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European Journal of Pediatrics

, Volume 178, Issue 2, pp 161–172 | Cite as

Central nervous system-active drug abused and overdose in children: a worldwide exploratory study using the WHO pharmacovigilance database

  • Carla CarnovaleEmail author
  • Faizan Mahzar
  • Sara Scibelli
  • Marta Gentili
  • Elena Arzenton
  • Ugo Moretti
  • Olivia Leoni
  • Marco Pozzi
  • Gabriëlla G.A.M. Peeters
  • Emilio Clementi
  • Massimo Medaglia
  • Sonia Radice
Original Article

Abstract

Recent epidemiological studies have reported an increase in central nervous system (CNS)-active drug abuse rates in paediatric settings, raising several public health concerns. No study to date has explored this issue worldwide. We performed an extensive analysis of drugs abuse/overdose reported for children in the last decade by using the largest pharmacovigilance database, i.e. the VigiBase, collecting adverse drug reaction reports that involved at least one suspect drug belonging to the Anatomical Therapeutic Chemical code “Nervous System” through the Standardised Medical Dictionary for Drug Regulatory Affairs Queries for Drug abuse. 8.682 reports matched our criteria. An increase in reporting activity was observed, starting from 2014; an intentional overdose was reported more frequently than an accidental one, with a difference between age groups. We retrieved 997 reports with death outcome. These referred more to adolescents (n = 538) than subjects of any other paediatric age group. Paracetamol and opioid analgesics were the most common suspect drugs in deaths across all age groups due to hypoxic-ischaemic encephalopathy, brain death, and cardio-respiratory arrest.

Conclusion: The number of reports associated with drug abuse and overdose is increasing (for opioid and paracetamol-containing products) and a considerable number of adverse drug reactions are serious. Data on the patterns of use of such medicines from each country may help in implementing strategies of risk-minimisation and renewing healthcare recommendations worldwide. An increased clinical awareness of drug abuse and overdose is warranted, while continuing to provide effective treatments.

What is Known:

The large increase in paediatric prescriptions for CNS-active drugs in the last 20 years has recently raised public health concerns about drug abuse and overdose.

No study to date has examined this issue in paediatric patients worldwide.

What is New:

The number of paediatric reports associated with CNS drug abuse and intentional overdose is increasing, including those with fatal outcome; over 4 years; more than 35% of the reports was entered from European countries.

Opioid and paracetamol were most frequently suspected for ADRs with fatal outcome across all age groups, due to hypoxic-ischaemic encephalopathy and cardio-respiratory arrest, suggesting the need to implement strategies of risk-minimisation.

Keywords

Drug abuse Overdose Drug safety Paediatrics Pharmacovigilance Spontaneous reporting system database 

Abbreviations

ADRs

Adverse drug reactions

ATC

Anatomical Therapeutic Chemical

CNS

Central nervous system

FDA

Food and Drug Administration

ICSRs

Individual case safety reports

MedDRA

Medical Dictionary for Drug Regulatory Affairs

MHPRA

Medicines and Healthcare Products Regulatory Agency

OTC

Over-the-counter

PT

Preferred term

USA

United States of America

WHO

World Health Organization

Notes

Acknowledgments

Faizan Mazhar is supported by the 33rd cycle Ph.D. programme in “Scienze Farmacologiche Sperimentali e Cliniche”, Università degli Studi di Milano.

Authors’ Contributions

Dr. C. Carnovale conceptualised and designed the study, interpreted the data drafted the manuscript, and revised and approved the final manuscript as submitted.

Dr. F. Mahzar participated in the conceptualisation and design of the study, carried out the initial analyses, revised the manuscript, and approved the final manuscript as submitted.

Dr. S. Scibelli participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, revised the article, and approved the final article as submitted.

Dr. M. Gentili participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, revised the article, and approved the final article as submitted.

Dr. E. Arzenton participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, revised the article, and approved the final article as submitted.

Dr. U. Moretti participated in the analysis and interpretation of the data, supervised data collection, revised the manuscript, and approved the final manuscript as submitted.

Dr. O. Leoni participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Dr. M. Pozzi participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Dr. G. Peeters participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Prof E. Clementi participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Dr. M. Medaglia participated in the conceptualisation and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Dr. S. Radice conceptualised and designed the study, interpreted the data, coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

Funding

This study was supported by the Centre of Pharmacovigilance of Regione Lombardia (MEAP project, Monitoraggio degli eventi avversi nelle popolazioni a rischio, to EC) and by the Italian Ministry of Health (RC 2018 to MP).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Not applicable.

References

  1. 1.
    Aagaard L, Strandell J, Melskens L, Petersen PSG, Hansen EH (2012) Global patterns of adverse drug reactions over a decade. Drug Saf 35(12):1171–1182CrossRefGoogle Scholar
  2. 2.
    Bakhaidar M, Jan S, Farahat F, Attar A, Alsaywid B, Abuznadah W (2015) Pattern of drug overdose and chemical poisoning among patients attending an emergency department, western Saudi Arabia. J Community Health 40(1):57–61CrossRefGoogle Scholar
  3. 3.
    Bateman DN, Carroll R, Pettie J, Yamamoto T, Elamin MEMO, Peart L, Dow M, Coyle J, Cranfield KR, Hook C, Sandilands EA, Veiraiah A, Webb D, Gray A, Dargan PI, Wood DM, Thomas SHL, Dear JW, Eddleston M (2014) Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol 78(3):610–618CrossRefGoogle Scholar
  4. 4.
    Boyd CJ, McCabe SE, Cranford JA et al (2006) Adolescents’ motivations to abuse prescription medications. Paediatrics 118(6):2472–2480CrossRefGoogle Scholar
  5. 5.
    Boyd CJ, McCabe SE, Teter CJ (2006) Medical and nonmedical use of prescription pain medication by youth in a Detroit-area public school district. Drug Alcohol Depend 81(1):37–45CrossRefGoogle Scholar
  6. 6.
    Boyer EW (2012) Management of opioid analgesic overdose. N Engl J Med 367(2):146–155CrossRefGoogle Scholar
  7. 7.
    Bronstein AC, Spyker DA, Cantilena LR, Green JL, Rumack BH, Dart RC (2011) 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila) 49(10):910–941CrossRefGoogle Scholar
  8. 8.
    Califano JA (2005) Under the counter: the diversion and abuse of controlled prescription drugs in the US. National Center on Addiction and Substance Abuse, Columbia University, New York, NYGoogle Scholar
  9. 9.
    Capuano A, Scavone C, Rafaniello C, Arcieri R, Rossi F, Panei P (2014) Atomoxetine in the treatment of attention deficit hyperactivity disorder and suicidal ideation. Expert Opin Drug Saf 1:S69–S78CrossRefGoogle Scholar
  10. 10.
    Centers for Disease Control and Prevention (2018) Unintentional drug poisoning in the United States. September 2010. Available at https://www.cdc.gov/HomeandRecreationalSafety/Poisoning/index.html (accessed January 17)
  11. 11.
    Croteau C, Mottron L, Presse N et al (2017) Increase in psychoactive drug prescriptions in the years following autism spectrum disorder diagnosis: a population-based cohort study. J Popul Ther Clin Pharmacol 24(3):e19–e32Google Scholar
  12. 12.
    Darnis D, Mahé J, Vrignaud B, Guen CGL, Veyrac G, Jolliet P (2015) Adverse drug reactions in paediatric emergency medicine. Ann Pharmacother 49(12):1298–1304CrossRefGoogle Scholar
  13. 13.
    European Medicines Agency (2007) ICH topic ICH E 11: clinical investigation of medicinal products in the paediatric population. Guide to paediatric clinical research: Karger Publishers. p. 33–37Google Scholar
  14. 14.
    FDA (2018) Drug Safety and Risk Management Advisory Committee Drug Safety “Cardiovascular risk with drug treatments of ADHD: feasibility of available study methods in children and adults”. Available at https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_06_01_Gelperin.pdf (accessed January 28, 2018)
  15. 15.
    Ghodse H (2002) Drugs and addictive behaviour: a guide to treatment. Cambridge University PressGoogle Scholar
  16. 16.
    Gould MS, Walsh BT, Munfakh JL et al (2009) Sudden death and use of stimulant medications in youths. Am J Psychiatry 166(9):992–1001CrossRefGoogle Scholar
  17. 17.
    Hall KM, Irwin MM, Bowman KA, Frankenberger W, Jewett DC (2005) Illicit use of prescribed stimulant medication among college students. J Am Coll Heal 53(4):167–174CrossRefGoogle Scholar
  18. 18.
    Hawton K, Townsend E, Deeks J et al (2001) Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. BMJ 322(7296):1203CrossRefGoogle Scholar
  19. 19.
    Hiremath M, Craig S, Graudins A (2016) Adolescent deliberate self-poisoning in South-East Melbourne. Emerg Med Australas 28(6):704–710CrossRefGoogle Scholar
  20. 20.
    Hodges NL, Spiller HA, Casavant MJ, Chounthirath T, Smith GA (2018) Non-health care facility medication errors resulting in serious medical outcomes. Clin Toxicol (Phila) 56(1):43–50CrossRefGoogle Scholar
  21. 21.
    Hosseini SH, Ahmadi A (2015) Abuse potential of carbamazepine for euphorigenic effects. Drug Res 65(4):223–224Google Scholar
  22. 22.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (2018) ICH E2A guideline: clinical safety data management: definitions and standards for expedited reporting E2A. 1994. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf Accessed 15 March, 2018
  23. 23.
    International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (2016). Medical dictionary for regulatory activities (MedDRA®). Standardised MedDRA® Queries. http://www.meddra.org/ standardised-meddra-queries (2016). Accessed 15 May 2017
  24. 24.
    Karanges EA, Stephenson CP, McGregor IS (2014) Longitudinal trends in the dispensing of psychotropic medications in Australia from 2009–2012: focus on children, adolescents and prescriber specialty. Aust N Z J Psychiatry 48(10):917–931CrossRefGoogle Scholar
  25. 25.
    Knipper E, Banta-Green CJ, Jimenez N (2017) Opioid use disorder and misuse: a review of the epidemiology and medical implications for paediatric anesthesiologists. Paediatr Anaesth 27(11):1070–1076CrossRefGoogle Scholar
  26. 26.
    Lesko SM, Mitchell AA (1999) The safety of acetaminophen and ibuprofen among children younger than two years old. Paediatrics 104(4):e39–e39CrossRefGoogle Scholar
  27. 27.
    Lessenger JE, Feinberg SD (2008) Abuse of prescription and over-the-counter medications. J Am Board Fam Med 21(1):45–54CrossRefGoogle Scholar
  28. 28.
    Lifshitz M, Gavrilov V, Sofer S (2000) Signs and symptoms of carbamazepine overdose in young children. Pediatr Emerg Care 16(1):26–27CrossRefGoogle Scholar
  29. 29.
    McCabe SE, Teter CJ, Boyd CJ (2006) Medical use, illicit use, and diversion of abusable prescription drugs. J Am Coll Heal 54(5):269–278CrossRefGoogle Scholar
  30. 30.
    McClain C, Holtzman J, Allen J et al (1988) Clinical features of acetaminophen toxicity. J Clin Gastroenterol 10(1):76–80CrossRefGoogle Scholar
  31. 31.
    McKinnon B, Gariépy G, Sentenac M, Elgar FJ (2016) Adolescent suicidal behaviours in 32 low-and middle-income countries. Bull World Health Organ 94(5):340–350FCrossRefGoogle Scholar
  32. 32.
    Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M (2007) National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry 64(9):1032–1039CrossRefGoogle Scholar
  33. 33.
    Mund ME, Quarcoo D, Gyo C, Brüggmann D, Groneberg DA (2015) Paracetamol as a toxic substance for children: aspects of legislation in selected countries. J Occup Med Toxicol 10(1):43CrossRefGoogle Scholar
  34. 34.
    National Institute on Drug Abuse (NIDA) (2003) Preventing drug use among children and adolescents: a research-based guide. For parents, Educators and community leader. Second Edition. US Health & Human Services- Bethesda MarylandGoogle Scholar
  35. 35.
    Olfson M, Gameroff MJ, Marcus SC, Jensen PS (2003) National trends in the treatment of attention deficit hyperactivity disorder. Am J Psychiatry 160(6):1071–1077CrossRefGoogle Scholar
  36. 36.
    Olfson M, Gameroff MJ, Marcus SC, Waslick BD (2003) Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 60(12):1236–1242CrossRefGoogle Scholar
  37. 37.
    Ott P, Dalhoff K, Hansen P et al (1990) Consumption, overdose and death from analgesics during a period of over-the-counter availability of paracetamol in Denmark. J Intern Med 227(6):423–428CrossRefGoogle Scholar
  38. 38.
    Pirmohamed M, Atuah KN, Dodoo AN et al (2007) Pharmacovigilance in developing countries. BMJ 335(7618):462CrossRefGoogle Scholar
  39. 39.
    Pozzi M, Radice S, Clementi E, Molteni M, Nobile M (2016) Antidepressants and, suicide and self-injury: causal or casual association? Int J Psychiatry Clin Pract 20(1):47–51CrossRefGoogle Scholar
  40. 40.
    Sessa M, di Mauro G, Mascolo A, Rafaniello C, Sportiello L, Scavone C, Capuano A (2018) Pillars and pitfalls of the new pharmacovigilance legislation: consequences for the identification of adverse drug reactions deriving from abuse, misuse, overdose, occupational exposure, and medication errors. Front Pharmacol 9:611CrossRefGoogle Scholar
  41. 41.
    Shafi H, Imran M, Usman HF, Sarwar M, Tahir MA, Naveed R, Ashiq MZ, Tahir AM (2016) Deaths due to abuse of dextromethorphan sold over-the-counter in Pakistan. Egypt J Forensic Sci 6(3):280–283CrossRefGoogle Scholar
  42. 42.
    Sharma B, Nam EW, Kim HY, Kim J (2015) Factors associated with suicidal ideation and suicide attempt among school-going urban adolescents in Peru. Int J Environ Res Public Health 12(11):14842–14856CrossRefGoogle Scholar
  43. 43.
    Steinhausen H-C (2015) Recent international trends in psychotropic medication prescriptions for children and adolescents. Eur Child Adolesc Psychiatry 24(6):635–640CrossRefGoogle Scholar
  44. 44.
    The European Parliament- Regulation (EU) (2010) NO 1235/2010 of the European Parliament and of the Council of 15 December 2010, 726/2004Google Scholar
  45. 45.
    Tong HY, Medrano N, Borobia AM, Ruiz JA, Martínez AM, Martín J, Quintana M, García S, Carcas AJ, Ramírez E (2017) Hepatotoxicity induced by acute and chronic paracetamol overdose in children: where do we stand? World J Pediatr 13(1):76–83CrossRefGoogle Scholar
  46. 46.
    US Food Drug Administration (2018) All manufacturers of prescription combination drug products with more than 325 mg of acetaminophen have discontinued marketing. Available at: https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm390509.htm Accessed 15 March, 2018
  47. 47.
    US Food Drug Administration-FDA drug safety communication: FDA (2018) restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm Accessed 15 March, 2018
  48. 48.
    World Health Organization (2017) Curbing prescription opioid dependency-an epidemic of overdoses and deaths from opioids is fuelled by increased prescribing and sales in North. America Bull World Health Organ 95:318–319CrossRefGoogle Scholar
  49. 49.
    World Health Organization (2018) The Anatomical Therapeutic Chemical Classification system with defined daily doses (ATC/DDD). https://www.whocc.no/atc_ddd_index / (2018). Accessed 15 May 2017
  50. 50.
    World Health Organization-Uppsala Monitoring Centre (2018) The use of the WHO-UMC system for standardised case causality assessment. Available at https://www.who-umc.org/media/2768/standardised-case-causality-assessment.pdf (accessed February 15, 2018)
  51. 51.
    Zakharov S, Navratil T, Pelclova D (2013) Suicide attempts by deliberate self-poisoning in children and adolescents. Psychiatry Res 210(1):302–307CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Carla Carnovale
    • 1
    Email author
  • Faizan Mahzar
    • 1
  • Sara Scibelli
    • 1
  • Marta Gentili
    • 1
  • Elena Arzenton
    • 2
  • Ugo Moretti
    • 2
  • Olivia Leoni
    • 3
  • Marco Pozzi
    • 4
  • Gabriëlla G.A.M. Peeters
    • 1
  • Emilio Clementi
    • 1
    • 4
  • Massimo Medaglia
    • 3
  • Sonia Radice
    • 1
  1. 1.Unit of Clinical Pharmacology Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University HospitalUniversità di MilanoMilanItaly
  2. 2.Department of Diagnostics and Public Health, Section of PharmacologyUniversity of VeronaVeronaItaly
  3. 3.Regional Pharmacovigilance Center of LombardyMilanItaly
  4. 4.Scientific InstituteIRCCS E. MedeaBosisio PariniItaly

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