ORIGINAL RESEARCH published: 28 April 2021 doi: 10.3389/fpsyt.2021.676224 Non-medical Use of Prescription Gabapentinoids (Gabapentin and Pregabalin) in Five European Countries Francina Fonseca 1,2,3† , William Lenahan 4† , Richard C. Dart 4 , Esther Papaseit 5,6 , Paul I. Dargan 7,8 , David M. Wood 7,8 , Marilena Guareschi 9 , Icro Maremmani 10 , Marc Auriacombe 11,12,13 , Magí Farré 5,6‡ , Norbert Scherbaum 14‡ and Marta Torrens 1,2,3*‡ 1 Hospital del Mar, Institut de Neuropsiquiatria i Addiccions (INAD), Barcelona, Spain, 2 Grup de Recerca en Addiccions, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain, 3 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain, 4 Rocky Mountain Poison and Drug Safety, Denver Edited by: Health and Hospital Authority, Denver, CO, United States, 5 Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Fabrizio Schifano, Pujol (HUGTP-Germans Trias i Pujol Research Institute), Badalona, Spain, 6 Department of Pharmacology, Therapeutics and University of Hertfordshire, Toxicology, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain, 7 Clinical Toxicology, Guy’s and St United Kingdom Thomas’ NHS Foundation Trust, London, United Kingdom, 8 Clinical Toxicology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom, 9 Association for the Application of Neuroscientific Knowledge to Social Reviewed by: Aims (AU-CNS), Lucca, Italy, 10 Vincent P. Dole Research Group, Santa Chiara University Hospital, University of Pisa, Pisa, Georgios Demetrios Kotzalidis, Italy, 11 Addiction Psychiatry Department, University of Bordeaux, Bordeaux, France, 12 Addiction Team, Sanpsy Centre Sapienza University of Rome, Italy National de la Recherche Scientifique (CNRS) USR 3413, Bordeaux, France, 13 Pôle Addictologie et Filière Régionale, Centre Amira Guirguis, Hospitalier (CH) Charles Perrens and Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France, 14 LVR-Hospital Swansea University, United Kingdom Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany *Correspondence: Marta Torrens mtorrens@imim.es Background: Non-medical use (NMU) of prescription GABA analogs (pregabalin and † These authors have contributed gabapentin) has been reported especially in opiate dependent persons. However, by equally to this work and share first now the prevalence of NMU of gabapentinoids in the general population has not been authorship sufficiently evaluated. The aim of this research paper is to determine the prevalence of ‡ These authors share prescription GABA analog NMU and associated demographics in five European countries senior authorship with special detail of Spain. Specialty section: Methods: The RADARS Survey of Non-Medical Use of Prescription Drugs Program This article was submitted to (NMURx) is a harmonized series of contemporaneous cross-sectional surveys of adults Addictive Disorders, a section of the journal conducted in multiple countries. NMURx collects data from the general population in Frontiers in Psychiatry each participating country about NMU of prescription drugs, illicit drugs, and associated Received: 04 March 2021 demographics. NMU was defined as “using a medication without a doctor’s prescription Accepted: 29 March 2021 Published: 28 April 2021 or for any reason other than what was recommended by their doctor.” Responses from Citation: Spain (4Q2017, n=10,062) were analyzed in detail. Comparative data were available Fonseca F, Lenahan W, Dart RC, from France, Germany, Italy, and UK. Responses were collected using non-probability Papaseit E, Dargan PI, Wood DM, quota sampling and post-stratification population weighting was applied to reflect the Guareschi M, Maremmani I, Auriacombe M, Farré M, national distributions of adults, based on age, gender, and census region. Rates of NMU Scherbaum N and Torrens M (2021) and associated demographics were reported as rate of past 90-day NMU per 100,000 Non-medical Use of Prescription Gabapentinoids (Gabapentin and adult population with 95% confidence intervals. Pregabalin) in Five European Results: Germany (1,197 per 100,000 adult population [95% CI: 1,004.3–1,379.1]) Countries. Front. Psychiatry 12:676224. and United Kingdom (1,067 per 100,000 adult population [95% CI: 851.3–1,283.2]) doi: 10.3389/fpsyt.2021.676224 presented the highest prevalence of gabapentinoids NMU. In Spain the prevalence Frontiers in Psychiatry | www.frontiersin.org 1 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain of past 90 days GABA analog NMU was: 344.4, 95% (CI 204.8–484.0), with male predominance. Those who non-medically use GABA analogs had a higher prevalence of lifetime chronic pain, lifetime illicit drug use, and previous substance abuse treatment. In Spain, 20% of respondents who ever have used gabapentinoids, reported a lifetime NMU; the prevalence was higher for pregabalin 624 (6.2%) than for gabapentin 444 (4.4%). The main reasons for use were to self-treat pain and other medical conditions. Conclusions: The risk of NMU of gabapentinoids should not be neglected. Subjects with a history of chronic pain and lifetime substance use disorders had an increased risk of NMU of gabapentinoids. Keywords: gabapentin, pregabalin, non-medical use, prescription drugs, misuse INTRODUCTION gabapentin bioavailability changes with dosage, from 60% at 900 mg/day to 33% at 3,600 mg/day. On the other hand, similarities Gabapentinoids, pregabalin and gabapentin, are widely in pharmacokinetics are: both can be given without regard used for the treatment of neuropathic pain and epileptic of meals, they do not bind to plasma proteins and both are disorders according to the United States (US) Food and Drug excreted renally with an elimination half-live of 6 h (7). The linear Administration (FDA). Both gabapentin and pregabalin have pharmacokinetics of pregabalin and its greater potency explains been approved by the European Medicine Agency (EMA) for its steep dose-response relationship and differences in abuse neuropathic pain and generalized anxiety disorder, respectively. potential and severe adverse events as respiratory depression. Additionally, some off-label uses of gabapentinoids include Evidence regarding misuse and diversion of gabapentinoids treatment for chronic lower back pain, insomnia, migraine, has grown in recent years (8–10). The first description of their social phobia, panic disorder, mania, bipolar disorder, and misuse and abuse were published in 2010 (11). Prevalence of alcohol withdrawal (1, 2). misuse and abuse in the general population is an estimated 2.5% Gabapentinoids are now among the most commonly (12) but, the rates in people suffering a substance use disorder prescribed medications in most countries (3). For instance, the (SUD) is higher (pregabalin: 3–68%; gabapentin: 15–22%) (1). overall rate of pregabalin prescriptions use increased from 1.0 In a systematic review aimed to evaluate the abuse liability of per 1,000 individuals in 2013 to 22.0 per 1,000 individuals in gabapentin and pregabalin, the authors found that pregabalin 2014 in Ontario, Canada (4). Also, there has been a progressive had a greater potential for addiction than gabapentin based on increase in the reported cases of misuse and dependence to the magnitude of behavioral dependence symptoms, transitions the European Medicines Agency’s EudraVigilance database, from prescription to self-administration, and the durability of the specifically in subjects with previous history of substance self-administrations (8). use disorders (3). Current research suggests that the addictive potential of At the pharmacological level, gabapentinoids selectively gabapentinoids is primarily a concern among patients with bind to the α2δ-subunit of voltage-gated calcium channels other substance use disorders, especially opioid use disorder (8). in central nervous system neuronal tissues. This in turn The reasons that motivate gabapentinoid misuse and abuse are increases the GABA levels and decreases other excitatory not clearly described. Also, the subjective effects described by neurotransmitters (5). This mechanism is associated with people who report non-medical use are multiple: self-treatment their antinociceptive, anticonvulsant, anxiolytic, and sleep- of pain and other medical conditions, pursuit of changes in modulating effects (6). Gabapentinoids have significant risks states of consciousness, and “to get high” (1, 13). According despite their reputation as safe drugs. Sedation, dizziness, gait to a recent systematic review (13), one of the most predictive instability, and feeling of intoxication are quite common side factors associated with gabapentinoid use was the concomitant effects; as many as one in three patients taking therapeutic use of opioids. doses experience dizziness or somnolence (7). Although, both The neurobiological mechanism involved in the abuse liability substances share some mechanisms of action, they also have of gabapentinoids has not been yet clearly investigated. The some pharmacokinetic differences that could explain differences usual increase in the dopamine levels at the mesolimbic in their abuse potential; for instance, pregabalin is absorbed more brain circuits has not been proved in preclinical studies rapidly by oral route, with maximum plasma concentrations (14, 15). Gabapentinoids have been reported to produce attained within 1 h, whereas, maximum plasma concentrations alcohol/gamma hydroxybutyrate (GHB)/benzodiazepine-type of gabapentin are detected 3–4 h after oral administration. effects mixed with euphoria. Rates of euphoria have been Pregabalin absorption is linear, and gabapentin absorption is reported at between 1 and 12% but this has been for saturable (non-linear –zero-order- process) with less predictable therapeutic doses. Other reported effects include dissociative pharmacokinetics. Bioavailability is also different; pregabalin feeling, improved sociability, relaxation and sense of calm, and has a 90% bioavailability independently from the dosage, but psychedelic effects (10, 16). Frontiers in Psychiatry | www.frontiersin.org 2 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain On the other hand, however, there are studies indicating that Respondents and/or surveys were excluded from the analysis if gabapentin could be an useful treatment for alcohol use disorder. the respondent met criteria for careless response as defined by For instance, a recent randomized controlled trial showed efficacy the validation study (21). of gabapentin in the treatment of alcohol use disorder, improving Calibration weights were applied to the survey population to the alcohol withdrawal syndrome, reducing the heavy drinking be representative of the distribution of the adult population of days and more total abstinence in the group treated with 1,200 mg each of the countries included in the study based on geographic of gabapentin (17). Also, in a meta-analysis of seven studies, region, age, sex, limitations in daily activities, and smoking gabapentin showed efficacy in the treatment of alcohol use status (21). National data utilized for this weighting scheme disorder, reducing the number of heavy drinking days (18). was calculated from estimates from Eurostat and the European In countries as United Kingdom gabapentinoids have been Social Survey; NMURx was approved by the Colorado Multiple reclassified as Class C controlled drugs under the Misuse of Drugs Institutional Review Board (Protocol Number: 13-2394) and Act, from 1 April 2019 (19). That means that it is illegal to locally by the Parc de Salut Mar Ethics Committee (Protocol dispense them without a signed prescription, but that they do not Number: 2017/7331/I). Data used in this analysis is from the require safe custody in controlled drug cabinets. In Spain, Italy, surveys launched in the second half of 2017 (17Q4). Germany, and France, gabapentin and pregabalin are available both only under a medical prescription. Alternatively, in the Measures USA, the Drug Enforcement Administration (DEA) classifies Respondents were asked if they had ever used prescription pregabalin as a Schedule V controlled substance, or the lowest gabapentin or pregabalin for any reason in their lifetime; a “yes” abuse potential among controlled substances, and gabapentin as response classified lifetime use. If respondents reported lifetime a non-controlled substance (20). use, they were asked about last 12- month use and last 12-month The aim of this study is to determine the prevalence of NMU, where NMU was defined as “in a way not directed by your prescription gabapentinoids non-medical use and associated healthcare provider.” demographics in five European countries (France, Germany, Basic demographics (age and gender) were collated together Italy, Spain, and the United Kingdom) and to evaluate the main with data on prevalence of last 12-month gabapentin/pregabalin factors related with its misuse in Spain. use and NMU. Analyses MATERIALS AND METHODS The weighted proportion and 95% confidence intervals (CIs) Design and Participants of select demographic and respondent characteristics were The data were obtained from the Researched, Abuse, Diversion calculated to describe the population. Weighted prevalence and Addiction Related Surveillance (RADARS R ) System Survey estimates and 95% CIs were calculated for last 12-month use of Non-Medical Use of Prescription Drugs (NMURx) Program and NMU of prescription gabapentin only, pregabalin only, and that collects data on respondent demographics and the pregabalin and gabapentin. The prevalence of prescription or prevalence, reasons of use, routes of administration, and method NMU in the last 12 months was estimated by gender and age. of drug acquisition for NMU of prescription drugs across Differences in prevalence of prescription and were compared multiple countries. The methodology and the validity of this by gender and age range (18–24, 25–34, 35–44, 45–54, 55– program is explained in its validation study (21, 22). 64, 65+ years). Analyses were conducted in SPSS Version 25.0 The whole program collects information from France, (Armonk, NY). Germany, Italy, Spain, and the United Kingdom. Recruitment and data collection are delivered to country-based members RESULTS through a global survey panel company, in the native language of the country where the survey is undertaken and in English. Survey Termination and Completion for the Each launch has a “soft launch” of around 500 participants to Five Countries ensure proper data collection. The surveys were available during In the last quarter of 2017, approximately 63,450 French panelists the following timeframes: In France: from 2017 December 13 to were invited to participate in the survey. Of the 16,903 who 2018, January, 7: in Germany: from 2017 December 12 to 2018, initiated the survey, the inclusion and exclusion criteria below January, 16; in Italy: 2017, from December 14 to December 26; in were applied and a total of 10,072 respondents were included in Spain: From 2017 December 12 to 2018, January, 4; and in UK: the analysis (5,058 (50.2%) females, 46.8±15.17 years). 2017, from September 28 to December 1. In Germany, ∼64,982 German panelists were invited to The inclusion criteria were: agree to be included and give participate in the survey. Of the 21,977 who initiated the survey, informed consent at the beginning of the survey; adult age that 15,051 completed it and fulfilled the inclusion criteria (7,531 was defined as ages 15–110 years in Spain, 16–110 years in the (50.0%) female, mean age 46.8 ± 14.24 years). United Kingdom, and 18–110 in France, Germany, and Italy; in In Italy, 41,167 Italian panelists were invited to participate order to reflect the geographical and gender distribution of the in the survey. Of the 12,766 who initiated the survey, the country, surveys from different countries and regions have been inclusion and exclusion criteria below were applied and 10,019 included if region/sex sampling strata that has not yet met its surveys were included (5,019 females (50.1%), mean age 43.5 ± sampling quota; and have completed the survey in its entirety. 13.72 years). Frontiers in Psychiatry | www.frontiersin.org 3 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain FIGURE 1 | Final analytic sample flowchart. In Spain, 26,498 panelists were invited to participate in the NMU was evenly distributed between genders except in survey. Of the 15,798 who initiated the survey, the inclusion and Spain which showed a male predominance (Table 2). Those who exclusion criteria below were applied (Figure 1). Finally, 10,062 non-medically use GABA analogs were estimated to have higher people completed the survey (5,030 (50.0%) female, mean age: incidence of lifetime chronic pain, lifetime illicit drug use, and 41.6 ± 12.74 years). previous substance abuse therapy (Table 2). In the United Kingdom, there were 108,633 panelists invited to participate in the survey, of which 13,036 initiated the survey Spanish Respondents Characteristics and 10,004 were included in the analysis (5,003 (50.0%) females, Approximately 26,498 Spanish panelists were invited to mean age 51.6 ± 15.33 years). participate in the survey. Of the 15,798 who initiated the survey, the inclusion and exclusion criteria below were applied Comparison of Five Countries (Figure 1). Finally, 10,062 people completed the survey (5,030 Prevalence of past 90 day GABA analog NMU was highest (50.0%) female, mean age: 41.6 + 12.74 years). The main in Germany (1,191.7 per 100,000 population, 95% CI 1,004.3– characteristics (unweighted and weighted) of the respondents 1,379.1) and the UK (1,067.2, 95% CI 851.3–1,283.2), and lowest are described in Table 3. The responses are weighted to represent in Spain (344.4, 95% CI 204.8–484.0) and Italy (366.2, 95% CI the population above 15 years old in Spain by region, gender 207.7–524.6) (Table 1). and age. Frontiers in Psychiatry | www.frontiersin.org 4 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain A total of 1,003 (10.0%) respondents referred a lifetime use Respondents said that they main method of drug acquisition of gabapentinoids; after weighting the responses a 9.9% (95% CI: in Spain was by a prescription of a doctor/dentist (61.3% for 9.2–10.6) (Table 4). gabapentin and 69.8% for pregabalin), however, they used several From the total Spanish sample, 444 (4.4%) respondents methods to acquire them including family or friends (either have ever used gabapentin and 624 (6.2%) pregabalin. Out of bought or given), taken from family, friends and other people, them, 84 (18.9%), and 126 (20.6%) reported non-medical use bought outside the country, by internet or to a dealer (Table 7). of gabapentin and pregabalin, respectively (cave: according to Finally, in Table 8, is described the last purchase of gabapentin Table 4 the % of respondents with NMU of gabapentinoids and pregabalin where respondents said that they have obtained should be something higher >>2.9 out of 9.9.% = 29.3%. The the substances from a dealer of bought in internet. The median others respondents were not sure (40 (9.0%) for gabapentin and price paid for both was similar (10 e). 33 (5.3%) for pregabalin) about their NMU (that means, that they were not sure whether they followed the recommendations of the prescriber) or answered that they do not use for NMU (320 DISCUSSION (72.1%) for gabapentin and 465 (74.5%) for pregabalin). The main finding of this study is that it confirms the potential Characteristics of Non-medical Use in abuse liability and then non-medical use of the gabapentinoids Spain gabapentin and pregabalin. When comparing the five European The main reasons for non-medical use were to self-treat pain and countries, those who non-medically use gabapentinoids were other medical condition different from pain (Table 5). estimated to have a higher likelihood of chronic pain, use of illicit Respondents who declare NMU of gabapentinoids, usually substances, and history of substance abuse treatment compared used the oral route of administration (either swallowed or to the general population. These results are in concordance with chewed and then swallowed). Those of them who used to country surveys, reviews and metanalyses published previously get high, reported to inject gabapentin (41%) and pregabalin (8, 23, 24). (14.3%) (Table 6). There are differences in the rate per 100,000 people among the five countries, with Germany and UK the countries having a higher rate compared to France, Italy and Spain. Reasons for these differences could be related to the availability of other TABLE 1 | Last 90 day non-medical use of GABA analogs by country. sedative type substances in those countries. According to the France Germany Italy Spain UK European Drug Report of the same year that the information of this study was recorded (25), the prevalence of cannabis Rate (95% CI) 574.2 1191.7 366.2 344.4 1067.2 use in France, Italy, and Spain was higher than 15%, whereas, per 100,000 (424.4, (1004.3, (207.7, (204.8, (851.3, in Germany and United Kingdom the prevalence was lower Adult 724.0) 1379.1) 524.6) 484.0) 1283.2) than 15%. We can hypothesize that some reasons for using Populationa cannabis and gabapentinoids could be similar: to treat pain Rate (95% CI) 216.8 470.4 242.6 105.9 174.0 per 100,000 (160.2, (396.5, (137.6, (63.0, (138.8, and anxiety symptoms; in countries with higher availability Standard Unitsb 273.4) 544.4) 347.6) 148.9) 209.2) of cannabinoids and opioids, subjects could prefer them to a Rates based on the weighted estimated number of adults who reported NMU of each gabapentinoids. Also, in some countries, gabapentinoids might drug class in the last 90 days per 100,000 adult population. replace partially benzodiazepines; in Spain, a general population b Rates are based on the weighted estimated number of adults who reported NMU of survey performed every 2 years, showed data on life-time NMU each drug class in the last 90 days per 100,000 standard units sold. of benzodiazepines about 3.0% in male and 3.1% in female (26). TABLE 2 | Demographics of those who have non-medically used GABA Analogs in the last 90 days vs. the general adult population demographics. France Germany Italy Spain UK GABA General GABA General GABA General GABA General GABA General analog NMU population analog NMU population analog NMU population analog NMU population analog NMU population Male 56.8% 47.6% 54.0% 48.6% 45.0% 49.1% 65.7% 48.6% 46.8% 48.8% (48.19, 65.36) (46.59, 48.68) (48.13, 59.90) (47.79, 49.49) (33.54, 56.38) (47.89, 50.21) (53.60, 77.79) (47.47, 49.79) (39.82, 53.83) (47.61, 49.94) Chronic pain 72.1% 33.0% 77.6% 39.2% 68.6% 29.4% 63.1% 30.9% 70.3% 38.9% during lifetime (64.39, 79.88) (32.03, 34.05) (72.26, 82.46) (38.41, 40.09) (57.86, 79.26) (28.29, 30.47) (51.92, 74.37) (29.82, 32.05) (63.79, 76.72) (37.84, 40.04) Lifetime illicit 33.9% 18.2 (17.39, 28.7% 25.4% 37.8% 20.5% 42.0% 24.4% 48.0% 27.3% drug use (25.71, 42.05) 18.94) (23.42, 34.05) (24.70, 26.17) (26.47, 49.04) (19.64, 21.38) (30.86, 53.20) (23.45, 25.32) (40.95, 54.98) (26.22, 28.31) Previous 11.5% (6.04, 1.7% (1.46, 7.7% (4.56, 1.8% (1.59, 3.8% (0.00, 0.6% (0.47, 13.3% (6.45, 2.2% (1.92, 19.3% 1.7% (1.41, substance 16.89) 1.97) 10.91) 2.05) 8.40) 0.80) 20.21) 2.55%) (13.35, 25.21) 2.02) abuse treatment Frontiers in Psychiatry | www.frontiersin.org 5 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain TABLE 3 | Spanish survey respondents’ demographics (N = 10,062). TABLE 3 | Continued Variable Unweighted Weighteda Variable Unweighted Weighteda N (%) % (95% CI) N (%) % (95% CI) Gender e7.000 or more 92 (0.9%) 0.8 (0.7, 1.0) Male 5,032 (50.0%) 48.8 (47.6, 49.9) Prefer not to say 783 (7.8%) 8.5 (7.8, 9.2) Age (years) Marital status Mean (STD) 41.6 (12.74) 45.7 (0.2) Single 3,709 (36.9%) 32.3 (31.3, 33.3) Median (IQR) 41.0 (32.0, 50.0) 46.0 (33.6, 56.9) Married 5,463 (54.3%) 55.5 (54.3, 56.6) Range (15.0, 90.0) (15.0, 90.0) Separated/divorced 760 (7.6%) 9.5 (8.7, 10.3) Age categories (years) Widowed 130 (1.3%) 2.7 (2.2, 3.2) 15–24 1,008 (10.0%) 0 (0.0, 0.0) Education achieved 25–34 2,021 (20.1%) 0 (0.0, 0.0) No studies or incomplete primary studies 25 (0.2%) 0.3 (0.2, 0.5) 35–44 2,999 (29.8%) 14.4 (13.8, 15.0) Comprehensive primary education 174 (1.7%) 2.3 (1.9, 2.7) 45–54 2,391 (23.8%) 19.8 (19.0, 20.5) Secondary studies 1st stage 1,481 (14.7%) 15.8 (14.9, 16.7) 55+ 1,643 (16.3%) 18.2 (17.5, 19.0) Secondary studies 2nd stage 3,544 (35.2%) 35.9 (34.8, 37.0) Territory of residence Middle University studies 2,274 (22.6%) 22.0 (21.0, 22.9) Andalucía 1,813 (18.0%) 18.0 (17.1, 18.9) Higher University studies 2,564 (25.5%) 23.7 (22.7, 24.6) Aragón 570 (5.7%) 5.7 (5.2, 6.3) Student within the last 3 months Canarias 467 (4.6%) 4.7 (4.2, 5.1) Yes 1,403 (13.9%) 13.6 (12.8, 14.3) Cantabria 51 (0.5%) 0.5 (0.3, 0.7) No 8,659 (86.1%) 86.4 (85.7, 87.2) Castilla y León 617 (6.1%) 6.1 (5.5, 6.7) A member or former member of the armed forces Castilla-La Mancha 424 (4.2%) 4.1 (3.6, 4.6) Yes 479 (4.8%) 4.6 (4.2, 5.1) Cataluña 1,673 (16.6%) 17.1 (16.3, 18.0) No 9,583 (95.2%) 95.4 (94.9, 95.8) Ciudad Autónoma de Ceuta 2 (0.0%) 0.0 (0.0, 0.0) Currently a healthcare professional Ciudad Autónoma de Melilla 10 (0.1%) 0.2 (0.1, 0.3) Yes 615 (6.1%) 5.6 (5.1, 6.1) Comunidad de Madrid 1,380 (13.7%) 13.7 (12.9, 14.5) No 9,447 (93.9%) 94.4 (93.9, 94.9) Comunidad Foral de Navarra 65 (0.6%) 0.6 (0.5, 0.8) Pregnancy statusb Comunidad Valenciana 1,105 (11.0%) 10.4 (9.8, 11.1) Yes 250 (5.0%) 3.3 (2.9, 3.8) Extremadura 188 (1.9%) 1.9 (1.5, 2.2) No 4,780 (95.0%) 96.7 (96.2, 97.1) Galicia 643 (6.4%) 6.2 (5.6, 6.7) Gestationc (months) Illes Balears 131 (1.3%) 1.3 (1.1, 1.6) Mean (STD) 4.8 (2.08) 4.8 (0.1) La Rioja 39 (0.4%) 0.4 (0.2, 0.5) Median (IQR) 5.0 (3.0,6.0) 4.4 (2.6,5.9) País Vasco 290 (2.9%) 2.9 (2.5, 3.3) Range (1.0, 9.0) (1.0, 9.0) Principado de Asturias 283 (2.8%) 3.0 (2.6, 3.5) Survey language Región de Murcia 311 (3.1%) 3.1 (2.7, 3.5) English 197 (2.0%) 2.1 (1.8, 2.5) Region of residence Spanish 9,865 (98.0%) 97.9 (97.5, 98.2) Noroeste 977 (9.7%) 9.7 (9.0, 10.5) CI, Confidence Interval; STD, Standard deviation; IQR, Interquartile range. Noreste 964 (9.6%) 9.6 (9.0, 10.3) a Responses are weighted to represent the distribution of adults (ages 15+) in Spain by Comunidad de Madrid 1,380 (13.7%) 13.7 (12.9, 14.5) region, gender, and age. b Among females only (n = 5,030). Centro 1,229 (12.2%) 12.1 (11.3, 12.9) c Among pregnant females only (n = 250). Este 2,909 (28.9%) 28.9 (27.9, 29.9) Sur 2,136 (21.2%) 21.3 (20.3, 22.2) Canarias 467 (4.6%) 4.7 (4.2, 5.1) Some studies have tried to analyze the possible usefulness of Net monthly household income pregabalin and gabapentin in the treatment of benzodiazepine Under e499 404 (4.0%) 4.0 (3.5, 4.4) use disorder, but there are no clear results regarding this (27, 28). Between e500 and e799 430 (4.3%) 4.6 (4.1, 5.1) When evaluating the rates by drug, as described before, Between e800 and e999 588 (5.8%) 5.9 (5.3, 6.4) pregabalin has more endorsements than gabapentin, for example, Between e1.000 and e1.499 2,145 (21.3%) 20.5 (19.6, 21.4) in a recent paper describing data from addictovigilance Between e1.500 and e1.999 1,723 (17.1%) 16.6 (15.8, 17.5) monitoring for gabapentinoids (24). Some publications have Between e2.000 and e2.499 1,472 (14.6%) 14.4 (13.5, 15.2) described a higher abuse liability for pregabalin compared to Between e2.500 and e2.999 1,105 (11.0%) 11.1 (10.4, 11.9) gabapentin. One of the explanations of this difference could be Between e3.000 and e4.999 1,116 (11.1%) 11.5 (10.7, 12.2) the higher prevalence of euphoria in pregabalin compared to Between e5.000 and e6.999 204 (2.0%) 2.1 (1.8, 2.5) gabapentin. The studies that have described this effect reported that this is a dose-dependent effect and it is not related to (Continued) treatment indication, nor previous abuse of substances; its Frontiers in Psychiatry | www.frontiersin.org 6 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain prevalence varies among different studies from 1 to 40% (10, 29). Another aspect to take into account may be the The theory of people taking pregabalin to experience euphoria polymedication risk. Pregabalin and gabapentin are usually and to get high it is not completely explained by our results, prescribed with other pain medications, mainly with opioids; as the majority of the respondents used pregabalin as self- among 50–70% were reported in a recent paper (23). This treatment. The differences between the two substances could combination could increase the risk for overdose death (30). also be explained by the different pharmacokinetic characteristics Otherwise, the usefulness of the combination of pregabalin and of both molecules; pregabalin has more rapid absorption than opioids for the treatment of some kind of pain is not clear, as gabapentin; also, the peak plasma concentration is more rapidly some researchers have described that pregabalin plus opioids achieved with pregabalin (1 h compared to 4–5 h) and has a was associated with more pain severity and higher oral doses longer half-life (7). of opioids; furthermore, pregabalin use was not associated with In the subsample of Spanish population evaluated, about 20% improvements on mental health symptoms (31). of all persons ever using gabapentinoids report on NMU of these When prescribing these medications it is important to be substances. A risk for NMU that should not be neglected. The aware and monitor for signs of misuse and overdosification, main reason for non-medical use was in both medications for mainly in patients with risk factors for NMU (previous history self-treat any pain, followed to treat other medical conditions; few of substance use disorder and chronic pain). It is important to respondents used them to get high or to come down; also, there remark that, although NMU of gabapentinoids is more frequent were a percentage of people using them to prevent withdrawal in patients with previous substance use disorder, there are symptoms. Another article, based on data of pharmavigilance described cases of a primary abuse in people without any of (24), found that the use of pregabalin was not only related the known risk factors (24), for this reason, it is important to to the objective to get high, but also, to prevent withdrawal monitor for signs of NMU in all patients in treatment with symptoms, as a substitute of other substances and to potentiate gabapentinoids. The detection of NMU could be complicated as the effect of other drugs (mainly benzodiazepines and opioids). these medications are not detected in routine toxicology urine In our sample, the inhaled and intravenous route were mainly controls. Furthermore, prescribers should be aware of the risk of reported for those who use pregabalin and gabapentin to prevent NMU, when patients request for specific drugs of higher doses, withdrawal syndrome, to come down and to get high. It is when they obtain medications from different sources (doctor important to consider the possibility of using the intravenous shopping), when the medications are lost or stolen frequently or route, and asking patients about it to prevent the transmission they ask for new prescriptions too early (1). of blood borne infections (Hepatitis B and C, and HIV). The NMURx survey methodology is useful to identify under- documented use and misuse of medication and can detect changes in trends of substance use and misuse; also, it permits to make comparisons among different countries. The large sample TABLE 4 | Respondents that reported use of gabapentinoids (from total survey size and post-stratification weighting applied creates estimates respondents n = 10,062). that are representative of general populations. However, there Unweighted N (%) Weighteda % (95% CI) are some limitations related to online surveys, in first place the reliance of participants to provide honest responses; also, Lifetime use 1,003 (10.0%) 9.9 (9.2, 10.6) another limitation of the study is that respondents who have Lifetime non-medical use 323 (3.2%) 2.9 (2.6, 3.3) acquired a gabapentinoid product from a family member, friend, Last 12 month non-medical use 169 (1.7%) 1.5 (1.2, 1.7) or dealer may not be aware whether it was initially obtained Last 90 day non-medical use 45 (0.4%) 0.4 (0.3, 0.6) with a prescription or from another source. However, these Last 30 day non-medical use 42 (0.4%) 0.4 (0.3, 0.6) limitations will apply to all surveys so still allow for comparison Last 7 day non-medical use 35 (0.3%) 0.4 (0.2, 0.5) across countries. In conclusion, in spite of the risk of NMU, gabapentinoids CI, Confidence Interval. a Responses are weighted to represent the distribution of adults (ages 15+) in Spain by are useful medications in the treatment of neuropathic pain, region, gender, and age. generalized anxiety disorder, and some forms of epilepsy. TABLE 5 | Reasons for non-medical use in the Spanish sample. Na To self-treat To treat a medical For enjoyment To come To prevent or Other my pain condition, other than to get high down treat withdrawal reason N (%) pain N (%) N (%) symptoms N (%) N (%) N (%) Gabapentin 124 65 (52.4%) 40 (32.3%) 12 (9.7%) 10 (8.1%) 13 (10.5%) 20 (16.1%) Pregabalin 159 76 (47.8%) 45 (28.3%) 14 (8.8%) 9 (5.7%) 9 (5.7%) 28 (17.6%) a Includes all survey respondents who report non-medical use of the product. Respondents may check multiple options, percentages may not sum to 100. Frontiers in Psychiatry | www.frontiersin.org 7 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain TABLE 6 | Route of administration by reason for non-medical use in Spain. Reason for NMU Na Swallowed Chewed and Dissolved in mouth (e.g., Inhaled Injected (shot Other route N (%) then swallowed between cheek and gum, (snorted or it up) N (%) N (%) under tongue) smoked) N (%) N (%) N (%) Gabapentin (e.g., Gabatur, Neurontin®, or generic), tablets/capsules To self-treat my pain 65 47 (72.3%) 24 (36.9%) 19 (29.2%) 13 (20.0%) 12 (18.5%) 10 (15.4%) To treat a medical condition, other than pain 40 27 (67.5%) 13 (32.5%) 14 (35.0%) 7 (17.5%) 9 (22.5%) 3 (7.5%) For enjoyment/to get high 12 4 (33.3%) 5 (41.7%) 3 (25.0%) 1 (8.3%) 5 (41.7%) 2 (16.7%) To come down 10 3 (30.0%) 5 (50.0%) 6 (60.0%) 1 (10.0%) 3 (30.0%) 0 (0.0%) To prevent or treat withdrawal symptoms 13 5 (38.5%) 6 (46.2%) 7 (53.8%) 6 (46.2%) 4 (30.8%) 4 (30.8%) Other reason 20 10 (50.0%) 6 (30.0%) 5 (25.0%) 6 (30.0%) 3 (15.0%) 5 (25.0%) Pregabalin (e.g., Lyrica® or generic), tablets/capsules To self-treat my pain 76 53 (69.7%) 19 (25.0%) 13 (17.1%) 12 (15.8%) 8 (10.5%) 5 (6.6%) To treat a medical condition, other than pain 45 30 (66.7%) 21 (46.7%) 8 (17.8%) 4 (8.9%) 5 (11.1%) 1 (2.2%) For enjoyment/to get high 14 2 (14.3%) 6 (42.9%) 8 (57.1%) 4 (28.6%) 2 (14.3%) 1 (7.1%) To come down 9 1 (11.1%) 7 (77.8%) 3 (33.3%) 3 (33.3%) 2 (22.2%) 1 (11.1%) To prevent or treat withdrawal symptoms 9 5 (55.6%) 6 (66.7%) 4 (44.4%) 4 (44.4%) 3 (33.3%) 1 (11.1%) Other reason 28 17 (60.7%) 9 (32.1%) 7 (25.0%) 5 (17.9%) 4 (14.3%) 10 (35.7%) a Includes all survey respondents who report each reason for non-medical use of the product. Respondents may check multiple options, percentages may not sum to 100. TABLE 7 | Reported method of drug acquisition in Spain. Na Was prescribed Bought it or was Took it from Took it from Bought it abroad Bought it on the Bought it from a it by a doctor or given it by friends or family someone other (outside Spain) internet without dealer dentist friends or family members than friends/ without a Rx a Rx N (%) N (%) N (%) members without their family without N (%) N (%) knowledge their knowledge N (%) N (%) Gabapentin 124 76 (61.3%) 35 (28.2%) 30 (24.2%) 39 (31.5%) 33 (26.6%) 32 (25.8%) 38 (30.6%) Pregabalin 159 111 (69.8%) 51 (32.1%) 40 (25.2%) 33 (20.8%) 41 (25.8%) 39 (24.5%) 46 (28.9%) a Includes all survey respondents who report non-medical use of the product. Respondents may check multiple options, percentages may not sum to 100. Professionals prescribing these medications should be aware and TABLE 8 | Last purchase characteristics in Spain. actively search for signs of misuse and diversion. Na Number/volume Strengthb Total price paid purchased (e) DATA AVAILABILITY STATEMENT Gabapentin 45 N: 45 N: 12 N: 45 Mean (STD): 5.8 Mean (STD): 38.9 Mean (STD): 14.4 The raw data supporting the conclusions of this article will be (8.53) (49.44) (15.42) made available by the authors, without undue reservation. Median (IQR): 2.0 Median (IQR): 8.0 Median (IQR): 10.0 (1.0, 6.0) (2.0, 100.0) (2.0, 20.0) Range: (0.0, 33.0) Range: (1.0, 120.0) Range: (0.0, 55.0) ETHICS STATEMENT Pregabalin 52 N: 52 N: 16 N: 52 Mean (STD): 5.4 Mean (STD): 26.3 Mean (STD): The studies involving human participants were reviewed (7.65) (61.40) 185,204.8 and approved by the Colorado Multiple Review Board Median (IQR): 2.0 Median (IQR): 3.5 (1,302,466.10) (Protocol Number: 13-2394) and locally by the Parc de Salut (1.0, 6.0) (2.0, 27.0) Median (IQR): 10.0 Range: (0.0, 35.0) Range: (1.0, 250.0) (2.0, 32.0) Mar Ethics Committee (Protocol Number: 2017/7331/I). Range: (0.0, Written informed consent to participate in this study 9,393,939.0) was provided by the participants’ legal guardian/next of kin. STD, Standard deviation; IQR, Interquartile Range. a Includes all survey respondents who report non-medical use of the product and “Bought it from a dealer” or “Bought it on the internet”. b Strength: MG per tablet/capsule, MCG/h per patch, MG per oral film, MG/ML per AUTHOR CONTRIBUTIONS liquid, MCG per lollipop, MCG per lozenge, MG per suppository; All non-numeric entries were excluded. FF, PD, DW, NS, MG, IM, MA, and RD were responsible to Respondents have option to check ‘I’m not sure’ under strength. prepare and adapt the country protocols. MG and RD were Frontiers in Psychiatry | www.frontiersin.org 8 April 2021 | Volume 12 | Article 676224 Fonseca et al. Non-medical Use of Gabapentinoids in Spain responsible for the project concept and study design. FF, WL, EP, reporting services. RADARS System is the property of Denver and MF contributed to drafting the manuscript. MF, NS, and MT Health and Hospital Authority, a political subdivision of were responsible for the final revision. 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Lang N, Sueske E, Hasan A, Paulus W, Tergau F. Pregabalin exerts participated in clinical trials financed by the pharmaceutical industry. IM served oppositional effects on different inhibitory circuits in human motor cortex: as Board Member for Angelini, Camurus, CT Sanremo, D&A Pharma, Gilead, a double-blind, placebo-controlled transcranial magnetic stimulation study. Indivior, Lundbeck, Molteni, MSD, and Mundipharma. MA over the past 3 years Epilepsia. (2006) 47:813–9. doi: 10.1111/j.1528-1167.2006.00544.x has interacted directly or through the University of Bordeaux Foundation with 30. Bykov K, Bateman BT, Franklin JM, Vine SM, Patorno E. Association of Camurus, Mundipharma, Accord Healthcare, Indivior for expert advice and/or gabapentinoids with the risk of opioid-related adverse events in surgical funding donation grants. patients in the United States. JAMA Netw Open. (2020) 3:e2031647. doi: 10.1001/jamanetworkopen.2020.31647 The remaining authors declare that conflicts of interest had no role in the design 31. Nielsen S, Gisev N, Leung J, Clare P, Bruno R, Lintzeris N, et al. Clinical of the study, data collection, analyses, and interpretation, in the writing of the correlates and outcomes associated with pregabalin use among people manuscript, or in the decision to publish the results. prescribed opioids for chronic non-cancer pain: A five-year prospective cohort study. Br J Clin Pharmacol. (2020). doi: 10.1111/bcp.14715. [Epub Copyright © 2021 Fonseca, Lenahan, Dart, Papaseit, Dargan, Wood, Guareschi, ahead of print]. Maremmani, Auriacombe, Farré, Scherbaum and Torrens. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC Conflict of Interest: FF has received during the last 3 years travel grants from BY). The use, distribution or reproduction in other forums is permitted, provided Lundbeck, Otsuka, Indivior, Pfizer, Gilead, Angelini, and Servier; and she the original author(s) and the copyright owner(s) are credited and that the original has received grant/research support from Indivior and Servier. MT has been publication in this journal is cited, in accordance with accepted academic practice. consultant/advisor and/or speaker for Gilead Sciences, Merck Sharp and Dohme No use, distribution or reproduction is permitted which does not comply with these Corp, Indivior, Mundipharma Pharmaceutics, Servier, and Adamed. NS received terms. Frontiers in Psychiatry | www.frontiersin.org 10 April 2021 | Volume 12 | Article 676224