Drug Safety

, Volume 38, Issue 9, pp 811–822 | Cite as

The Risk of Opioid Intoxications or Related Events and the Effect of Alcohol-Related Disorders: A Retrospective Cohort Study in German Patients Treated with High-Potency Opioid Analgesics

  • K. Jobski
  • B. Kollhorst
  • T. Schink
  • Edeltraut GarbeEmail author
Original Research Article



Intoxications involving prescription opioids are a major public health problem in many countries. When taken with opioids, alcohol can enhance the effects of opioids, particularly in the central nervous system. However, data quantifying the impact of alcohol involvement in opioid-related intoxications are limited.


Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a retrospective cohort study based on users of high-potency opioid (HPO) analgesics during the years 2005–2009. HPO use was classified as extended-release, immediate-release or both. We calculated incidence rates (IRs) for opioid intoxications or related events as well as adjusted IR ratios (aIRR) comparing HPO-treated patients with alcohol-related disorders (ARDs) to those without ARDs overall and within each HPO category.


During the study period, 308,268 HPO users were identified with an overall IR of 340.4 per 100,000 person-years [95 % confidence interval (CI) 325.5–355.7]. The risk was highest when patients received concomitant treatment with extended- and immediate-release HPOs (IR 1093.8; 95 % CI 904.6–1310.9). ARDs increased the risk during HPO use by a factor of 1.7 and the highest aIRR was seen when comparing patients simultaneously exposed to extended- and immediate-release HPOs with ARDs to those without ARD also after excluding patients with potential improper/non-medical HPO use.


Physicians should be aware of these elevated risks in HPO patients with ARDs. Active patient education by healthcare providers regarding the risk of opioid intoxications or related events due to alcohol in conjunction with HPOs is warranted.


Buprenorphine Oxycodone Acamprosate Cohort Entry Prescription Drug Monitoring Program 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Inga Schaffer and Stefanie Heidbreder for contributing to the statistical analyses and Heike Gerds for editing the manuscript. The authors are grateful to all statutory health insurances that provided data for this study, namely the AOK Bremen/Bremerhaven, the DAK-Gesundheit, the Techniker Krankenkasse (TK) and the hkk.

Compliances with ethical standard

Funding source

This study was funded by Mundipharma Research GmbH & Co. KG. The authors had complete autonomy for the process of establishing the protocol, carrying out the analyses and interpreting the results. This also includes the full right to publish the results without limitation. Mundipharma Research GmbH & Co. KG was provided the opportunity to review a preliminary version of this manuscript for factual accuracy but the authors are solely responsible for final content and interpretation.

Conflict of interest

Edeltraut Garbe is running and Kathrin Jobski, Bianca Kollhorst and Tania Schink are working for a department that occasionally performs studies for pharmaceutical industries. These companies include Bayer, Celgene, GlaxoSmithKline, Mundipharma, Novartis, Purdue, Sanofi-Aventis, Sanofi Pasteur MSD and STADA. Edeltraut Garbe served in an advisory or consultancy role for Bayer-Pharma, Nycomed, GlaxoSmithKline, Schwabe, Teva and Novartis. These advisory functions were unrelated to the topic of this study.

Supplementary material

40264_2015_312_MOESM1_ESM.pdf (130 kb)
Supplementary material 1 (PDF 130 kb)


  1. 1.
    Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–30.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Dhalla IA, Persaud N, Juurlink DN. Facing up to the prescription opioid crisis. BMJ. 2011;343:d5142.CrossRefPubMedGoogle Scholar
  3. 3.
    Reinecke H, Sorgatz H. S3 guideline LONTS. Long-term administration of opioids for non-tumor pain. Schmerz. 2009;23(5):440–7. doi: 10.1007/s00482-009-0839-9.CrossRefPubMedGoogle Scholar
  4. 4.
    Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146–55. doi: 10.1056/NEJMra1202561.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Fischer B, Jones W, Urbanoski K, Skinner R, Rehm J. Correlations between prescription opioid analgesic dispensing levels and related mortality and morbidity in Ontario, Canada, 2005–2011. Drug Alcohol Rev. 2014;33(1):19–26. doi: 10.1111/dar.12089.CrossRefPubMedGoogle Scholar
  6. 6.
    Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309(7):657–9. doi: 10.1001/jama.2013.272.CrossRefPubMedGoogle Scholar
  7. 7.
    Paulozzi LJ. Prescription drug overdoses: a review. J Saf Res. 2012;43(4):283–9. doi: 10.1016/j.jsr.2012.08.009.CrossRefGoogle Scholar
  8. 8.
    Paulozzi LJ, Jones CM, Mack KA, Rudd RA. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487–92.Google Scholar
  9. 9.
    Atluri S, Sudarshan G, Manchikanti L. Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011. Pain Physician. 2014;17(2):E119–28.PubMedGoogle Scholar
  10. 10.
    United Nations Office on Drugs and Crime. The non-medical use of prescription drugs—policy direction issues. 2011. Accessed 28 Apr 2015.
  11. 11.
    Rehm J. Prescription opioids and public health in the European Union (Policy Paper 4) Addictions and lifestyles in contemporary Europe—reframing addictions policy. 2013. Accessed 12 Nov 2014.
  12. 12.
    Calcaterra S, Glanz J, Binswanger IA. National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999–2009. Drug Alcohol Depend. 2013;131(3):263–70. doi: 10.1016/j.drugalcdep.2012.11.018.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Hakkinen M, Launiainen T, Vuori E, Ojanpera I. Comparison of fatal poisonings by prescription opioids. Forensic Sci Int. 2012;222(1–3):327–31. doi: 10.1016/j.forsciint.2012.07.011.CrossRefPubMedGoogle Scholar
  14. 14.
    Hakkinen M, Launiainen T, Vuori E, Ojanpera I. Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning. Eur J Clin Pharmacol. 2012;68(3):301–9. doi: 10.1007/s00228-011-1122-4.CrossRefPubMedGoogle Scholar
  15. 15.
    Weathermon R, Crabb DW. Alcohol and medication interactions. Alcohol Res Health. 1999;23(1):40–54.PubMedGoogle Scholar
  16. 16.
    Jones CM, Lurie P, Woodcock J. Addressing prescription opioid overdose: data support a comprehensive policy approach. JAMA. 2014;312(17):1733–4. doi: 10.1001/jama.2014.13480.CrossRefPubMedGoogle Scholar
  17. 17.
    Walden M, Nicholls FA, Smith KJ, Tucker GT. The effect of ethanol on the release of opioids from oral prolonged-release preparations. Drug Dev Ind Pharm. 2007;33(10):1101–11.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    EMA. Assessment report for authorised modified-release oral medicinal products of the WHO level III scale for the management of pain. 2011. Accessed 12 Nov 2014.
  19. 19.
    Schubert I, Ihle P, Sabatowski R. Increase in opiate prescription in Germany between 2000 and 2010: a study based on insurance data. Dtsch Arztebl Int. 2013;110(4):45–51. doi: 10.3238/arztebl.2013.0045.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Jobski K, Schmid U, Behr S, Andersohn F, Garbe E. 3-Year prevalence of alcohol-related disorders in German patients treated with high-potency opioids. Pharmacoepidemiol Drug Saf. 2012;21(10):1125–9. doi: 10.1002/pds.3268.CrossRefPubMedGoogle Scholar
  21. 21.
    Fassmer A, Schink T. Representativity of outpatient drug prescriptions in the German Pharmacoepidemiological Research Database (GePaRD). In: Annual Conference of the German Society for Epidemiology (DGEpi); 17–20 Sept 2014; Ulm.
  22. 22.
    Pigeot I, Ahrens W. Establishment of a pharmacoepidemiological database in Germany: methodological potential, scientific value and practical limitations. Pharmacoepidemiol Drug Saf. 2008;17(3):215–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Schink T, Garbe E. Assessment of the representativity of in-patient hospital diagnoses in the German Pharmacoepidemiological Research Database (Abstracts of the 26th International Conference on Pharmacoepidemiology & Therapeutic Risk Management, 19–22 August 2010, Brighton, UK). Pharmacoepidemiol Drug Saf. 2010;19:S178–9.Google Scholar
  24. 24.
    Garbe E, Jobski K, Schmid U. Utilisation of transdermal fentanyl in Germany from 2004 to 2006. Pharmacoepidemiol Drug Saf. 2012;21(2):191–8. doi: 10.1002/pds.2164.CrossRefPubMedGoogle Scholar
  25. 25.
    WHO. Cancer pain relief and palliative care. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1990;804:1–75.Google Scholar
  26. 26.
    Greevy RA Jr, Huizinga MM, Roumie CL, Grijalva CG, Murff H, Liu X, et al. Comparisons of persistence and durability among three oral antidiabetic therapies using electronic prescription-fill data: the impact of adherence requirements and stockpiling. Clin Pharmacol Ther. 2011;90(6):813–9. doi: 10.1038/clpt.2011.228.CrossRefPubMedGoogle Scholar
  27. 27.
    Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315–21.CrossRefPubMedGoogle Scholar
  28. 28.
    AKDAE. Tumorschmerzen [Empfehlungen zur Therapie von Tumorschmerzen]. 3. Aufl. ed. Arzneiverordnung in der Praxis, vol 34, 2007 Sonderh 1. Köln: Arzneimittelkomm. der Dt. Ärzteschaft; 2007.Google Scholar
  29. 29.
    Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85–92.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Teichtahl H, Wang D. Sleep-disordered breathing with chronic opioid use. Expert Opin Drug Saf. 2007;6(6):641–9. doi: 10.1517/14740338.6.6.641.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim HM, Smith EG, Stano CM, Ganoczy D, Zivin K, Walters H, et al. Validation of key behaviourally based mental health diagnoses in administrative data: suicide attempt, alcohol abuse, illicit drug abuse and tobacco use. BMC Health Serv Res. 2012;12:18. doi: 10.1186/1472-6963-12-18.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Hall AJ, Logan JE, Toblin RL, Kaplan JA, Kraner JC, Bixler D, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300(22):2613–20. doi: 10.1001/jama.2008.802.CrossRefPubMedGoogle Scholar
  33. 33.
    Katz N, Panas L, Kim M, Audet AD, Bilansky A, Eadie J, et al. Usefulness of prescription monitoring programs for surveillance–analysis of Schedule II opioid prescription data in Massachusetts, 1996–2006. Pharmacoepidemiol Drug Saf. 2010;19(2):115–23. doi: 10.1002/pds.1878.CrossRefPubMedGoogle Scholar
  34. 34.
    Jones HE. Practical considerations for the clinical use of buprenorphine. Sci Pract Perspect. 2004;2(2):4–20.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009;13(3):219–30. doi: 10.1016/j.ejpain.2008.04.011.CrossRefPubMedGoogle Scholar
  36. 36.
    Coplan P, DeVeaugh-Geiss A, Kadakia A. Comparison of the risk of opioid overdose among patients prescribed immediate-release and extended-release opioid analgesics (abstracts presented at the 33rd Annual Scientific Meeting of the American Pain Society). J Pain. 2014;15(4 Suppl):S9.Google Scholar
  37. 37.
    Scharnagel R, Kaiser U, Schutze A, Heineck R, Gossrau G, Sabatowski R. Chronic non-cancer-related pain. Long-term treatment with rapid-release and short-acting opioids in the context of misuse and dependency. Schmerz. 2013;27(1):7–19. doi: 10.1007/s00482-012-1278-6.CrossRefPubMedGoogle Scholar
  38. 38.
    FDA. FDA issues second safety warning on fentanyl skin patch. 2007. Accessed 12 Nov 2014.
  39. 39.
    FDA. Extended-release (ER) and long-acting (LA) opioid analgesics Risk Evaluation and Mitigation Strategy (REMS). 2013. Accessed 23 Jan 2015.
  40. 40.
    AKDAE. UAW-News International: Die unkritische Anwendung von Fentanylpflastern erhöht das Risiko für schwerwiegende Nebenwirkungen. Dtsch Arztebl International. 2012;109(14):724–5.Google Scholar
  41. 41.
    Dhalla IA, Mamdani MM, Sivilotti ML, Kopp A, Qureshi O, Juurlink DN. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ. 2009;181(12):891–6. doi: 10.1503/cmaj.090784.CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    FDA. FDA approves new extended-release oxycodone with abuse-deterrent properties. 2014. Accessed 28 Apr 2015.
  43. 43.
    Sessler NE, Downing JM, Kale H, Chilcoat HD, Baumgartner TF, Coplan PM. Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation. Pharmacoepidemiol Drug Saf. 2014;23(12):1238–46. doi: 10.1002/pds.3658.CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    FDA. New safety measures announced for extended-release and long-acting opioids. 2014. Accessed 12 Nov 2014.
  45. 45.
    King S, Forbes K, Hanks GW, Ferro CJ, Chambers EJ. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med. 2011;25(5):525–52. doi: 10.1177/0269216311406313.CrossRefPubMedGoogle Scholar
  46. 46.
    Office of National Drug Control Policy. Prescription Drug Monitoring Programs. 2011. Accessed 12 Nov 2014.
  47. 47.
    Schneeweiss S, Avorn J. A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol. 2005;58(4):323–37.CrossRefPubMedGoogle Scholar
  48. 48.
    Narcotic Drugs Prescription Ordinance (BtMVV). Bundesgesundheitsblatt 1998;1(4):74–80.Google Scholar
  49. 49.
    Radbruch L, Glaeske G, Grond S, Munchberg F, Scherbaum N, Storz E, et al. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Subst Abus. 2013;34(3):313–20. doi: 10.1080/08897077.2012.735216.CrossRefPubMedGoogle Scholar
  50. 50.
    Jann M, Kennedy WK, Lopez G. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Pract. 2014;27(1):5–16. doi: 10.1177/0897190013515001.CrossRefPubMedGoogle Scholar
  51. 51.
    GBA. Appendix III: overview of limitations and exclusions on prescriptions [in German]. 2013. Accessed 23 Jan 2015.
  52. 52.
    Hoffmann F, Hies M, Glaeske G. Regional variations of private prescriptions for the non-benzodiazepine hypnotics zolpidem and zopiclone in Germany. Pharmacoepidemiol Drug Saf. 2010;19(10):1071–7. doi: 10.1002/pds.2013.CrossRefPubMedGoogle Scholar
  53. 53.
    King NB, Fraser V, Boikos C, Richardson R, Harper S. Determinants of increased opioid-related mortality in the United States and Canada, 1990–2013: a systematic review. Am J Public Health. 2014;104(8):e32–42. doi: 10.2105/ajph.2014.301966.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    McDonald DC, Carlson K, Izrael D. Geographic variation in opioid prescribing in the U.S. J Pain. 2012;13(10):988–96. doi: 10.1016/j.jpain.2012.07.007.CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Coplan P, Wentworth C, Sessler N, Downing J, Alexander L, Chilcoat.H. Opioid analgesic dosage strength as a predictor of overdose risk in the UK (Abstracts of the 29th International Conference on Pharmacoepidemiology & Therapeutic Risk Management, August 25–28, 2013, Montréal, Canada). Pharmacoepidemiol Drug Saf. 2013;22(Suppl. 1):120. doi: 10.1002/pds.3512.
  56. 56.
    Pain Treatment Topics. Opioid dose alone may not influence overdose risk. 2013. Accessed 12 Nov 2014.
  57. 57.
    Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths—United States, 2010. MMWR Morb Mortal Wkly Rep. 2014;63:881–5.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • K. Jobski
    • 1
  • B. Kollhorst
    • 1
  • T. Schink
    • 1
  • Edeltraut Garbe
    • 1
    • 2
    Email author
  1. 1.Leibniz Institute for Prevention Research and Epidemiology - BIPS GmbHBremenGermany
  2. 2.Core Scientific Area ‘Health Sciences’, University of BremenBremenGermany

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