level on how to optimize Buvidal by selecting the most suitable populations of patients with OUD.

3.3.5. Future challenges about Buvidal in Spain

Barriers to Buvidal access in Spain are many and should be addressed. The regulatory requirements for Buvidal prescription are important and should be alleviated. The education of OAT prescribers should also be improved, as many physicians are not sufficiently aware of the advantages and benefits that long-acting forms of buprenorphine can provide, for both patients and the society.

3.4. France

3.4.1. Proportion of people treated with Buvidal in France

Since its marketing in 2021, the observed dissemination of Buvidal in France has remained more than marginal, with only approximately 600 patients treated at least once with Buvidal, according to Camurus internal data. As the estimated total number of people receiving a prescription of OAT at least once a year in France is 180,000 [24], this makes approximately 0.3% of them on Buvidal.

3.4.2. Medication circuit of Buvidal in France

The prescription of Buvidal in France is restricted to physicians belonging to hospitals or outpatient specialized centers [25]. While advanced nurses do exist in France, their importance on the field has regrettably remained limited so far. Only a hospital pharmacy can dispense Buvidal, while community pharmacies cannot. This is unusual in the French system of access to OAT, in particular the access to buprenorphine, which has largely been based on GPs and community pharmacies so far (see below). Moreover, while the average cost of a monthly treatment with sublingual buprenorphine is 56 €, Buvidal average cost is more around 300 €. This cost has to be assumed by the hospital on the constrained annual budget provided by the French state. Some extra budgetary envelopes have been bestowed by the Ministry for Health, via the National Health Agencies, but these funds are not sustainable at this stage, and they remain very limited since they do not allow at all to treat all possible candidates for Buvidal.

3.4.3. Impact of Buvidal marketing on access to treatment

Given the points explained above, the marketing of Buvidal has had almost no impact on the general landscape of OAT access in France, in which the primary model is based on a large and swift access to sublingual buprenorphine, which is prescribed by GPs, and dispensed by community pharmacies. Moreover, the supervision of treatment compliance is relatively limited in France, and, with respect to buprenorphine, patients can be delivered their doses for one month very quickly after initiation. In this situation, the benefits for patients treated by sublingual buprenorphine for switching to Buvidal, or another long-acting buprenorphine, are more limited, compared to countries in which sublingual buprenorphine is dispensed on a daily basis or several times per week. In such countries, the switch into a monthly treatment can be more easily perceived as a gain of freedom by patients [26]. Moreover, due to the restrictions for dispensing Buvidal in France, that is, only in hospital pharmacies, and at their cost, the practical implementation of this new treatment option was extremely limited.

3.4.4. Main categories of public concerned by Buvidal

The French state has issued that Buvidal should be preferred in prison settings [27]. Apart from that, the main clinical situations for which Buvidal is used are patients who divert methadone or buprenorphine and are offered a one-month treatment rather than a daily supervised oral treatment, and very stable patients willing to avoid an oral daily intake, even if they have a one-month take-home dispensation.

3.4.5. Future challenges about Buvidal in France

France, in a similar way as other European countries, is facing a general context of a rising demand of OAT, in particular as there is an increase in the number of patients developing an OUD after being prescribed painkillers. In addition, there is a dramatic wave of nurses and doctors leaving the public health system. For all these reasons, long-acting forms of buprenorphine should be largely promoted. However, despite French authorities have stated a reasonable evaluation of the therapeutic value of Buvidal, compared to previous sublingual formulations, there remain considerable structural obstacles to the access of Buvidal in France. It is important that national and regional decision makers understand the benefits that long-acting buprenorphine can represent for people with OUD and the general healthcare system in general, and thereafter contribute to alleviate the current barriers to the access of long-acting forms of buprenorphine.

4. Discussion

The main objective of this study was to describe and compare the on-the-ground implementation of Buvidal in four European countries, that is, the UK, Finland, Spain, and France, respectively. Overall, we have found very heterogeneous situations. Whereas, Buvidal has rapidly become a relatively common type of OAT in Finland, it has remained a more limited option in the UK and Spain so far, while its use in France is still anecdotal. If some similarities can be found between the access of Buvidal across the four countries (e.g. it is free of costs for patients), there are also some important differences that may contribute to explain the gaps observed in Buvidal uptake.

First, while the costs of Buvidal are directly covered by the community in Finland and the UK, they remain at the charge of the hospitals in both France and Spain, which may contribute to restrain its use by addiction treatment centers and hospital pharmacies. Moreover, in the UK, Buvidal is accessible in community pharmacies, whereas it is not the case in France, Spain, and Finland, respectively. However, other factors should also be taken into consideration, in particular the pre-Buvidal OAT treatment coverage in the four countries. Spain and France had amongst the highest rates of OAT treatment coverage, i.e. 90% for Spain, and 80% for France [28], while it has been estimated to reach 40% to 50% in Finland [29], and in a similar range in the UK − 45% for Scotland and 54% for England [30]. Consequently, another possible factor for the limited success of Buvidal in both France and Spain was that the need to increase treatment coverage was lower in these two countries. However, increasing the access to OATs should probably not be the only reason for implementing long-acting formulations of buprenorphine, as, relative to sublingual forms, long-acting buprenorphine increases quality of life and the overall patient satisfaction [31].

Regarding the initial target populations, reports from the UK, Finland, and France suggest that prison settings have been prioritized, even if the intention in France was not actually achieved. People who bear neither sublingual buprenorphine forms nor methadone, those who want to stop daily intake, or those who misuse buprenorphine, also constitute the main candidates for a Buvidal treatment, in the four countries studied. A few reports mention the particular interest of Buvidal for people with prescription analgesic OUD, although this use seems to have remained extremely limited so far. Overall, the initial preferred populations for which long-acting formulations were identified with a specific interest [3–7] have had an enhanced access to Buvidal. However, in Finland and in the UK, it seems that Buvidal has not been particularly prioritized for target populations, but largely offered to any patient with OUD.

The future challenges about Buvidal and other long-acting buprenorphine formulations largely differ, depending on each of the four countries studied. While Buvidal is well-established in Finland, the access to long-acting forms in the UK could be enhanced by an improved regulatory system of storage. By contrast, the situation in Spain, and even more in France, reflects some issues in the implementation of Buvidal in the national OUD healthcare system. The obstacles may be related to the specificities in the medication status, which have been addressed above, and in particular the impossibility for community pharmacies to deliver it, even if it is also the case in Finland, where Buvidal is widespread. Thus, the very limited success of Buvidal in Spain and France could also be related to a lack of interest by the healthcare community, possibly in part because the access to OAT is relatively easy in the two countries, and Buvidal might not have been perceived as a particularly expected new option.

Though it highlighted some important discrepancies in the implementation of Buvidal in four European countries, our study has some limitations. First, the choice of the four countries was quite discretionary. We aimed to compare countries from both the Northern and Southern parts of Western Europe as Buvidal is not available in Eastern European countries. However, exploring the same questions in other countries could have been worthy, for example, in Italy, which now has an electronic health record system for supervising OAT [32], or in Germany, which is the most populous country of the European Union, and has a national system of OAT access which is in part based on GPs [33], which is similar in some aspects to what exists in France. Another limitation of our study is that only one expert was contacted in each of the four studied countries. A panel of national experts might have brought more detailed answers and would have allowed for a checking of the data and regulatory features provided at the national level. Moreover, we did not have any validated framework to compare the different national policies. A last limitation is that the survey did not explore what could be the place of Buvidal in a European landscape of opioid use that could quickly and dramatically change, in view of the possible spreading of illicit synthetic opioids over the continent [34].

5. Conclusion

The practical implementation of Buvidal is extremely heterogeneous, depending on the European countries studied, ranging from the top-used OAT in Finland to anecdotal therapeutic option in Spain and France. Reasons for these differences vary widely between countries. Regulatory issues in the medication status can in part explain this situation, and facilitating the access to Buvidal is crucial in Spain and France, for example, in allowing community pharmacies to deliver Buvidal. However, other reasons could be related to the national system of OAT offer as Spain and France already have a large OAT coverage among people who use opioid drugs, and Buvidal could not have been considered as a game changer, as it has been in some other countries in which OAT coverage was lower. Should these disparities persist in the following years, it will be important to study whether the countries which have largely developed the option of long-acting buprenorphine formulations have benefitted from this choice with respect to important public health indicators, such as treatment coverage, recovery levels, overdose deaths, or medico-economic impact.

Declarations of interest

B Rolland reports having received consultancy or lecture fees from Janssen, Abbvie, Gilead, Camurus, Indivior, Recordati, PileJe, HAC Pharma, and Ethypharm. C Matheson has received a Research grant from Camurus to study the use of long acting buprenorphine in the homeless community. In addition, they have received consultancy training fees to provide training to Carumus staff on stigma in drug use and on the management of benzodiazepines with OAT (neither topics related to Buvidal). They have received research grants from both the Scottish and UK government research councils relating to OAT, benzodiazepine use and to reducing drug-related deaths. None relates directly to long acting buprenorphine. A Kaski reports having received consultancy or lecture fees from Camurus, Indivior, Abbvie, and Osion Pharma. C Roncero reports having received fees for consultancy or lectures from Janssen, Gilead, MSD, Excelto, Abbvie, Carnot, Agenllini, Camusu, Esteva, and Takeda. M Kosim is employed by Camurus France. F Vorspan and B Rolland received research fees from Camurus to conduct the study and write the manuscript.

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.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a consultant to Braeburn (the U.S licensee of Brixadi) on research involving injectable buprenorphine.

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

B Rolland and F Vorspan designed the survey and built the questionnaire. C Matheson, A Kaski, C Roncero, and F Vorspan answered the survey. B Rolland and F Vorspan wrote the first draft of the manuscript. All authors drafted the work and reviewed it critically for important intellectual content

Acknowledgments

The authors thank Camurus staff in the four countries studied, for providing national data on Buvidal use.

Additional information

Funding

This paper was funded by Camurus Lipid Research Foundation.