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.
Compliance with Ethical Standards
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.
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).
- 3.European Medicines Agency. Assessment report for codeine-containing medicinal products indicated in the management of pain in children 2013. https://www.ema.europa.eu/documents/referral/codeine-article-31-referral-prac-assessment-report_en.pdf. Accessed 14 Feb 2019.
- 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.Google Scholar
- 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.XI Report Health Search. 2018 Edition n.d. https://www.healthsearch.it/report/. Accessed 12 Feb 2019.
- 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.WHO Collaborating Centre for Drug Statistics Methodology. 2017. https://www.whocc.no/. Accessed 14 Feb 2019.
- 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. https://doi.org/10.1684/ejd.2010.1017.
- 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.Google Scholar
- 16.Smith HS. Rapid onset opioids in palliative medicine. Ann Palliat Med. 2012;1:45–52. https://doi.org/10.3978/j.issn.2224-5820.2012.01.01.Google Scholar
- 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. https://doi.org/10.1016/j.transci.2018.04.009.CrossRefGoogle Scholar
- 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.Google Scholar
- 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. https://doi.org/10.1080/03007995.2017.1308920.CrossRefGoogle Scholar
- 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. https://doi.org/10.4088/pcc.11m01326.
- 37.FDA. Release from postmarketing requirement n.d. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM484415.pdf. Accessed 12 Feb 2019.