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Drug Safety

, Volume 35, Issue 9, pp 745–758 | Cite as

Drug Interactions in Dying Patients

A Retrospective Analysis of Hospice Inpatients in Germany
  • Sebastian Frechen
  • Anna Zoeller
  • Klaus Ruberg
  • Raymond Voltz
  • Jan Gaertner
Original Research Article

Abstract

Background: Patients at the end of life often receive numerous medications for symptom management. In contrast to all other clinical situations, the aim of pharmacotherapy is strictly focused on quality of life.

Objective: The primary aims of this study were to assess the potential for drug-drug interactions (DDIs) in patients at the very end of life by identifying drug combinations and risk factors associated with a high risk of DDIs; and evaluate the clinical relevance of the potential DDIs in this unique patient population. Secondary objectives were to increase prescriber awareness and to derive a comprehensive framework for physicians to minimize DDIs in this specific setting of end-of-life care.

Materials and Methods: Charts of 364 imminently dying inpatients of two hospices were reviewed retrospectively. Drugs prescribed during the last 2 weeks of life were screened for DDIs by the electronic database of the Federal Union of German Associations of Pharmacists, which classifies DDIs by therapeutic measures required to reduce possible adverse events according to the ORCA system (OpeRational ClAssification of Drug Interactions).

Results: Potential DDIs were detected in 223 patients (61%). In a multivariate analysis, polypharmacy was the major predictor for DDIs (odds ratio 1.5, 95% CI 1.4, 1.6). The drugs most commonly involved in therapeutically rel evant potential DDIs were antipsychotics, antiemetics (e.g. metoclopramide, antihistamines), antidepressants, insulin, glucocorticoids, cardiovascular drugs and, in particular, NSAIDs. The most prevalent potential adverse effects were pharmacodynamically additive anticholinergic, antidopaminergic, cardiac (QT interval prolongation) and NSAID-associated toxicity (e.g. gastrointestinal, renal).

Conclusion: In the context of end-of-life care, the clinical relevance of DDIs differs from other clinical settings. Most DDIs can be prevented if the prescribing physician considers a few therapeutic principles. Specifically, this concerns the awareness of futile and high-risk medications, as well as rational alternatives.

Keywords

Palliative Care Clopidogrel Pregabalin Dipyrone Hospice Care 
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.

Notes

Acknowledgements

This study was supported by an unrestricted research grant from Mundipharma. The scientific work of the Department of Palliative Medicine, University Clinic of Cologne, is supported by the Federal Ministry for Education and Science (BMBF 01KN1106). The clinical and academic activities of the Department of Palliative Medicine, University Clinic of Cologne, are substantially supported by the German Cancer Aid (Deutsche Krebshilfe e.V.).

The authors declare no conflicts of interest.

The authors would like to thank the Managing Directors of the two hospices, Verena Tophofen (“Haus Erftaue”, Erftstadt, Germany) and Sebastian Roth (“Stationäres Hospiz im Waldkrankenhaus”, Bad Godesberg, Germany) for their kind and helpful cooperation that made this study possible.

References

  1. 1.
    Riechelmann RP, Tannock IF, Wang L, et al. Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst 2007; 99(8): 592–600PubMedCrossRefGoogle Scholar
  2. 2.
    van Leeuwen RW, Swart EL, Boom FA, et al. Potential drug interactions and duplicate prescriptions among ambulatory cancer patients: a prevalence study using an advanced screening method. BMC Cancer 2010; 10: 679PubMedCrossRefGoogle Scholar
  3. 3.
    Girre V, Arkoub H, Puts MT, et al. Potential drug interactions in elderly cancer patients. Crit Rev Oncol Hematol 2011; 78(3): 220–6PubMedCrossRefGoogle Scholar
  4. 4.
    van Leeuwen RW, Swart EL, Boven E, et al. Potential drug interactions in cancer therapy: a prevalence study using an advanced screening method. Ann Oncol 2011; 22(10): 2334–41PubMedCrossRefGoogle Scholar
  5. 5.
    Lal LS, Zhuang A, Hung F, et al. Evaluation of drug interactions in patients treated with antidepressants at a tertiary care cancer center. Support Care Cancer 2012; 20(5): 983–9PubMedCrossRefGoogle Scholar
  6. 6.
    Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol 2000; 18(8): 1780–99PubMedGoogle Scholar
  7. 7.
    Gaertner J, Ruberg K, Schlesiger G, et al. Drug interactions in palliative care: it’s more than cytochrome P450. Palliat Med. Epub 2011 Jul 7Google Scholar
  8. 8.
    Riechelmann RP, Zimmermann C, Chin SN, et al. Potential drug interactions in cancer patients receiving supportive care exclusively. J Pain Symptom Manage 2008; 35(5): 535–43PubMedCrossRefGoogle Scholar
  9. 9.
    Kohler GI, Bode-Boger SM, Busse R, et al. Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use. Int J Clin Pharmacol Ther 2000; 38(11): 504–13PubMedGoogle Scholar
  10. 10.
    Juurlink DN, Mamdani M, Kopp A, et al. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289(13): 1652–8PubMedCrossRefGoogle Scholar
  11. 11.
    Miranda V, Fede A, Nobuo M, et al. Adverse drug reactions and drug interactions as causes of hospital admission in oncology. J Pain Symptom Manage 2011; 42(3): 342–53PubMedCrossRefGoogle Scholar
  12. 12.
    von Gunten CF. Humpty-dumpty syndrome. Palliat Med 2007; 21(6): 461–2CrossRefGoogle Scholar
  13. 13.
    National Hospice and Palliative Care Organization. Standards of practice for hospice programs. Alexandria (VA): National Hospice and Palliative Care Organization, 2000Google Scholar
  14. 14.
    National Hospice and Palliative Care Organization. NHPCO facts and figures: hospice care in America. 2010 ed. [online]. Available from URL: http://www.nhpco.org/files/public/Statistics_Research/Hospice_Facts_Figures_Oct-2010.pdf [Accessed 2011 Jun 30]
  15. 15.
    Carlson MD, Morrison RS, Holford TR, et al. Hospice care: what services do patients and their families receive? Health Serv Res 2007; 42(4): 1672–90PubMedCrossRefGoogle Scholar
  16. 16.
    Klaschik E, Nauck F, Radbruch L, et al. Palliative medicine: definitions and principles [in German]. Internist 2000; 41(7): 606–11PubMedCrossRefGoogle Scholar
  17. 17.
    Salloch S, Breitsameter C. Morality and moral conflicts in hospice care: results of a qualitative interview study. J Med Ethics 2010; 36(10): 588–92PubMedCrossRefGoogle Scholar
  18. 18.
    van der Sijs H, Aarts J, Vulto A, et al. Overriding of drug safety alerts in computerized physician order entry. J Am Med Inform Assoc 2006; 13(2): 138–47PubMedCrossRefGoogle Scholar
  19. 19.
    Isaac T, Weissman JS, Davis RB, et al. Overrides of medication alerts in ambulatory care. Arch Intern Med 2009; 169(3): 305–11PubMedCrossRefGoogle Scholar
  20. 20.
    Mille F, Schwartz C, Brion F, et al. Analysis of overridden alerts in a drug-drug interaction detection system. Int J Qual Health Care 2008; 20(6): 400–5PubMedCrossRefGoogle Scholar
  21. 21.
    Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational ClassificAtion of drug interactions. J Am Pharm Assoc (Wash) 2001; 41(2): 161–5Google Scholar
  22. 22.
    Zagermann-Muncke P. New classification of interactions: ABDA database as guide in the jungle of interactions [in German]. Pharm Ztg 2009; 154(1–2): 26–30Google Scholar
  23. 23.
    O’Mahony D, O’Connor MN. Pharmacotherapy at the end-of-life. Age Ageing 2011; 40(4): 419–22PubMedCrossRefGoogle Scholar
  24. 24.
    Holmes HM, Hayley DC, Alexander GC, et al. Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006; 166(6): 605–9PubMedCrossRefGoogle Scholar
  25. 25.
    Riechelmann RP, Krzyzanowska MK, Zimmermann C. Futile medication use in terminally ill cancer patients. Support Care Cancer 2009; 17(6): 745–8PubMedCrossRefGoogle Scholar
  26. 26.
    Fede A, Miranda M, Antonangelo D, et al. Use of un necessary medications by patients with advanced cancer: cross-sectional survey. Support Care Cancer 2011; 19(9): 1313–8PubMedCrossRefGoogle Scholar
  27. 27.
    Harrington CJ, Zaydfudim V. Buprenorphine maintenance therapy hinders acute pain management in trauma. Am Surg 2010;76(4): 397–9PubMedGoogle Scholar
  28. 28.
    Preston KL, Bigelow GE, Liebson IA. Butorphanol-precipitated withdrawal in opioid-dependent human volunteers. J Pharma col Exp Ther 1988; 246(2): 441–8Google Scholar
  29. 29.
    Oifa S, Sydoruk T, White I, et al. Effects of intravenous patient-controlled analgesia with buprenorphine and morphine alone and in combination during the first 12 post-operative hours: a randomized, double-blind, four-arm trial in adults undergoing abdominal surgery. Clin Ther 2009; 31(3): 527–41PubMedCrossRefGoogle Scholar
  30. 30.
    Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009; 13(3): 219–30PubMedCrossRefGoogle Scholar
  31. 31.
    Lertxundi U, Peral J, Mora O, et al. Antidopaminergic therapy for managing comorbidities in patients with Parkinson’s disease. Am J Health Syst Pharm 2008; 65(5): 414–9PubMedCrossRefGoogle Scholar
  32. 32.
    Cuisset T, Frere C, Quilici J, et al. Comparison of omepra-zole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009; 54(13): 1149–53PubMedCrossRefGoogle Scholar
  33. 33.
    Perucca E. Clinically relevant drug interactions with anti-epileptic drugs. Br J Clin Pharmacol 2006; 61(3): 246–55PubMedCrossRefGoogle Scholar
  34. 34.
    Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs 2011; 71(4): 489–514PubMedGoogle Scholar
  35. 35.
    Semel D, Murphy TK, Zlateva G, et al. Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies. BMC Fam Pract 2010; 11:85PubMedCrossRefGoogle Scholar
  36. 36.
    Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res 2000; 47(2): 219–33PubMedCrossRefGoogle Scholar
  37. 37.
    Shah RR. Drug-induced QT interval prolongation: regulatory perspectives and drug development. Ann Med 2004; 36 Suppl. 1:47–52PubMedCrossRefGoogle Scholar
  38. 38.
    Shephard DA. Principles and practice of palliative care. Can Med Assoc J 1977; 116(5): 522–6PubMedGoogle Scholar
  39. 39.
    Wilcock A, Beattie JM. Prolonged QT interval and metha-done: implications for palliative care. Curr Opin Support Palliat Care 2009; 3(4): 252–7PubMedCrossRefGoogle Scholar
  40. 40.
    Flockhart DA, Desta Z, Mahal SK. Selection of drugs to treat gastro-oesophageal reflux disease: the role of drug interactions. Clin Pharmacokinet 2000; 39(4): 295–309PubMedCrossRefGoogle Scholar
  41. 41.
    Glare PA, Dunwoodie D, Clark K, et al. Treatment of nausea and vomiting in terminally ill cancer patients. Drugs 2008; 68(18): 2575–90PubMedCrossRefGoogle Scholar
  42. 42.
    Harris DG. Nausea and vomiting in advanced cancer. Br Med Bull 2010; 96: 175–85PubMedCrossRefGoogle Scholar
  43. 43.
    Davis MP, Hallerberg G. A systematic review of the treat ment of nausea and/or vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manage 2010; 39(4): 756–67PubMedCrossRefGoogle Scholar
  44. 44.
    Weschules DJ. Tolerability of the compound ABHR in hospice patients. J Palliat Med 2005; 8(6): 1135–43PubMedCrossRefGoogle Scholar
  45. 45.
    Wilens TE, Stern TA, O’Gara PT. Adverse cardiac effects of combined neuroleptic ingestion and tricyclic antidepressant overdose. J Clin Psychopharmacol 1990; 10(1): 51–4PubMedCrossRefGoogle Scholar
  46. 46.
    Ness J, Hoth A, Barnett MJ, et al. Anticholinergic medications in community-dwelling older veterans: prevalence of anticholinergic symptoms, symptom burden, and adverse drug events. Am J Geriatr Pharmacother 2006; 4(1): 42–51PubMedCrossRefGoogle Scholar
  47. 47.
    Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry 2001; 62 Suppl. 21: 11–4PubMedGoogle Scholar
  48. 48.
    Moore AR, O’Keeffe ST. Drug-induced cognitive impair ment in the elderly. Drugs Aging 1999; 15(1): 15–28PubMedCrossRefGoogle Scholar
  49. 49.
    Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008; (2): CD006722PubMedGoogle Scholar
  50. 50.
    Mishra S, Bhatnagar S, Nirvani Goyal G, et al. A comparative efficacy of amitriptyline, gabapentin, and prega-balin in neuropathic cancer pain: a prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care 2012; 29(3): 177–82PubMedCrossRefGoogle Scholar
  51. 51.
    Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355(9209): 1048–52PubMedCrossRefGoogle Scholar
  52. 52.
    Piper JM, Ray WA, Daugherty JR, et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991; 114(9): 735–40PubMedCrossRefGoogle Scholar
  53. 53.
    Simon ST, Bausewein C. Management of refractory breath-lessness in patients with advanced cancer. Wien Med Wochenschr 2009; 159(23-24): 591–8PubMedCrossRefGoogle Scholar
  54. 54.
    Shih A, Jackson KC. Role of corticosteroids in palliative care. J Pain Palliat Care Pharmacother 2007; 21(4): 69–76PubMedCrossRefGoogle Scholar
  55. 55.
    Gannon C, Dando N. Dose-sensitive steroid-induced hyperglycaemia. Palliat Med 2010; 24(7): 737–9PubMedCrossRefGoogle Scholar
  56. 56.
    Christensen RC, Byerly MJ. Mandibular dystonia asso ciated with the combination of sertraline and metoclopramide [letter]. J Clin Psychiatry 1996; 57(12): 596PubMedCrossRefGoogle Scholar
  57. 57.
    Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother 2002; 36(1): 67–71PubMedCrossRefGoogle Scholar
  58. 58.
    Jackson N, Doherty J, Coulter S. Neuropsychiatric complications of commonly used palliative care drugs. Postgrad Med J 2008; 84(989): 121–6; quiz 5PubMedCrossRefGoogle Scholar
  59. 59.
    Vandraas KF, Spigset O, Mahic M, et al. Non-steroidal anti-inflammatory drugs: use and co-treatment with potentially interacting medications in the elderly. Eur J Clin Pharmacol 2010; 66(8): 823–9PubMedCrossRefGoogle Scholar
  60. 60.
    Schug SA, Manopas A. Update on the role of non-opioids for postoperative pain treatment. Best Pract Res Clin Anaesthesiol 2007; 21(1): 15–30PubMedCrossRefGoogle Scholar
  61. 61.
    Portenoy RK. Treatment of cancer pain. Lancet 2011; 377(9784): 2236–47PubMedCrossRefGoogle Scholar
  62. 62.
    McNicol E, Strassels SA, Goudas L, et al. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev 2005; (1): CD005180PubMedGoogle Scholar
  63. 63.
    Wilcock A, Thomas J, Frisby J, et al. Potential for drug interactions involving cytochrome P450 in patients at tending palliative day care centres: a multicentre audit. Br J Clin Pharmacol 2005; 60(3): 326–9PubMedCrossRefGoogle Scholar
  64. 64.
    Haddad A, Davis M, Lagman R. The pharmacological im portance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions. Support Care Cancer 2007; 15(3): 251–7PubMedCrossRefGoogle Scholar
  65. 65.
    Regnard C, Hunter A. Increasing prescriber awareness of drug interactions in palliative care. J Pain Symptom Manage 2005; 29(3): 219–21PubMedCrossRefGoogle Scholar
  66. 66.
    O’Connor M, Pugh J, Jiwa M, et al. The palliative care interdisciplinary team: where is the community pharmacist?. J Palliat Med 2011; 14(1): 7–11PubMedCrossRefGoogle Scholar
  67. 67.
    Borgsteede SD, Rhodius CA, De Smet PA, et al. The use of opioids at the end of life: knowledge level of pharmacists and cooperation with physicians. Eur J Clin Pharmacol 2011; 67(1): 79–89PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Sebastian Frechen
    • 1
    • 2
  • Anna Zoeller
    • 1
  • Klaus Ruberg
    • 3
    • 4
  • Raymond Voltz
    • 1
    • 5
    • 6
  • Jan Gaertner
    • 1
    • 5
    • 6
  1. 1.Department of Palliative CareCologne University HospitalCologneGermany
  2. 2.Department of Pharmacology, Clinical PharmacologyCologne University HospitalCologneGermany
  3. 3.Kronen Pharmacy, Hospital and Community PharmacyWesselingGermany
  4. 4.Working Group Pharmacists of the German Association of Palliative CareBerlinGermany
  5. 5.Center for Integrated Oncology Cologne/BonnCologne University HospitalCologneGermany
  6. 6.Cologne Clinical Trials CenterCologneGermany

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