Prescribing Trends of Codeine-containing Medications and Other Opioids in Primary Care After A Regulatory Decision: An Interrupted Time Series Analysis


Background and Objectives

In 2014, the Italian Medicines Agency (AIFA) amended the summary of product characteristics of codeine-containing medications limiting their use for maximum three days. This study attempted to clarify the impact of AIFA intervention on prescribing trends and appropriateness of use of codeine-containing medications and other opioids.


Using the Health Search Database, a quasi-experimental interrupted time series analysis was conducted to evaluate changes in prescribing trends and appropriateness of use of codeine-containing medications and opioids between 2013 and 2015.


Prescribing trends of codeine-containing medications significantly decreased (on average, − 352 days of treatment per month of observation), while long-acting opioids (LAOs) had an overall increase. Trends of inappropriate prescriptions significantly increased for two LAOs (i.e. tapentadol, naloxone-oxycodone), both before and after AIFA intervention.


The use of paracetamol-codeine combination was effectively decreased in Italy because of AIFA intervention. Instead, prescriptions of tapentadol and oxycodone-naloxone stably increased over the study period irrespective of regulatory intervention. Given that the choice of the most appropriate opioid therapy is not straightforward, especially in elderly and/or comorbid patients, general practitioners should consider carefully alternative therapies on the bases of regulatory interventions.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. 1.

    Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129:e1343–7.

    Article  PubMed  Google Scholar 

  2. 2.

    Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361:827–8.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    European Medicines Agency. Assessment report for codeine-containing medicinal products indicated in the management of pain in children 2013. Accessed 14 Feb 2019.

  4. 4.

    Benini F, Barbi E. Doing without codeine: why and what are the alternatives? Ital J Pediatr. 2014;40:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Agenzia Italiana del Farmaco (AIFA). Comunicazione relativa a divieto di utilizzo al di sotto dei 12 anni di età per medicinali antidolorifici contenenti codeina e ritiro delle confezioni ad esclusivo uso in bambini al di sotto dei 12 anni. n.d.

  6. 6.

    Fleming DM, Schellevis FG, Van Casteren V. The prevalence of known diabetes in eight European countries. Eur J Public Health. 2004;14:10–4.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Gijsen R, Poos MJJC. Using registries in general practice to estimate countrywide morbidity in The Netherlands. Public Health. 2006;120:923–36.

    Article  PubMed  Google Scholar 

  8. 8.

    Sessa ESF, Niccolai C, Pecchioli S, Ventriglia G, Mazzag Sessa E, Samani F, Niccolai C, Pecchioli S, Ventriglia GMG. La creazione di un campione validato di medici di medicina generale creazione di un campione validato di medici di medicina generale nel database nel database di Health Search di Health Search. SIMG. 2004;3:10–4.

    Google Scholar 

  9. 9.

    XI Report Health Search. 2018 Edition n.d. Accessed 12 Feb 2019.

  10. 10.

    Mazzaglia G, Sessa E, Samani F, Cricelli CFL. Use of Computerized General Practice Database for epidemiological studies in Italy: a comparative study with the official national statistics. J Epidemiol Commun Health. 2004;58:A133.

    Google Scholar 

  11. 11.

    WHO Collaborating Centre for Drug Statistics Methodology. 2017. Accessed 14 Feb 2019.

  12. 12.

    Cricelli C, Mazzaglia G, Samani F, Marchi M, Sabatini A, Nardi R, et al. Prevalence estimates for chronic diseases in Italy: exploring the differences between self-report and primary care databases. J Public Health Med. 2003;25:254–7.

    Article  PubMed  Google Scholar 

  13. 13.

    Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, et al. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation. 2009;120:1598–605.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Vena GA, Altomare G, Ayala F, Berardesca E, Calzavara-Pinton P, Chimenti S, et al. Incidence of psoriasis and association with comorbidities in Italy: a 5-year observational study from a national primary care database. Eur J Dermatol 20:593–8.

  15. 15.

    Filippi A, Vanuzzo D, Bignamini AA, Mazzaglia G, Cricelli C, Catapano AL. The database of Italian general practitioners allows a reliable determination of the prevalence of myocardial infarction. Ital Heart J. 2005;6:311–4.

    PubMed  Google Scholar 

  16. 16.

    Smith HS. Rapid onset opioids in palliative medicine. Ann Palliat Med. 2012;1:45–52.

    Article  PubMed  Google Scholar 

  17. 17.

    Zhang F, Wagner AK, Ross-Degnan D. Simulation-based power calculation for designing interrupted time series analyses of health policy interventions. J Clin Epidemiol. 2011;64:1252–61.

    Article  PubMed  Google Scholar 

  18. 18.

    Zhang F, Wagner AK, Soumerai SB, Ross-Degnan D. Methods for estimating confidence intervals in interrupted time series analyses of health interventions. J Clin Epidemiol. 2009;62:143–8.

    Article  PubMed  Google Scholar 

  19. 19.

    Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27:299–309.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ. 2005;330:644–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Benneyan JC, Lloyd RC, Plsek PE. Statistical process control as a tool for research and healthcare improvement. Qual Saf Health Care. 2003;12:458–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Pereira P, Seghatchian J, Caldeira B, Xavier S, de Sousa G. Statistical control of the production of blood components by control charts of attribute to improve quality characteristics and to comply with current specifications. Transfus Apher Sci. 2018;57:285–90.

    Article  PubMed  Google Scholar 

  23. 23.

    Ting S, Schug S. The pharmacogenomics of pain management: prospects for personalized medicine. J Pain Res. 2016;9:49–56.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002;3:229–43.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenom J. 2005;5:6–13.

    Article  CAS  Google Scholar 

  26. 26.

    Crews KR, Caudle KE, Dunnenberger HM, Sadhasivam S, Skaar TC. Considerations for the utility of the CPIC guideline for CYP2D6 genotype and codeine therapy. Clin Chem. 2015;61:775–6.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84:602–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Battaggia A, Lora Aprile P, Cricelli I, Fornasari D, Fanelli A, Cricelli C, et al. Paracetamol: a probably still safe drug. Ann Rheum Dis. 2016;75:e57.

    Article  PubMed  Google Scholar 

  29. 29.

    Franceschi F, Iacomini P, Marsiliani D, Cordischi C, Forte E, Antonini S, et al. Safety and efficacy of the combination Acetaminophen-Codeine in the treatment of pain of different origin. Eur Rev Med Pharmacol Sci. 2013;17:2129–35.

    CAS  PubMed  Google Scholar 

  30. 30.

    Vannacci A, Lombardi N, Simonetti M, Fornasari D, Fanelli A, Cricelli I, et al. Regular use of acetaminophen or acetaminophen–codeine combinations and prescription of rescue therapy with non-steroidal anti-inflammatory drugs: a population-based study in primary care. Curr Med Res Opin. 2017;33:1141–8.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Harned M, Sloan P. Safety concerns with long-term opioid use. Expert Opin Drug Saf. 2016;15:955–62.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Baldini A, Von Korff M, Lin EHB. A review of potential adverse effects of long-term opioid therapy: a practitioner’s guide. prim care companion. CNS Disord 2012.

  33. 33.

    Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain–development of a typology of chronic pain patients. Drug Alcohol Depend. 2009;104:34–42.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Boscarino JA, Rukstalis M, Hoffman SN, Han JJ, Erlich PM, Gerhard GS, et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction. 2010;105:1776–82.

    Article  PubMed  Google Scholar 

  35. 35.

    Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8:573–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Reid MC, Engles-Horton LL, Weber MB, Kerns RD, Rogers EL, O’Connor PG. Use of opioid medications for chronic noncancer pain syndromes in primary care. J Gen Intern Med. 2002;17:173–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    FDA. Release from postmarketing requirement n.d. Accessed 12 Feb 2019.

Download references

Author information



Corresponding author

Correspondence to Francesco Lapi.

Ethics declarations


This work was supported by the Italian College of General Practitioners and Primary Care, who played no role in the study design, execution, analysis or interpretation of data, writing of the paper, or decision to submit the paper for publication.

Conflicts of interest

Francesco Lapi provided consultancies in protocol preparation for epidemiological studies and data analyses for IBSA and Angelini. Claudio Cricelli provided clinical consultancies for IBSA, Angelini, Grunenthal, Alfa Wasserman, Pfizer, Prostrakan, Molteni, Dompè and Teva. Alberto Magni provided clinical consultancies for Bayer, Angelini, Doc and AlfaSigma. Niccolò Lombardi, Alfredo Vannacci, Alessandra Bettiol, Ettore Marconi, Serena Pecchioli, have no conflict of interest to disclose.

Ethical approval

With regard to the classification and implementation of observational drug-related research, as issued by the Italian National Drug Agency (an entity belonging to the Italian Ministry of Health), the present study does not require approval by an Ethics Committee in Italy (Italian Drug Agency note dated 3 August 2007).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 338 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lombardi, N., Vannacci, A., Bettiol, A. et al. Prescribing Trends of Codeine-containing Medications and Other Opioids in Primary Care After A Regulatory Decision: An Interrupted Time Series Analysis. Clin Drug Investig 39, 455–462 (2019).

Download citation