Последствия применения обеспеченных предписаний для амбулаторного использования прегабалина во Франции: региональная оценка во Французском Нувеле-Аквитане.

What is already known about this subject

Many countries have implemented regulations on the prescribing and dispensing of pregabalin to reduce its misuse, with varying results. In France, the implementation of secure prescriptions for zolpidem in 2017 led to notable changes in its use.

What this study adds

The implementation of secure prescriptions for pregabalin in France had a significant impact on its use in Nouvelle‐Aquitaine, leading to a significant decrease in treatment initiations and new misuses. This study confirms the effectiveness of secure prescriptions in reducing medication misuse for substances with abuse potential.

INTRODUCTION

Pregabalin, a gamma‐aminobutyric acid ( GABA )‐like molecule, 1 has been approved by the United States Food and Drug Administration in 2004 for the treatment of neuropathic pain and epilepsy. It was immediately classified by the Drug Enforcement Administration as a Schedule V controlled substance, 2 indicating a low abuse potential related to its potential for producing euphoric and dissociative effects. In Europe, the European Medicines Agency first authorized pregabalin in 2004 for the treatment of partial epilepsy; its indications were enlarged in 2006 to the management of neuropathic pain and generalized anxiety disorder. 3 , 4 Pregabalin use increased quickly afterwards; this raise was accompanied by a widespread misuse across Europe. 5 , 6 , 7 , 8 , 9 In 2009, pregabalin reports were among the three most frequent to the European Monitoring Centre for Drugs and Drug Addiction. 10 The risk of developing pregabalin misuse appeared higher in users being male, of young age, low socio‐economic status, having chronic conditions (especially psychiatric and addiction disorders), a history of drug abuse or being concomitant users of benzodiazepines or antipsychotics. 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20

Because of this important misuse, since 2015, numerous countries (e.g. Argentina, Turkey, Norway, Sweden, Finland, Russia, United Arab Emirates) have implemented regulations on pregabalin prescription and dispensing 9 to control for its rising consumption and reduce its misuse. In the United Kingdom, for instance, pregabalin was classified as a Class C controlled substance in April 2019—requiring prescriptions on specially secured forms to prevent falsification; its possession without a prescription is now illegal. 21

Later in France, on 24 May 2021, secure prescriptions were implemented to reduce pregabalin misuses and limit doctor shopping, prescription forgery and potential for drug dealing. 9 , 22 French secure prescriptions are printed on secure, high‐density, azure‐free paper, featuring a two‐tone watermarked caduceus, the prescriber's address and registration number with the French health insurance system and a micro‐lettering box for recording the number of prescribed drugs, all printed in blue. The prescriber must specify the dosage and exact regimen in full, and the designated pharmacy for dispensing must also be indicated. For pregabalin, prescriptions are limited to a maximum duration of 6 months. 22 , 23 Secure prescriptions are usually required when a product is first placed on the market, but they can also be made compulsory later in the event of abuse. A similar approach was previously applied to zolpidem in 2017, leading to notable changes in its use. 24 , 25

The aim of our study was to evaluate the impact of the introduction in France of secure prescriptions for pregabalin on its use and misuse in the Nouvelle‐Aquitaine region (southwest), which has a population of around six million.

METHODS

Data source

This study was conducted using data from the Nouvelle‐Aquitaine French regional health care insurance system, specifically the ‘Datamart de Consommation Inter Régimes’ (DCIR) and hospital data from the ‘Programme de Médicalisation des Systèmes d'Information’ (PMSI), both parts of the French SNDS (Système National des Données de Santé) database. This dataset covers 98.8% of the Nouvelle‐Aquitaine regional population (over 6 million people, nearly one‐tenth of the French population), from birth (or immigration) to death (or emigration). It includes anonymized individual‐level data such as sociodemographic information, outpatient drug dispensations and healthcare reimbursements, hospital discharge summaries and registration status for a list of 30 costly and severe long‐term diseases (LTDs) eligible for full healthcare costs reimbursement (e.g. diabetes and cancer). Medications are coded according to the Anatomical Therapeutic Chemical (ATC) classification, hospital‐related diagnoses and LTDs according to ICD‐10 and surgical and medical procedures according to the French ‘Classification Commune des Actes Médicaux’ (CCAM). 26 , 27

Population

All individuals residing in Nouvelle‐Aquitaine (France) aged 18 and over who had at least one pregabalin (ATC5: N03AX16) prescribed and then dispensed in a pharmacy between 24 May 2020 and 24 May 2022 were included.

Variables of interest

To assess the potential impact of implementing secure prescriptions for pregabalin, we studied the evolution of pregabalin prevalence and incidence of use, users' characteristics and the evolution of misuse and misusers' characteristics.

Time periods

Two time‐periods were compared: (i) the 12 months prior to 24 May 2021 (i.e. the date of implementation of secure prescriptions; 24 May 2020 to 23 May 2021) and (ii) the 12 months following it (24 May 2021 to 23 May 2022).

Pregabalin use assessment

Pregabalin prevalent and incident use

Pregabalin use was identified considering outpatient dispensings associated with the ATC code N03AX16. Over a studied time period, a prevalent user was defined as a patient who had at least one dispensing for pregabalin, 28 , 29 and an incident user was defined as a patient for whom a dispensing of pregabalin was identified with no prior dispensing in the preceding 6 months. 29

Pregabalin misuse

Misuse of pregabalin over a studied time period was defined by the presence of at least one of the following criteria: (i) an average dispensed daily dose exceeding 600 mg (the maximum authorized in France), (ii) dispensings identified from strictly more than two different pharmacies or (iii) dispensings from prescriptions originating from strictly more than two different prescribers. 11 , 30 , 31 , 32 , 33 , 34 Pregabalin daily doses were calculated by dividing the total quantity of pregabalin dispensed over a time period (into mg, after conversion from individual pill dosage and number of pills per dispensed box) by the period total number of days.

Characteristics of pregabalin users and misusers

Pregabalin users were described for each study period in terms of age, sex, precariousness (patients having C2S, a supplementary health insurance financed by the government, intended for people with modest incomes, to minimize their healthcare costs), area of residence, comorbidities associated with pregabalin indications ( 5 , 6 , 7 , 13 ; Annex 1) and prescriber specialty. Comorbidities were identified considering hospitalization information (PMSI) and LTDs in the 6‐year history available in the database. The use of other drugs of interest (analgesics, psychotropics; list in Annex 2) was also assessed for each period of interest, based on pharmacy dispensing.

Statistical analyses

Quantitative variables were described in terms of mean and standard deviation and qualitative variables in terms of numbers and proportions. Potential changes for the variables studied were assessed by estimating the rate of change in the variables over the two periods of interest and calculating its 95% confidence interval (CI). Analyses were performed using SAS 9.4 (SAS Institute).

Ethics

VM ( Direction Régionale du Service Médical de Nouvelle Aquitaine [DRSM] ) had necessary authorizations to work on the databases used. No individual data were exported from these databases. Data transmitted were anonymized and aggregated. According to French law, neither ethics committee approval nor informed consent were required for this observational study based on anonymized French medico‐administrative databases.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. 35

RESULTS

Evolution in pregabalin use and misuse

Compared with the previous 12‐month period, prevalence of pregabalin use decreased by 16.9% [16.5; 17.3] in the 12‐month period following implementation of secure prescriptions (from 102 660 to 85 332 prevalent users). Similarly, the incidence of pregabalin use decreased by 36.6% [36.1; 37.1] (from 59 335 to 37 622 incident users; Table 1 ).

In the 12 months prior to the implementation of secure prescriptions, 24 868 prevalent users (24.2% of all prevalent users) and 6082 incident users (10.3% of all incident users) were identified as potential misusers. Among them, 6680 prevalent users (6.5% of all prevalent users and 26.8% of prevalent misusers) and 370 incident users (0.6% of all incident users and 6.1% of incident misusers) received a daily dose exceeding 600 mg during this period. In the 12 months following implementation, prevalent misuse decreased by 7.7% [7.0; 8.4] and incident misuse by 71.5% [69.3; 73.6].

Evolution of pregabalin users' characteristics

The characteristics of prevalent and incident pregabalin users are presented in Table 1 , by period of interest. In the 12 months prior to implementation, the average age of prevalent users was of 65 years, and that of incident users 62.1 years. Of all prevalent pregabalin users, 59.9% were women, 9.4% were precarious, 31.3% had a LTD, 7.5% had a psychiatric illness, 65.9% had a chronic painful illness, and most were being treated with opioids, antidepressants or anxiolytics. In the 12 months following implementation, prevalent users appeared older (mean age: 66.1 years) and more likely to be treated with antidepressants (66.5% vs . 55.0%), opioids (85.1% vs . 77.2%), antipsychotics (11.4% vs . 9.6%) and anxiolytics (75.5% vs . 66.4%). General practitioners represented most prescribers in both periods. There were few differences in the characteristics of prevalent misusers between the two periods studied. Incident users were younger than prevalent users (mean age: 62.1 years in the previous period, 62.9 in the following period); they were less precarious (8.6% and 7.2%, respectively, for the previous and following periods) and less often treated with other psychotropics, especially antidepressants (31.2% and 34.7%, respectively) and anxiolytics (43.4% and 40.2%, respectively). Compared with incident misusers identified in the 12 months prior to implementation, those identified in the 12 months following it appeared to be younger (mean age: 60.4 years vs . 62.1) and more often male (44.8% vs . 40.9%).

DISCUSSION

The introduction in France of secure prescriptions for pregabalin on 24 May 2021 has led to a significant decrease in its use in the Nouvelle‐Aquitaine region, particularly in terms of incident use (−36.6%) and incident misuse (−71.5%). This was accompanied by changes in the characteristics of pregabalin users in Nouvelle‐Aquitaine, with prevalent users tending to be older and potentially more complex (more psychiatric or addictive disorders, more associated drugs with significant potential for misuse—such as opioids, anxiolytics and hypnotics—over the period) and incident users tending to have lower frequencies of opioids and anxiolytic use. This may reflect that the reduction in incident use was achieved by otherwise selecting those patients least likely to develop pregabalin (or related drugs) misuse, although stopping pregabalin treatment in complex patients was less easy to achieve.

Internationally, similar regulatory measures have produced varied results. In Saudi Arabia, the reclassification of pregabalin as a controlled substance in 2018 led to a 21.5% decrease in the number of users. 36 In the United States, stricter prescribing regulations, such as prior authorization and step therapy, have led to significant declines in pregabalin use. 37 In contrast, the United Kingdom has seen no significant initial change in the existing downward trend in pregabalin use following its reclassification as a controlled drug in April 2019. 20 This can be explained by historical and sociological reasons (medication use and prescription), but also by different healthcare systems and regulatory frameworks, which mean that comparable but different regulatory actions had varied results.

Our results are consistent with those of studies carried out in other French regions, which observed reduction of almost 50% in prescriptions suspected to be falsified or abusive. 38 They are also consistent with the rapid effectiveness of other campaigns to introduce secure drug prescriptions in France, as highlighted in 2017 for zolpidem, for example. 24 , 25

The characteristics of the patients we were able to study are also in line with the literature, with most pregabalin users being women over 60, often with multiple comorbidities and psychotropic or opioid co‐treatments. 15 Consistently, men, people in precarious situations and patients suffering from psychiatric or addictive disorders were more represented among misusers. 5 , 14 , 15 , 16 , 17 , 39

The decrease in pregabalin use appeared to be less significant for chronic (prevalent) users than for new (incident) users. It was even less for prevalent misusers, conversely to what was observed for incident misusers. This was consistently observed across all misuse criteria studied. Previous studies have highlighted the reluctance of prescribers to adopt secure forms. 40 Conversely to what was reported for the implementation for secured forms for zolpidem, the decrease in pregabalin chronic use appeared moderate. This specificity may be explained by the difficulty of finding effective alternatives to treat epilepsy, severe anxiety or neuropathic pain in patients with complex comorbidities, including psychiatric or addictive disorders. Moreover, pregabalin is often a second‐ or third‐line treatment, and fear of disrupting carefully titrated regimens may have discouraged treatment changes. 20 , 39 The situation differed from zolpidem in 2017 in France, when zopiclone offered a simple, non‐restricted alternative. 24 , 25 This may explain why the measure was mainly limited treatment initiation, whereas most chronic pregabalin users and misusers could have continued their treatment.

STRENGTHS AND LIMITATIONS

A key strength of this study is its use of exhaustive regional drug reimbursement data, covering all dispensed pregabalin prescriptions for all Nouvelle‐Aquitaine inhabitants, a region representing nearly 10% of the French population. To our knowledge, there are currently no data in the literature suggesting that pregabalin consumption and consumer profiles differ significantly in our region compared to other regions of France. 11 , 14 , 38 Our data are therefore certainly representative of the situation throughout France.

However, the database lacked detailed clinical information, making it impossible to directly identify prescription indications. This limitation did not have a major impact on our study, because our objective was to study all uses of pregabalin, whether they were recognized indications.

Information was lacking for some drugs that could have been interesting, including sedative antihistamines that could however not have been fully studied are some of them can be obtained over the counter.

Misuse was identified using criteria commonly used in database studies of controlled drugs: the use of supra‐therapeutic doses, doctor and pharmacy shopping, which are typically described as being associated with misuse and the risk of complications related to such misuse. 31 , 32 , 33 , 34 , 41 , 42 The thresholds used for these different indicators were chosen based on comparable data from the literature and adapted to the French healthcare context. 31 , 32 , 33 , 34 , 41 , 42 The average 600 mg/day dosage criterion had already been used and was the maximum authorized in France. 11 , 30 Sensitivity analyses could have been conducted on the choice of selecting three or more prescribers or dispensing pharmacies. However, the results were consistent across the criteria, both in terms of their magnitude and their evolution. The fact that they were all comparably impacted in new misusers reassured us regarding the risk of overestimating misuse, even though this risk cannot be ruled out, particularly for the last two criteria.

Finally, the design we used is particularly adapted to the study of changes in drug policies or regulatory interventions. As these equally affect all individuals in a population, all are exposed to the intervention and other designs comparing exposed to non‐exposed cannot be used. Its limitation, however, is the inability to differentiate the effect of the intervention (here the implementation of secure prescriptions for pregabalin) from that of other potential events, which would affect the availability of the drug. The possibility of having attributed part of other event effects to the implementation of secure prescriptions nevertheless appears unlikely in the study we report. The periods studied were of similar length, limiting the influence of seasonal variations (which are also not known to affect pregabalin use), no shortages affecting pregabalin or its alternatives occurred during the study period, and COVID‐19 did not appear to affect pregabalin use nationally. 43

CONCLUSION

The implementation of secure prescriptions for pregabalin had a significant impact on its use in Nouvelle‐Aquitaine, resulting in a marked decrease in treatment initiation and incident misuses. This study confirms the effectiveness of secure prescriptions in reducing medication misuse for substances with abuse potential. Further research is needed to assess the long‐term effects of this measure.

AUTHOR CONTRIBUTIONS

Study concept and design : Maika Munech‐Herran, Véronique Moysan, Bruno Lescarret, Antoine Pariente and Nicolas Rousselot. Acquisition : Véronique Moysan and Bruno Lescarret. Analysis or interpretation of data : All authors. Drafting of the manuscript : Maika Munech‐Herran, Antoine Pariente and Nicolas Rousselot. Critical revision of the manuscript for important intellectual content : All authors. Statistical analysis : Maika Munech‐Herran, Véronique Moysan, Clément Mathieu, Antoine Pariente and Nicolas Rousselot. Study supervision : Nicolas Rousselot.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest that are directly relevant to the content of this article.

ACKNOWLEDGEMENTS

Not applicable. Open access publication funding provided by COUPERIN CY26.

DATA AVAILABILITY STATEMENT

The data are not publicly available due to privacy or ethical restrictions.

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Annex 1: Comorbidities identified in hospital‐related diagnoses or long‐term diseases

Comorbidities ICD‐10 code LTD number Cancers C00‐97, D00‐09 ALD 30 Diabetes E10‐14, G59.0, G63.2, H28.0, H36.0, M14.2, N08.3 ALD 8 Arthropathies or dorsopathies M00‐25, M40‐54 ALD 22; 26; 27 Multiple sclerosis/demyelinating diseases of the central nervous system G35‐37 ALD 25 Nerve, plexus, Polyneuritis G50‐59, G60‐64 / Epilepsy G40‐41 ALD 9 Substance use disorder F10‐19, Z72.1, Z72.2 / Schizophrenia F20‐29 ALD 23 Mood disorder F30‐39 ALD 23 Anxiety disorders F40‐48 ALD 23 Personality disorders F60‐69 ALD 23 Abbreviation: LTD, long‐term disease, from a list of 30 costly severe long‐term diseases allowing to get full healthcare cost reimbursements (‘ALD, Affection longue durée’ in French).

Annex 2: Other drugs of interest studied

Drugs ATC code Opioids N02A Tramadol N02AX02 Tramadol in combination N02AJ13; N02AJ14; N02AJ15 Antipsychotics N05A Anxiolytics N05B Benzodiazepines N05BA; N05CD; N05CF Clonazepam N03AE01 Diazepam N05BA01 Hypnotics and sedatives N05C Antidepressants N06A Psychostimulants for ADHD N06B Buprenorphine N07BC01 Methadone N07BC02 Buprenorphine in combination (Suboxone) N07BC51