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.
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References
Riechelmann RP, Tannock IF, Wang L, et al. Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst 2007; 99(8): 592–600
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: 679
Girre V, Arkoub H, Puts MT, et al. Potential drug interactions in elderly cancer patients. Crit Rev Oncol Hematol 2011; 78(3): 220–6
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): 2334–41
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): 983–9
Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol 2000; 18(8): 1780–99
Gaertner J, Ruberg K, Schlesiger G, et al. Drug interactions in palliative care: it’s more than cytochrome P450. Palliat Med. Epub 2011 Jul 7
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): 535–43
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): 504–13
Juurlink DN, Mamdani M, Kopp A, et al. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289(13): 1652–8
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): 342–53
von Gunten CF. Humpty-dumpty syndrome. Palliat Med 2007; 21(6): 461–2
National Hospice and Palliative Care Organization. Standards of practice for hospice programs. Alexandria (VA): National Hospice and Palliative Care Organization, 2000
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]
Carlson MD, Morrison RS, Holford TR, et al. Hospice care: what services do patients and their families receive? Health Serv Res 2007; 42(4): 1672–90
Klaschik E, Nauck F, Radbruch L, et al. Palliative medicine: definitions and principles [in German]. Internist 2000; 41(7): 606–11
Salloch S, Breitsameter C. Morality and moral conflicts in hospice care: results of a qualitative interview study. J Med Ethics 2010; 36(10): 588–92
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): 138–47
Isaac T, Weissman JS, Davis RB, et al. Overrides of medication alerts in ambulatory care. Arch Intern Med 2009; 169(3): 305–11
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): 400–5
Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational ClassificAtion of drug interactions. J Am Pharm Assoc (Wash) 2001; 41(2): 161–5
Zagermann-Muncke P. New classification of interactions: ABDA database as guide in the jungle of interactions [in German]. Pharm Ztg 2009; 154(1–2): 26–30
O’Mahony D, O’Connor MN. Pharmacotherapy at the end-of-life. Age Ageing 2011; 40(4): 419–22
Holmes HM, Hayley DC, Alexander GC, et al. Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006; 166(6): 605–9
Riechelmann RP, Krzyzanowska MK, Zimmermann C. Futile medication use in terminally ill cancer patients. Support Care Cancer 2009; 17(6): 745–8
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): 1313–8
Harrington CJ, Zaydfudim V. Buprenorphine maintenance therapy hinders acute pain management in trauma. Am Surg 2010;76(4): 397–9
Preston KL, Bigelow GE, Liebson IA. Butorphanol-precipitated withdrawal in opioid-dependent human volunteers. J Pharma col Exp Ther 1988; 246(2): 441–8
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): 527–41
Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009; 13(3): 219–30
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): 414–9
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): 1149–53
Perucca E. Clinically relevant drug interactions with anti-epileptic drugs. Br J Clin Pharmacol 2006; 61(3): 246–55
Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs 2011; 71(4): 489–514
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; 11:85
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): 219–33
Shah RR. Drug-induced QT interval prolongation: regulatory perspectives and drug development. Ann Med 2004; 36 Suppl. 1:47–52
Shephard DA. Principles and practice of palliative care. Can Med Assoc J 1977; 116(5): 522–6
Wilcock A, Beattie JM. Prolonged QT interval and metha-done: implications for palliative care. Curr Opin Support Palliat Care 2009; 3(4): 252–7
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): 295–309
Glare PA, Dunwoodie D, Clark K, et al. Treatment of nausea and vomiting in terminally ill cancer patients. Drugs 2008; 68(18): 2575–90
Harris DG. Nausea and vomiting in advanced cancer. Br Med Bull 2010; 96: 175–85
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): 756–67
Weschules DJ. Tolerability of the compound ABHR in hospice patients. J Palliat Med 2005; 8(6): 1135–43
Wilens TE, Stern TA, O’Gara PT. Adverse cardiac effects of combined neuroleptic ingestion and tricyclic antidepressant overdose. J Clin Psychopharmacol 1990; 10(1): 51–4
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): 42–51
Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry 2001; 62 Suppl. 21: 11–4
Moore AR, O’Keeffe ST. Drug-induced cognitive impair ment in the elderly. Drugs Aging 1999; 15(1): 15–28
Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008; (2): CD006722
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): 177–82
Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355(9209): 1048–52
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): 735–40
Simon ST, Bausewein C. Management of refractory breath-lessness in patients with advanced cancer. Wien Med Wochenschr 2009; 159(23-24): 591–8
Shih A, Jackson KC. Role of corticosteroids in palliative care. J Pain Palliat Care Pharmacother 2007; 21(4): 69–76
Gannon C, Dando N. Dose-sensitive steroid-induced hyperglycaemia. Palliat Med 2010; 24(7): 737–9
Christensen RC, Byerly MJ. Mandibular dystonia asso ciated with the combination of sertraline and metoclopramide [letter]. J Clin Psychiatry 1996; 57(12): 596
Fisher AA, Davis MW. Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction. Ann Pharmacother 2002; 36(1): 67–71
Jackson N, Doherty J, Coulter S. Neuropsychiatric complications of commonly used palliative care drugs. Postgrad Med J 2008; 84(989): 121–6; quiz 5
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): 823–9
Schug SA, Manopas A. Update on the role of non-opioids for postoperative pain treatment. Best Pract Res Clin Anaesthesiol 2007; 21(1): 15–30
Portenoy RK. Treatment of cancer pain. Lancet 2011; 377(9784): 2236–47
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): CD005180
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): 326–9
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): 251–7
Regnard C, Hunter A. Increasing prescriber awareness of drug interactions in palliative care. J Pain Symptom Manage 2005; 29(3): 219–21
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): 7–11
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): 79–89
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.
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Frechen, S., Zoeller, A., Ruberg, K. et al. Drug Interactions in Dying Patients. Drug Saf 35, 745–758 (2012). https://doi.org/10.1007/BF03261971
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DOI: https://doi.org/10.1007/BF03261971