ORIGINAL RESEARCH published: 20 April 2021 doi: 10.3389/fphar.2021.617687 Who Suffers From Pharmaceutical Poverty and What Are Their Needs? Evidence From a Spanish Region Maria Rubio-Valera 1,2*, Silvia Marqués-Ercilla 3,4, M Teresa Peñarrubia-María 2,3,4, Rosa M. Urbanos-Garrido 5, Carme Borrell 2,6, Jordi Bosch 7, Alba Sánchez-Viñas 1,2 and Ignacio Aznar-Lou 1,2 1 Research and Teaching Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain, 2The Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain, 3Centre d’Atenció Primària Bartomeu Fabrés Anglada, Direcció d’Atenció Primària Costa de Ponent, Institut Català de la Salut, Gavà, Spain, 4Unitat de Suport a la Recerca Costa de Ponent, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Cornellà de Llobregat, Spain, 5Department of Applied Economics, Public Economics and Political Economy, The Complutense University of Madrid, Madrid, Spain, 6Agència de Salut Pública de Barcelona, Barcelona, Spain, 7Pharmaceutical Bank, Barcelona, Spain Background: Pharmaceutical poverty occurs when a patient cannot afford the cost of Edited by: prescribed medication and/or medical products. Nonprofit organizations are covering the Joseph O Fadare, cost of medication to those patients in some contexts. The aim of the study was to Ekiti State University, Nigeria describe the population of beneficiaries of the PB, a nongovernmental organization based Reviewed by: Marina Morgado Garcia, on the primary healthcare system, which provides free-of-charge access to medicines and Minas Gerais State University, Brazil their utilization pattern of medicines and healthcare products. Brian Godman, University of Strathclyde, Methods: This was an observational study using PB beneficiary data collected between United Kingdom November 2017 and December 2018 in Catalonia. The Catalan Health Service provided *Correspondence: Maria Rubio-Valera information from the general population. A descriptive analysis of the beneficiaries’ mrubio@pssjd.org characteristics was conducted and compared to the general population. Specialty section: Results: The beneficiaries (N  1,206) were mainly adults with a low level of education, This article was submitted to unemployed, with functional disability, and with ≥1 child. Compared with the general Pharmaceutical Medicine and population, the beneficiaries were older, had a lower level of education, showed a higher Outcomes Research, a section of the journal prevalence of functional disability, were less likely to be Spanish, and were more likely to be Frontiers in Pharmacology divorced and unemployed. The beneficiaries were polymedicated, and most were using Received: 15 October 2020 medication related to the nervous (79%), musculoskeletal (68%), and cardiovascular Accepted: 08 February 2021 Published: 20 April 2021 system (56%) and alimentary tract and metabolism (68%). Almost 19% of beneficiaries Citation: used healthcare products. Female beneficiaries were older and more likely to be divorced Rubio-Valera M, Marqués-Ercilla S, or widowed, employed, and with children. Compared to men, women were more likely to Peñarrubia-María MT, use medicines for pain and mental disorders. The pediatric group used medications for Urbanos-Garrido RM, Borrell C, Bosch J, Sánchez-Viñas A and severe, chronic conditions (heart diseases, autoimmune diseases, conduct disorders, and Aznar-Lou I (2021) Who Suffers From attention deficit hyperactivity disorder). Pharmaceutical Poverty and What Are Their Needs? Evidence From a Spanish Region. Abbreviations: PB, Pharmaceutical Bank; WHO, World Health Organization; NHS, National Health System; NGOs, Non- Front. Pharmacol. 12:617687. Governmental Organizations; SMF, Social Medicine Fund; ESCA, Catalan Health Survey (Enquesta de Salut de Catalunyua, in doi: 10.3389/fphar.2021.617687 Catalan); ATC, Anatomical Therapeutic Chemical; ADHD, Attention Deficit Hyperactivity Disorder. Frontiers in Pharmacology | www.frontiersin.org 1 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? Conclusion: Patients with severe, chronic, and disabling conditions are affected by pharmaceutical poverty. While the system of copayment remains unchanged, family physicians and pediatricians should explore economic barriers to treatment and direct their patients to resources that help to cover the cost of treatment. Keywords: healthcare disparities (MeSH), primary care (MeSH), pharmaceutical poverty, pharmaceutical preparations, health services accessibility INTRODUCTION over-the-counter pharmacological treatments are dispensed in privately managed community pharmacies. Patients pay a part of Universal healthcare coverage aims to ensure that everyone can the cost of prescription medication, with the share dependent on use necessary health services without experiencing financial the medication and patients’ characteristics. The copayment hardship. However, medicines are subject to out-of-pocket applies to pensioners and nonpensioners and ranges from 0 to payments worldwide (Thomson et al., 2019). The cost of 60% depending on the annual income, with a 10% reduced medicines has been systematically identified as a factor that contribution for some medications (most chronic treatments) limits adherence to medications, mainly for disadvantaged (España’s, 2012). Upper limits to copayments are set only for populations (Choudhry et al., 2014; Simoens and Sinnaeve, pensioners, ranging from around 8 to 62 euros per month, and all 2014; Terraneo et al., 2014; Banerjee et al., 2016; Sinnott et al., patients pay 100% of the cost of medicines not covered by the 2016; Aznar-Lou et al., 2018). The failure to effectively use NHS. Over 70% of primary care attendees have an assigned prescription medicines can lead to worse health status and copayment of 40% or 10% (Aznar-Lou et al., 2018). Although higher costs to the healthcare system (Kesselheim et al., 2015). some particular groups are exempt from copayment (disabled Nonadherence worsens health outcomes and increases the risk of patients, people receiving noncontributory pensions, mortality and hospitalization (Xu et al., 2017; Kim et al., 2018). unemployed people whose benefits expired, or beneficiaries of Greater use of medical services and productivity losses are also social integration subsidies), in 2018, 3% of Spaniards reported consequences of medication nonadherence, which places a not having taken a medication prescribed in a public healthcare significant cost burden on healthcare systems (Aznar-Lou center because they could not afford it (de Investigaciones et al., 2017; Cutler et al., 2018). Nonadherence is higher when Sociológicas, 2018). more expensive medicines are prescribed and when copayment is In response to this situation, in recent years, several applied (Kazerooni et al., 2013; González López-Valcárcel et al., nongovernmental organizations (NGOs) have provided free- 2017; Aznar-Lou et al., 2018); interventions that reduce the of-charge access to medicines. This is the case of the NGO copayment contributions or exempt the patient from payment Pharmaceutical Bank (PB) which, in 2015, launched a pilot have effectively proven to reduce nonadherence (Chernew et al., program in Barcelona—the Social Medicine Fund (SMF)—to 2008; Maciejewski et al., 2010). fight against what was called “pharmaceutical poverty.” The The World Health Organization (WHO) defines catastrophic NGO, in collaboration with the Catalan Health Institute (which health spending as those health expenditures “greater than or manages 80% of Catalan primary care centers) and the local equal to 40% of a household’s non-subsistence income, council, began to cover the cost of prescribed medication and i.e., income available after basic needs have been met” (Xu medical products to those patients attended in primary care et al., 2005). In low- and middle-income countries, the cost of centers who could not afford their treatments. Since then, the medicines can be up to 60% of total healthcare expenditure program has been further extended and is now available not (Cameron et al., 2009) and family members becoming ill can only in the city of Barcelona, but also in eight other cities in the have catastrophic consequences (Barasa et al., 2017; Datta et al., metropolitan area and some cities outside the region of 2019). According to a recent report by the WHO, medicines are Catalonia. the main cause of out-of-pocket payments incurred by In order to benefit from the SMF, patients must first visit households with catastrophic health spending (i.e., households primary care social workers who corroborate their medical that cannot afford to meet basic needs like food, housing, and needs and verify their financial situation, through inspection heating because of a health-related condition) also in high- of tax returns, payrolls and rent or mortgage receipts, etc. Social income countries (Thomson et al., 2019). Catastrophic health workers provide the beneficiaries with a list of partner spending may lead to or deepen poverty, undermine health, and community pharmacies where they can get the medicines exacerbate health and socioeconomic inequalities (Thomson free of charge. The beneficiaries have to fulfill the following et al., 2019). criteria: 1) to be attended in a Catalan Health Institute primary In Spain, the National Health System (NHS) is taxpayer care center, 2) to require a treatment for at least 6 months which funded, covers residents and foreign nationals, and, with a few has a monthly cost of 20 Euros or more, and 3) to be in a exceptions, is free at the point of delivery. In Catalonia, one of the situation of financial hardship (defined as a monthly household most populated regions in Spain, where 7.6 million people live, income, after discounting rent or mortgage, lower than €550 for there are 371 publicly financed primary care centers that manage one person, €670 for two people, or €670 plus €75 per additional most of the prescriptions (Bolíbar et al., 2012). Prescription and person). Frontiers in Pharmacology | www.frontiersin.org 2 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? The SMF covers the patients’ total treatment cost for a period dressings, surgical wound dressings, varicose vein stockings and of six months, which may be renewed if the conditions have not socks, inhalation chambers, diapers, and allergen-specific changed. The aid covers the cost of prescription medicines and immunotherapy, with a final category left for other products. healthcare products. In exceptional cases, when it is clinically The Catalan Health Survey 2018 (ESCA; Enquesta de Salut de relevant, the SMF also covers the cost of over-the-counter Catalunya) was used as a source of data from the general Catalan medicines. The NGO Pharmaceutical Bank is partnered with population. ESCA is an official survey consisting of a multistage Catalan Health Institute primary care professionals and probability sample representative of noninstitutionalized pharmacists from several community pharmacies. In Catalonia residents of Catalonia, which includes information about in 2018, 124 primary care centers and 407 community personal characteristics, lifestyles, use of health services, and pharmacies were collaborating with the SMF. health indicators. Finally, the Catalan Health Service provided There is some evidence on inadequate access to medicines in information on the use of publicly financed medicines in 2018 for developing countries (Leisinger et al., 2012; Chan, 2017), but, to the total Catalan population. the best of our knowledge, no previous study has provided information on the use of medicines by patients in a situation Analysis Strategy of pharmaceutical poverty or on the characteristics of these A descriptive analysis of the beneficiaries’ characteristics was patients in western societies, although new tools to measure conducted using means for continuous variables and proportions access to medicines, which would allow for comparisons for categorical variables. Using data from the ESCA, the characteristics within countries, are being developed (Garcia et al., 2019). of the general Catalan population were also described. Probability This article gives a detailed description of SMF beneficiaries weights were applied to ensure representativeness. and of their pattern of utilization of medicines and healthcare First, we calculated the proportion of beneficiaries that products, which is compared with the pattern of use in the general received at least one medication by anatomical group and population in Catalonia. therapeutic subgroup, and the proportion of beneficiaries that received at least one healthcare product. Then, the overall use of medicines and healthcare products covered by the NGO and METHODS CatSalut was described (frequency and proportion of the total number of medicines—anatomical groups and therapeutic Design subgroups—and healthcare products were estimated). The This was an observational study using data from the profiles of medicine and healthcare product use are shown by Pharmaceutical Bank NGO database, collected between gender and age group (0–14, 15–64, and ≥65 years). November 2017 and December 2018 in Catalonia. Variables RESULTS Our database includes information on beneficiaries’ characteristics, including gender (female and male), age, Characteristics of Beneficiaries educational level (without formal education and primary, Between November 2017 and December 2018, 1,206 people secondary, or higher education), nationality (Spanish and benefited from the SMF and 227 (18.8%) and 147 (12.2%) other), presence of functional disability, and assigned renewed the help once and twice, respectively. Almost 96% percentage of copayment (10, 40, 50, or 60%). In the adult (1,154) of beneficiaries had an assigned copayment rate of population (≥18 years), civil status (married, single, divorced, 40% (corresponding to nonpensioners with annual incomes up widowed, or other), employment status (active, unemployed with to 18,000€), 3.1% (Evans-Lacko et al., 2013) had a copayment rate benefits, pensioner or beneficiary of social assistance, or of 10%, and the rest had a copayment rate of 50% or 60%. unemployed without benefits), and number of children were Table 1 compares the sociodemographic characteristics of also registered. beneficiaries of the NGO Pharmaceutical Bank in Catalonia Individuals were divided into three age groups (0–14, 15–64, and those of the general Catalan population. Mean age was and ≥65 years). In Spain, patients are considered pediatric from 0 almost 49 years, and 52% of the beneficiaries were female. to 14 years (and treated in specific services) and people retire at Most of the population was Spanish (62.1%), and a third the age of 65, when they began to present more chronic presented functional disability. Among the adult population, conditions. This classification was made to allow for most had primary or no formal education (68.3%), were comparison with data from the Catalan Health Department. unemployed without benefits (57.0%), and had up to two The number of children was also categorized (0, 1, 2, 3, 4, or children. Most common civil status in the adult population more). was married (38.4%), followed by single (28.9%) and divorced Permanence in the SMF was estimated by taking into account or separated (23.1%). the number of renewals and classified as no renewal (6 months), Compared with the general Catalan population, the one renewal (6–12 months), or more. population of beneficiaries was older, had a lower level of Medicines provided by the NGO were classified using the education, showed a higher prevalence of functional disability, Anatomical Therapeutic Chemical (ATC) system. The selected was less likely to be Spanish, and was more likely to be divorced healthcare products were those most frequently used: wound and unemployed. Frontiers in Pharmacology | www.frontiersin.org 3 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? TABLE 1 | Sociodemographic characteristics of the population. General populationa (n = 4,827) PB beneficiaries (n = 1,206) Female Male % [SE]b % (n)b beneficiaries (n = 623) beneficiaries (n = 583) Mean age (SE) 42.3 (0.31) 48.9 (0.53) 51.0 (0.70) 46.6 (0.78) Age group 0–14 years old 15.6 (0.47) 8.6 (104) 6.7 (42) 10.8 (63) 15–64 years old 65.8 (0.67) 76.1 (918) 75.1 (468) 77.5 (452) ≥65 years old 18.7 (0.55) 15.3 (184) 18.1 (113) 11.7 (68) Female 50.6 (0.75) 51.7 (623) - - Functional disability 11.8 (0.46) 34.7 (419) 36.3 (226) 33.1 (193) Nationality Spanish 85.7 (0.54) 62.1 (749) 64.0 (399) 60.0 (350) Other 11.8 (0.50) 37.5 (452) 35.5 (221) 39.6 (231) Spanish and other 2.5 (0.24) Na Na Na Missing 0.4 (5) 0.5 (3) 0.3 (2) Adult population (≥18 years old) (n  3,600) (n  1,065) (n  570) (n  495) Educational level Without education or primary education 19.6 (0.64) 68.3 (727) 70.5 (439) 70.2 (409) Secondary education 58.5 (0.84) 25.5 (272) 24.1 (150) 24.2 (141) Higher education 21.6 (0.72) 6.0 (64) 5.3 (33) 5.5 (32) Missing 0.3 (0.09) 0.2 (2) 0.2 (1) 0.2 (1) Civil statusc Married 57.2 (1.25) 38.4 (409) 33.2 (189) 44.4 (220) Single 28.8 (1.14) 28.9 (308) 25.4 (145) 32.9 (163) Divorced or separated 6.0 (0.49) 23.1 (246) 27.2 (155) 18.4 (91) Widowed 8.1 (0.69) 6.6 (70) 10.2 (58) 2.4 (12) Other - 2.8 (30) 3.9 (22) 1.6 (8) Missing - 0.2 (2) 0.2 (1) 0.2 (1) Employment status Active 55.7 (0.84) 19.0 (138) 14.9 (85) 10.7 (53) Unemployed with benefits 3.4 (0.32) 15.4 (164) 13.2 (75) 18.0 (89) Pensioner or beneficiary of social help 6.2 (0.38) 14.5 (154) 15.8 (90) 12.9 (64) Unemployed without benefits 2.7 (0.28) 57.0 (607) 56.0 (319) 58.2 (288) Housewife/husband 11.0 (0.42) Na Na Na Student 3.8 (0.32) Na Na Na Other Na Na Na Na Missing 0.3 (0.09) 0.0 (2) 0.2 (1) 0.2 (1) Number of children 0 Na 29.1 (310) 22.8 (130) 36.4 (180) 1 Na 18.2 (194) 20.2 (115) 16.0 (79) 2 Na 26.1 (278) 26.8 (153) 25.3 (125) 3 Na 11.9 (127) 14.6 (83) 8.9 (44) 4 or more children Na 14.7 (156) 15.6 (89) 13.5 (67) a Data from the Catalan Health Survey (Enquesta de Salut de Catalunya (ESCA)) in 2018. b With the exception of mean age (mean (SE)). c Data from the Catalan Health Survey (ESCA) in 2014 (this data was collected the previous year ) (n  1804). PB: Pharmaceutical Bank; Na: data not available or not applicable. Bold numbers indicate statistically significant differences (p < 0.05) between male and female beneficiaries on Students’ t test for mean age and chi-squared tests for categorical variables. In comparison with male beneficiaries, female beneficiaries The medications most commonly consumed by the were older, more likely to be active and divorced or widowed, and beneficiaries were those related to the “nervous system” more likely to have children. (78.9%), followed by those related to the “musculoskeletal system” (68.1%), “alimentary tract and metabolism” (67.7%), Patterns of Drugs Use and “cardiovascular system” (55.9%). Disaggregation by Proportion of Beneficiaries With At Least One therapeutic subgroup indicated that a large proportion of the Medicine From Each Group population received medication for pain-related disorders Tables 2 and 3 show the proportion of beneficiaries using at least [analgesics (56.0%); anti-inflammatory and antirheumatic one healthcare product or medicine from each anatomical group products (26.4%); and other antiepileptics (22.2%)], and therapeutic subgroup (therapeutic subgroups and type of gastrointestinal disorders [drugs for acid-related disorders healthcare product are only shown if they have been used by at (51.1%) and drugs for functional gastrointestinal disorders least 20% of beneficiaries; full data are shown in Supplementary (7.6%)], mental health–related disorders [psycholeptics (43.5%) Tables 1 and 2). This information was not available for the and psychoanaleptics (41.9%)], cardiovascular diseases [lipid- Catalan general population. modifying agents (38.6%), agents acting on the renin- Frontiers in Pharmacology | www.frontiersin.org 4 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? TABLE 2 | Proportion of beneficiaries that received at least one medicine or healthcare product overall and for gender, % (N). Medicines, anatomical group Total (n = 1,206) Females (n = 623) Males (n = 583) (ATC level 1), and therapeutic group (ATC level 2)a Alimentary tract and metabolism (A) 67.7 (817) 73.8 (460) 61.2 (357) Drugs for acid-related disorders (A02) 51.1 (616) 55.9 (348) 46.0 (268) Drugs used in diabetes (A10) 26.0 (314) 24.7 (154) 27.4 (160) Blood and blood-forming organs (B) 41.0 (495) 38.2 (238) 44.1 (257) Antithrombotic agents (B01) 30.8 (371) 24.4 (152) 37.6 (219) Cardiovascular system (C) 55.9 (674) 53.9 (336) 58.0 (338) Beta blocking agents (C07) 20.0 (241) 13.2 (82) 27.3 (159) Agents acting on the renin-angiotensin system (C09) 36.0 (434) 35.0 (218) 37.1 (216) Lipid-modifying agents (C10) 38.6 (466) 32.9 (205) 44.8 (261) Dermatologicals (D) 20.4 (246) 25.0 (156) 15.4 (90) Genitourinary system and sex hormones (G) 11.4 (137) 11.2 (70) 11.5 (67) Systemic hormonal preparations, excluding sex hormones and insulin (H) 17.3 (209) 23.4 (146) 10.8 (63) Anti-infectives for systemic use (J) 25.3 (305) 28.1 (175) 22.3 (130) Antibacterials for systemic use (J01) 23.6 (284) 26.0 (162) 20.9 (122) Antineoplastic and immunomodulating agents (L) 7.1 (86) 10.1 (63) 4.0 (23) Musculoskeletal system (M) 68.1 (821) 38.8 (242) 24.5 (143) Anti-inflammatory and antirheumatic products (M01) 26.4 (318) 34.0 (212) 18.2 (106) Nervous system (N) 78.9 (952) 84.3 (525) 73.2 (427) Analgesics (N02)b 56.0 (675) 65.8 (410) 45.5 (265) Other opioids (N02AX) 17.1 (206) 22.0 (137) 11.8 (69) Pyrazolones (N02BB) 18.9 (228) 23.9 (149) 13.6 (79) Anilides (N02BE) 44.4 (535) 51.4 (320) 36.9 (215) Antiepileptics (N03)b 26.5 (319) 29.1 (181) 23.7 (138) Other antiepileptics (N03AX) 22.2 (268) 26.0 (162) 18.2 (106) Psycholeptics (N05) 43.5 (525) 46.7 (291) 40.1 (234) Psychoanaleptics (N06) 41.9 (505) 49.1 (306) 34.1 (199) Antiparasitic products, insecticides, and repellents (P) 1.6 (19) 1.8 (11) 1.4 (8) Respiratory system (R) 32.1 (387) 34.0 (212) 30.0 (175) Drugs for obstructive airway diseases (R03) 21.3 (257) 21.4 (133) 21.3 (124) Sensory organs (S) 13.4 (161) 15.9 (99) 10.6 (62) Various (V) 1.8 (22) 2.1 (13) 1.5 (9) Healthcare products 18.7 (226) 20.7 (129) 16.6 (97) a Only the therapeutic groups and type of healthcare products that have been used by at least 20% of the beneficiaries are shown. Supplementary files show full data. b For analgesics and antiepileptics, which are highly heterogeneous, the anatomical therapeutic chemical level is shown if <10% of the beneficiaries have used medications. angiotensin system (36.0%), antithrombotic agents (30.8%), beta beneficiaries aged between 15 and 64 years. Over 80% of the blocking agents (20.0%), diuretics (14.9%), and calcium channel oldest group of beneficiaries was using medications for the blockers (14.1%)], diabetes [drugs used in diabetes (26.0%)], and “alimentary tract and metabolism,” “cardiovascular system,” allergies and asthma [drugs for obstructive airway diseases and “nervous system.” (21.3%) and antihistamines for systemic use (13.6%)]. Almost 19% of NGO beneficiaries used at least one healthcare product. Males and females followed a similar pattern (Table 2) Volume of Medicines and Healthcare although, compared with male beneficiaries, females were Products Covered by the PB and the more likely to use medication for pain-related disorders (e.g., CatSalut 65.8 vs. 45.5% in analgesics), gastrointestinal disorders (e.g., 55.9 Tables 4 and 5 (and Supplementary Tables 3 and 4) show the vs. 46.0% in drugs for acid-related disorders), and mental health relative weight of each medicine and healthcare product with disorders (e.g., 49.1 vs. 34.1% in psychoanaleptics) and less likely respect to the total number of units of medicines and healthcare to use medications for cardiovascular diseases (e.g., 32.9 vs. 44.8% products, for PB beneficiaries and for the whole Catalan in lipid-modifying agents) and diabetes (e.g., 24.7 vs. 27.4% in population. drugs used in diabetes). In comparison with the general Catalan population, among Among children (Table 3), the most frequently used beneficiaries, medicines in the “cardiovascular system,” medicines were those for the “nervous system” (61.0%), “genitourinary system and sex hormones,” and “sensory “respiratory system” (36.2%), and “musculoskeletal system” organs” anatomical groups represented a lower proportion of (21.9%). There was a highly prevalent use of medicines for the the total number of units of medications dispensed while “nervous system” (80.3%), “alimentary tract and metabolism” medications in the “antineoplastic and immunomodulating (70.6%), and “cardiovascular system” (55.6%) among agents” and “nervous system” groups represented a higher Frontiers in Pharmacology | www.frontiersin.org 5 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? TABLE 3 | Proportion of beneficiaries that received at least one medicine or healthcare product for age groups, % (N). Medicines, anatomical group ≤14 (n = 104) 15–64 (n = 918) ≥65 (n = 184) (ATC level 1), and therapeutic group (ATC level 2)a Alimentary tract and metabolism (A) 13.3 (14) 70.6 (647) 84.8 (156) Drugs for acid-related disorders (A02) 5.7 (6) 53.5 (491) 64.7 (119) Drugs used in diabetes (A10) 1.0 (1) 25.6 (235) 42.4 (78) Blood and blood-forming organs (B) 7.6 (8) 41.3 (379) 58.7 (108) Antithrombotic agents (B01) 0 (0) 30.2 (277) 51.2 (94) Cardiovascular system (C) 9.5 (10) 55.6 (510) 83.7 (154) Diuretics (C03) 0 (0) 14.5 (133) 25.5 (47) Beta blocking agents (C07) 2.9 (3) 20.6 (189) 26.6 (49) Calcium channel blockers (C08) 1.0 (1) 13.4 (123) 25.0 (46) Agents acting on the renin-angiotensin system (C09) 1.9 (2) 34.6 (317) 62.5 (115) Lipid-modifying agents (C10) 0 (0) 38.6 (354) 60.9 (112) Dermatologicals (D) 12.4 (13) 20.5 (188) 24.5 (45) Genitourinary system and sex hormones (G) 1.9 (2) 10.9 (100) 19.0 (35) Systemic hormonal preparations, excluding sex hormones and insulin (H) 10.5 (11) 17.9 (164) 18.5 (34) Anti-infectives for systemic use (J) 19.1 (20) 26.7 (245) 21.7 (40) Antibacterials for systemic use (J01) 18.1 (19) 24.9 (229) 19.9 (36) Antineoplastic and immunomodulating agents (L) 5.7 (6) 7.2 (66) 7.6 (14) Musculoskeletal system (M) 21.9 (23) 34.6 (317) 24.5 (45) Anti-inflammatory and antirheumatic products (M01) 21.0 (22) 28.6 (262) 18.5 (34) Nervous system (N) 61.0 (64) 80.3 (736) 82.6 (152) Analgesics (N02)b 22.9 (24) 58.2 (534) 63.6 (117) Other opioids (N02AX) 0 19.1 (175) 16.6 (31) Pyrazolones (N02BB) 0 20.2 (185) 23.0 (43) Anilides (N02BE) 21.2 (22) 44.7 (409) 55.6 (104) Antiepileptics (N03)b 9.5 (10) 30.0 (275) 18.5 (34) Other antiepileptics (N03AX) 3.9 (4) 25.4 (232) 17.1 (32) Psycholeptics (N05) 28.6 (30) 46.1 (423) 39.1 (72) Psychoanaleptics (N06) 33.3 (35 ) 43.4 (398) 39.1 (72) Antiparasitic products, insecticides, and repellents (P) 2.9 (3) 1.7 (16) 0 (0) Respiratory system (R) 36.2 (38) 31.5 (289) 32.6 (60) Drugs for obstructive airway diseases (R03) 26.7 (28) 20.0 (183) 25.0 (46) Antihistamines for systemic use (R06) 20.0 (21) 13.6 (125) 9.8 (18) Sensory organs (S) 12.4 (13) 11.2 (103) 24.5 (45) Ophthalmologicals (S01) 11.4 (12) 9.7 (89) 23.8 (43) Various (V) 0 (0) 2.2 (20) 1.1 (2) Healthcare products 38.1 (40) 14.4 (132) 29.4 (54) Diapers 10.5 (11) 4.8 (44) 21.2 (39) Allergen-specific immunotherapy 21.0 (22) 1.4 (13) 0 (0) a Only the therapeutic groups and type of healthcare products that have been used by at least 20% of the beneficiaries are shown. Supplementary files show full data. b For analgesics and antiepileptics, which are highly heterogeneous, the anatomical therapeutic chemical level is shown if <10% of the beneficiaries have used medications. proportion (Table 4). Furthermore, in female beneficiaries, represented a lower proportion (half or less) among medicines for the “cardiovascular system” represented a lower beneficiaries compared with the general population of children. proportion of medicines than in the general female population. The same was seen in males with medicines for the “genitourinary system and sex hormones” group (Table 4). DISCUSSION The largest variation in age groups was observed among children (0–14 years old) (Table 5). Compared with the general Beneficiaries were mainly adults, with functional disability population of the same age group, medicines in the groups and a low level of education, unemployed, and with one or “alimentary tract and metabolism,” “cardiovascular system,” more children. There is wide evidence regarding the “antineoplastic and immunomodulating agents,” and “nervous relationships between the level of education, as a measure system” represented a higher proportion (twice or higher) of socioeconomic position, and health (Furnee et al., 2008), among beneficiaries than in the general population. In contrast, and unemployment and health (Tøge and Blekesaune, 2015). medicines in the “dermatological,” “systemic hormonal The proportion of divorced people was higher in the general preparations,” “anti-infectives for systemic use,” population, which could indicate lower social support for PB “musculoskeletal system,” and “sensory organs” groups beneficiaries, compared with the rest of the population Frontiers in Pharmacology | www.frontiersin.org 6 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? TABLE 4 | Proportion of medicines and products used by the beneficiaries and the general population, % (N). Total Males Females PB Catalonia PB Catalonia PB Catalonia Medicines, anatomical group (ATC level 1) and therapeutic group 48,747 137,378,189 21,225 59,400,000 27,522 77,500,000 (ATC level 2)a Alimentary tract and metabolism (A) 16.0 (7,788) 14.3 15.9 14.5 (8,632,772) 16.0 (4,413) 14.1 (19,644,551) (3,375) (10,900,000) Drugs for acid related disorders (A02) 5.7 (2,777) 6.2 (8,547,897) 5.4 (1,136) 6.0 (3,571,192) 6.0 (1,641) 6.4 (4,950,959) Drugs used in diabetes (A10) 6.3 (3,081) 4.9 (6,777,457) 7.6 (1,621) 6.4 (3,814,420) 5.3 (1,460) 3.8 (2,945,215) Blood and blood forming organs (B) 6.3 (3,052) 6.1 (8,310,079) 8.1 (1711) 7.0 (4,163,092) 4.9 (1,341) 5.3 (4,123,536) Cardiovascular system (C) 19.1 (9,320) 25.0 24.9 29.0 14.7 (4,039) 22.1 (34,405,442) (5,281) (17,200,000) (17,100,000) Lipid modifying agents (C10) 5.8 (2,836) 6.6 (9,019,823) 7.7 (1,636) 8.0 (4,767,132) 4.4 (1,200) 5.5 (4,229,100) Dermatologicals (D) 2.0 (951) 1.7 (2,368,761) 1.4 (304) 1.8 (1,081,384) 2.4 (647) 1.7 (1,274,461) Genito urinary system and sex hormones (G) 1.4 (668) 2.7 (3,769,794) 1.7 (369) 4.3 (2,538,678) 1.1 (299) 1.6 (1,219,365) Systemic hormonal preparations, excl. Sex hormones and 1.5 (720) 1.8 (2,510,611) 0.7 (146) 1.3 (763,523) 2.1 (574) 2.2 (1,736,597) insulins (H) Antiinfectives for systemic use (J) 2.6 (1,247) 3.4 (4,598,444) 2.2 (473) 3.3 (1,942,406) 2.8 (774) 3.4 (2,610,900) Antineoplastic and immunomodulating agents (L) 2.1 (1,029) 1.0 (1,364,320) 1.7 (369) 0.9 (556,179) 2.4 (660) 1.0 (804,895) Musculo-skeletal system (M) 3.9 (1878) 1.5 (2,085,977) 3.0 (644) 4.4 (2,619,746) 4.5 (1,234) 4.7 (3,635,542) Nervous system (N) 36.9 27.3 32.2 21.3 40.5 31.9 (17,985) (37,443,242) (6,835) (12,600,000) (11,150) (24,700,000) Analgesics (N02) 14.1 (6,848) 9.7 (13,364,618) 11.0 7.1 (4,212,587) 16.4 (4,520) 11.8 (9,107,326) (2,328) Antiepileptics (N03) 5.1 (2,461) 2.3 (3,124,887) 4.8 (1,018) 2.3 (1,354,867) 5.2 (1,443) 2.3 (1,758,064) Psycholeptics (N05) 9.4 (4,563) 8.5 (11,614,648) 9.3 (1975) 6.9 (4,096,660) 9.4 (2,588) 9.7 (7,481,897) Psychoanaleptics (N06) 7.1 (3,472) 5.6 (7,703,802) 6.1 (1,302) 3.9 (2,296,327) 7.9 (2,170) 7.0 (5,387,490) Antiparasitic products, insecticides and repellents (P) 0.3 (134) 0.2 (301,954) 0.4 (84) 0.2 (101,466) 0.2 (50) 0.3 (198,061) Respiratory system (R) 6.3 (3,084) 5.5 (7,577,337) 6.2 (1,323) 6.2 (3,661,700) 6.4 (1761) 5.0 (3,882,757) Sensory organs (S) 1.6 (793) 6.2 (8,549,307) 1.2 (251) 5.7 (3,386,436) 2.0 (542) 6.6 (5,136,004) Various (V) 0.2 (98) 0.1 (159,982) 0.3 (60) 0.2 (86,633) 0.1 (38) 0.1 (73,017) HEALTHCARE PRODUCTS 2,276 Na 972 Na 1,304 Na Wound dressings 47.4 (1,079) Na 47.5 (462) Na 47.3 (617) Na Surgical wound dressings 20.0 (456) Na 27.9 (271) Na 14.2 (185) Na Diapers 27.9 (636) Na 20.4 (198) Na 33.6 (438) Na a The table only shows the therapeutic groups and type of healthcare products that represent at least a 5% of the total volume of medications and healthcare products, respectively. The whole table can be consulted in Supplementary Table 1. Na  not available. (Duffy, 1993; Kołodziej-Zaleska and Przybyła-Basista, 2016). unemployment, especially in males and individuals with low The beneficiaries were polymedicated, and most were using levels of education (Evans-Lacko et al., 2013). Thus, people medication for cardiovascular, mental, and pain-related disorders, with mental disorders may have experienced greater economic which would also explain the high use of drugs for acid-related hardship than those without mental disorders following the disorders, which are prescribed to prevent gastroduodenal side economic crisis. effects of polypharmacy and are generally overused (Forgacs and According to their profile of use of medicines and healthcare Loganayagam, 2008). Female beneficiaries were more likely to use products and in contrast to a typical primary care pediatric medicines for pain-related and mental disorders than male patient, the pediatric population of beneficiaries presented beneficiaries, which could be related to a higher burden of severe chronic conditions. Thus, this population presents the chronic diseases in women (Malmusi et al., 2012). most complex pediatric cases [such as heart diseases, The 12-month prevalence of use of psychotropic drugs autoimmune diseases, conduct disorders, and attention deficit (psycholeptics and psychoanaleptics) was high among PB hyperactivity disorder (ADHD)]. The complexity of these chronic beneficiaries (>42%) and higher than that reported in the and mental diseases may increase the vulnerability of the family, Spanish primary care (Rubio-Valera et al., 2012). which has to cover medical costs (such as medication and private Socioeconomic status, debt, workplace conditions, and social specialized care) and other costs (home adaptations, informal capital are determinants of mental health (Bambra et al., 2010; care, and educational accommodations) (McCann et al., 2012). In Ahnquist et al., 2012; Sweet et al., 2013). This may partly explain cases of economic hardship, children and adolescents are the higher use of psychotropic drugs among PB beneficiaries, who especially vulnerable (Rajmil et al., 2014). The high prevalence were in a situation of economic hardship and more likely to be of use of these treatments among young beneficiaries could be divorced than the general Catalan population. In addition, explained by the greater prevalence of these disorders among mental-health-related stigma increases vulnerability to disadvantaged populations (Reiss, 2013) but also by the high costs Frontiers in Pharmacology | www.frontiersin.org 7 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? TABLE 5 | Proportion of medicines and healthcare products used by age group, % (N). ≤14 15–64 ≥65 PB Catalonia PB Catalonia PB Catalonia Medicines, anatomical group (ATC level 1) and therapeutic group N  2,417 N  3,892,497 N  40,378 N  50,320,043 N  8,228 N  82,689,934 (ATC level 2)a Alimentary tract and metabolism (A) 11.3 (235) 5.22 (203,126) 15.8 (6,161) 13.0 (6,533,202) 17.9 15.5 (1,392) (12,800,000) Drugs for acid related disorders (A02) 0.9 (18) 0.37 (14,432) 5.9 (2,279) 5.2 (2,596,489) 6.2 (480) 7.2 (5,911,230) Drugs used in diabetes (A10) 0.2 (4) 0.53 (20,824) 6.2 (2,410) 4.7 (2,342,833) 8.6 (667) 5.3 (4,395,978) Other alimentary tract and metabolism products (A16) 5.7 (120) 0.15 (5,962) 0 (0) <0.1 (9,889) 0 (0) <0.1 (2,762) Blood and blood forming organs (B) 0.8 (16) 1.59 (61,871) 6.0 (2,315) 4.4 (2,201,112) 9.3 (721) 7.3 (6,023,645) Antithrombotic agents (B01) 0 (0) 0.1 (3,948) 4.3 (1,664) 2.8 (1,397,537) 6.5 (507) 6.0 (4,945,210) Cardiovascular system (C) 5.7 (120) 0.89 (34,789) 18.7 (7,286) 19.2 (9,654,331) 24.7 29.8 (1914) (24,600,000) Agents acting on the renin-angiotensin system (C09) 2.2 (46) 0.1 (3,756) 4.6 (1806) 7.0 (3,526,984) 7.2 (559) 9.5 (7,857,509) Dermatologicals (D) 2.9 (60) 6.34 (246,778) 2.0 (768) 2.2 (1,117,447) 1.6 (123) 1.2 (991,620) Genito urinary system and sex hormones (G) 0.4 (8) 0.22 (8,437) 1.2 (481) 2.8 (1,403,516) 2.3 (179) 2.8 (2,346,090) Systemic hormonal preparations, excl. Sex hormones and insulins (H) 2.1 (43) 5.58 (217,191) 1.4 (558) 2.4 (1,180,885) 1.5 (119) 1.3 (1,102,044) Antiinfectives for systemic use (J) 6.2 (129) 17.19 2.6 (1,012) 4.6 (2,332,305) 1.4 (106) 1.9 (1,552,050) (668,951) Antibacterials for systemic use (J01) 5.1 (107) 16.56 2.0 (759) 4.2 (2,087,746) 1.2 (93) 1.8 (1,448,848) (644,641) Antineoplastic and immunomodulating agents (L) 5.0 (105) 0.71 (27,603) 2.3 (878) 1.5 (743,741) 0.6 (46) 0.7 (589,730) Immunosuppressants (L04) 5.0 (105) 0.48 (18,616) 2.2 (841) 1.1 (552,983) 0.3 (20) 0.4 (310,146) Musculo-skeletal system (M) 3.3 (69) 11.91 4.2 (1,651) 6.9 (3,487,078) 2.0 (158) 2.8 (2,304,787) (463,423) Nervous system (N) 48.0 18.7 (727,716) 37.8 32.6 29.2 24.4 (1,004) (14,713) (16,400,000) (2,268) (20,200,000) Analgesics (N02) 2.91 (61) 9.52 (370,691) 14.5 (5,644) 8.7 (4,400,211) 14.7 10.3 (8,549,011) (1,143) Antiepileptics (N03) 9.8 (206) 2.27 (88,513) 5.3 (2062) 3.7 (1,834,870) 2.5 (193) 1.4 (1,189,548) Anti-Parkinson drugs (N04) 5.1 (107) 0.07 (2,687) 0.1 (51) 0.3 (171,035) 0.3 (21) 0.6 (489,661) Psycholeptics (N05) 15.0 (314) 2.56 (99,491) 9.8 (3,804) 11.7 (5,888,111) 5.7 (445) 6.8 (5,590,955) Psychoanaleptics (N06) 14.5 (303) 4.1 (159,702) 7.2 (2,794) 7.5 (3,761,175) 4.8 (375) 4.6 (3,762,940) Antiparasitic products, insecticides and repellents (P) 0.2 (4) 1.16 (45,153) 0.3 (130) 0.4 (193,986) 0 (0) 0.1 (60,388) Respiratory system (R) 12.7 (265) 15.46 6.3 (2,462) 6.5 (3,272,162) 4.6 (357) 4.4 (3,670,537) (601,758) Drugs for obstructive airway diseases (R03) 7.4 (154) 10.12 4.0 (1,544) 3.2 (1,622,557) 3.5 (268) 3.3 (2,714,370) (393,914) Sensory organs (S) 1.7 (35) 14.37 1.1 (412) 3.4 (1,715,146) 4.5 (346) 7.6 (6,247,954) (559,340) Various (V) 0 (0) 0.22 (8,459) 0.2 (67) 0.1 (58,570) 0.4 (31) 0.1 (92,621) HEALTHCARE PRODUCTS N  324 N  1,484 N  468 Wound dressings 12.0 (39) Na 58.2 (863) Na 37.82 Na (177) Surgical wound dressings 39.2 (127) Na 18.9 (280) Na 10.47 (49) Na Diapers 39.2 (127) Na 18.7 (277) Na 49.57 Na (232) Allergen-specific immunotherapy 7.1 (23) Na 0.9 (13) Na 0 (0) Na a The table only shows the therapeutic groups and type of healthcare products that represent at least a 5% of the total volume of medications and healthcare products, respectively. The whole table can be consulted in Supplementary Table 2. of these treatments. This vulnerability may be even more opioids in Europe and the United States (Kalkman et al., 2019; pronounced when the minor is presenting with severe Zhu et al., 2019), the prevalence of opioid use among PB diseases. It is necessary to evaluate the coverage of care needs beneficiaries is higher than that reported in previous studies. for the child, especially when careers are experiencing financial Similarly, the prevalence of use of other antiepileptics, which are problems. This would be the case, for instance, for approximately also used to deal with pain-related disorders, was also high. Pain is 30% of children and adolescents using psycholeptics and highly disabling (Rice et al., 2016), and some opioids and psychoanaleptics, usually indicated to treat conduct disorders antiepileptics, which are used in severe cases, are expensive. and ADHD in the pediatric population. People with symptomatic and disabling disorders are more More than half of the NGO beneficiaries were taking motivated to initiate a treatment (Gil-Girbau et al., 2019), medications for pain-related disorders, and over a third were which could partially explain why they seek help to cover the using opioids. Although there has been an increase in the use of treatment expenses when they are experiencing financial hardship. Frontiers in Pharmacology | www.frontiersin.org 8 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? However, chronic pain is associated with high productivity losses morbidity patterns differ between the populations in situations due to sick leave and unemployment, partly due to comorbidity of pharmaceutical poverty, which will be useful in better directing with mood disorders (Dorner et al., 2016), which increases the healthcare resources to vulnerable populations. vulnerability of people suffering from pain (Giladi et al., 2015). Low-wage workers and those with worse working conditions are at higher risk of developing pain-related disorders and experience CONCLUSION barriers to accessing quality care, which could hinder recovery (Frederiksen et al., 2015; Wami et al., 2019). Compared with the general population in Catalonia, patients Cardiovascular disease and mental disorders are both chronic presenting with pharmaceutical poverty were older and had a disabling conditions with serious clinical and economic lower level of education, showed a higher prevalence of functional consequences (Vigo et al., 2016; Roth et al., 2017). disability, were less likely to be Spanish, and were more likely to Nonadherence to medication for cardiovascular disease and be divorced and unemployed. These patients commonly mental disorders worsens clinical status and increases the consumed treatments for pain-related disorders, economic burden of these diseases (Lindström and Bingefors, gastrointestinal disorders, mental health–related disorders, and 2000; Bitton et al., 2013; Ettehad et al., 2016). The cost of cardiovascular diseases. medications is of potential importance in adherence with Compared with male beneficiaries, females were more likely to medications for these conditions (Mathes et al., 2014), and the use medication for pain-related disorders, gastrointestinal reduction of copayment increases adherence to chronic disorders, and mental health disorders and less likely to use medications, especially among the more vulnerable populations medications for cardiovascular diseases and diabetes. Compared (Choudhry et al., 2014; Simoens and Sinnaeve, 2014; Terraneo with the Catalan pediatric population, child and adolescent et al., 2014; Banerjee et al., 2016; Sinnott et al., 2016; Aznar-Lou beneficiaries were more likely to use medicines for severe et al., 2018). A high proportion of the beneficiaries were using chronic diseases. medication for the primary and secondary prevention of Decision makers should take these results into account when cardiovascular diseases and diabetes as well as medication for evaluating the existing copayment. A reformulation of the mental disorders. However, the cost of these treatments is low copayment law would be advisable. In the meantime, family and some patients in need for these treatments may not reach the physicians and pediatricians should explore economic barriers 20 Euros or more per month threshold set to claim benefit from the to access to treatment and direct their patients to resources to SMF. Therefore, there may be a number of patients with no access help cover the cost of their treatment, especially in the population to these treatments that have not yet been identified. at higher risk. Future studies should assess the impact of Economic burden increases the risk of developing several pharmaceutical poverty on health outcomes and explore this physical and mental disorders, which, in turn, could increase problem in populations presenting with acute conditions and in economic hardship, aggravating the situation of the patients those that do not attend or do not have access to public healthcare experiencing chronic diseases and economic problems. centers, such as homeless people and illegal immigrants. Although the welfare system should ensure access to medicines for patients with economic problems, 30% of the beneficiaries renewed the aid, which could indicate DATA AVAILABILITY STATEMENT chronification of pharmaceutical poverty. In the future, studies should be carried out to assess the prevalence of chronification of The raw data supporting the conclusions of this article will be pharmaceutical poverty and its impact on health. made available by the authors, without undue reservation, to any qualified researcher. Strengths and Limitations Interpretation of the results of this study should take the following limitations into account. First, the sample comprises ETHICS STATEMENT people who seek help and fulfill PB criteria to benefit from the SMF. Therefore, the results cannot be extrapolated to all patients The studies involving human participants were reviewed and in a situation of pharmaceutical poverty, such as those with acute approved by the Ethics Committee at the Sant Joan de Déu conditions, homeless people and illegal immigrants. Second, the Hospital (PIC31-20). Written informed consent from the information came from a small geographically restricted area participants’ legal guardian/next of kin was not required to where the SMF was available in 2018. As the aid is extended to participate in this study in accordance with the national other areas, deeper insight will be gained. Third, the study was legislation and the institutional requirements. based on patient registries, and information on some key variables, such as comorbidities, social support, and medication dose, was missing. AUTHOR CONTRIBUTIONS In spite of these limitations, to the best of our knowledge, this is the first study to describe the pattern of use of medicines in a Conceptualization was carried out by MRV; methodology was population affected by pharmaceutical poverty in a Western prepared by IAL and MRV; formal analysis was performed by country. In this paper, we provide some clues about how MRV and IAL; interpretation of results was carried out by all Frontiers in Pharmacology | www.frontiersin.org 9 April 2021 | Volume 12 | Article 617687 Rubio-Valera et al. Who Suffers from Pharmaceutical Poverty? authors; original draft was written by MRV; reviewing and editing Economy and Competitiveness (Spain) (CP19/00029). MM were performed by all authors. has a research intensification from the IDIAPJGol of Institut Català de la Salut (Spain) (7Z20/028). We thank Stephen Kelly for his help in editing the manuscript. This ACKNOWLEDGMENTS study was conducted without funding. This article has been released as a pre-print at Research Square (Rubio-valera et al., We thank the Catalan Health Service and Juan José Ferro, 2020). pharmacologist from SAP Delta del Llobregat, for providing data from the general population. We thank the CIBERESP (Centro de Investigación Biomedica en Red de Epidemiología SUPPLEMENTARY MATERIAL y Salud Pública, CB16/02/00322) and the European Regional Development Fund for its support in the development of this The Supplementary Material for this article can be found online at: study. MV has a “Miguel Servet” research contract from the https://www.frontiersin.org/articles/10.3389/fphar.2021.617687/ Instituto de Salud Carlos III (ISCIII) of the Ministry of full#supplementary-material. Choudhry, N. K., Bykov, K., Shrank, W. H., Toscano, M., Rawlins, W. S., Reisman, REFERENCES L., et al. (2014). Eliminating medication copayments reduces disparities in cardiovascular care. Health Aff. (Millwood) 33 (5), 863–870. doi:10.1377/ Ahnquist, J., Wamala, S. P., and and Lindstrom, M. (2012). Social determinants of hlthaff.2013.0654 health--a question of social or economic capital? interaction effects of Cutler, R. 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Health Care, 16, 26–52. doi:10.1177/1367493511420186 Conflict of Interest: The authors declare that the research was conducted in the Rajmil, L., Fernandez de Sanmamed, M. J., Choonara, I., Faresjö, T., Hjern, A., absence of any commercial or financial relationships that could be construed as a Kozyrskyj, A. L., et al. (2014). Impact of the 2008 economic and financial crisis potential conflict of interest. on child health: a systematic review. Int. J. Environ. Res. Public Health, 11, 6528–6546. doi:10.3390/ijerph110606528 Copyright © 2021 Rubio-Valera, Marqués-Ercilla, Peñarrubia-María, Urbanos- Reiss, F. (2013). Socioeconomic inequalities and mental health problems in Garrido, Borrell, Bosch, Sánchez-Viñas and Aznar-Lou. This is an open-access children and adolescents: a systematic review. Soc. Sci. Med. 90, 24–31. article distributed under the terms of the Creative Commons Attribution License (CC doi:10.1016/j.socscimed.2013.04.026 BY). The use, distribution or reproduction in other forums is permitted, provided the Rice, A. S. C., Smith, B. H., and and Blyth, F. M. (2016). Pain and the global burden original author(s) and the copyright owner(s) are credited and that the original of disease. Pain 157 (4), 791–796. doi:10.1097/j.pain.0000000000000454 publication in this journal is cited, in accordance with accepted academic practice. Roth, G. A., Johnson, C., Abajobir, A., Abd-Allah, F., Abera, S. F., Abyu, G., et al. No use, distribution or reproduction is permitted which does not comply with (2017). Global, regional, and national burden of cardiovascular diseases for 10 these terms. Frontiers in Pharmacology | www.frontiersin.org 11 April 2021 | Volume 12 | Article 617687