Skip to main content
Log in

Medication Withdrawal Trials in People Aged 65 Years and Older

A Systematic Review

  • Review Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

The objective of this review was to assess the benefits and risks of medication withdrawal in older people as documented in published trials of medication withdrawal. This was done by systematic review of the evidence from clinical trials of withdrawal of specific classes of medications in patient populations with a mean age of ≥65 years. We identified all relevant articles published between 1966 and 2007 initially through electronic searches on PubMed and manual searches of review articles. Numerous search terms related to the withdrawal of medication in older people were utilized. Clinical trials identified were reviewed according to predetermined inclusion/exclusion criteria. Only trials that focused on the withdrawal of specific classes of medication were included. Thirty-one published studies (n = 8972 subjects) met the inclusion criteria, including four randomized and placebo-controlled studies (n = 448 subjects) of diuretic withdrawal, nine open-label and prospective observational studies (n = 7188 subjects) of withdrawal of antihypertensives (including diuretics), 16 studies (n = 1184 patients) of withdrawal of sedative, antidepressant, cholinesterase inhibitor and antipsychotic medications, and 1 study each of withdrawal of nitrates and digoxin. These studies were of heterogeneous study design, patient selection criteria and follow-up. Withdrawal of diuretics was maintained in 51–100% of subjects and was unsuccessful primarily when heart failure was present. Adverse effects from medication withdrawal were infrequently encountered. After withdrawal of antihypertensive therapy, many subjects (20–85%) remained normotensive or did not require reinstatement of therapy for between 6 months and 5 years, and there was no increase in mortality. Withdrawal of psychotropic medications was associated with a reduction in falls and improved cognition. In conclusion, there is some clinical trial evidence for the short-term effectiveness and/or lack of significant harm when medication withdrawal is undertaken for antihypertensive, benzodiazepine and psychotropic agents in older people.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163–84

    Article  PubMed  CAS  Google Scholar 

  2. Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007; 21: 217–30

    Article  PubMed  CAS  Google Scholar 

  3. Anderson G, Kerluke K. Distribution of prescription drug exposures in the elderly: description and implications. J Clin Epidemiol 1996; 49: 929–35

    Article  PubMed  CAS  Google Scholar 

  4. Jorgensen T, Johansson S, Kennerfalk A, et al. Prescription drug use, diagnoses, and healthcare utilization among the elderly. Ann Pharmacother 2001; 35: 1004–9

    Article  PubMed  CAS  Google Scholar 

  5. Kennerfalk A, Ruigomez A, Wallander MA, et al. Geriatric drug therapy and healthcare utilization in the United Kingdom. Ann Pharmacother 2002; 36: 797–803

    Article  PubMed  Google Scholar 

  6. Ebrahim S. The medicalisation of old age. BMJ 2002; 324: 861–3

    Article  PubMed  Google Scholar 

  7. Abernethy DR. Aging effects on drug disposition and effect. Geriatr Nephrol Urol 1999; 9: 15–9

    Article  PubMed  CAS  Google Scholar 

  8. Le Couteur D, Naganathan V, Cogger VC, et al. Pharmacotherapy in the elderly: clinical issues and perspectives. In: Kohli K, Gupta M, Tejwani S, editors. Contemporary perspectives on clinical pharmacotherapeutics. New Delhi: Elsevier, 2006: 13

    Google Scholar 

  9. Milton JC, Hill-Smith I, Jackson HD. Prescribing for older people. BMJ 2008; 366: 606–9

    Article  Google Scholar 

  10. Cumming RG. Epidemiology of medication-related falls and fractures in the elderly. Drugs Aging 1998; 12: 43–53

    Article  PubMed  CAS  Google Scholar 

  11. Walker J, Wynne H. Review: the frequency and severity of adverse drug reactions in elderly people. Age Ageing 1994; 23: 255–9

    Article  PubMed  CAS  Google Scholar 

  12. Denham MJ. Adverse drug reactions. Br Med Bull 1990; 46: 53–62

    PubMed  CAS  Google Scholar 

  13. Mannesse CK, Derkx FH, de Ridder MA, et al. Adverse drug reactions in elderly patients as contributing factor for hospital admission: cross sectional study. BMJ 1997; 315: 1057–8

    Article  PubMed  CAS  Google Scholar 

  14. Bordet R, Gautier S, Le Louet H, et al. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin Pharmacol 2001; 56: 935–41

    Article  PubMed  CAS  Google Scholar 

  15. Carbonin P, Pahor M, Bernabei R, et al. Is age an independent risk factor of adverse drug reactions in hospitalized medical patients? J Am Geriatr Soc 1991; 39: 1093–9

    PubMed  CAS  Google Scholar 

  16. Hurwitz N. Predisposing factors in adverse reactions to drugs. BMJ 1969; 1: 536–9

    Article  PubMed  CAS  Google Scholar 

  17. Kellaway GS, McCrae E. Intensive monitoring for adverse drug effects in patients discharged from acute medical wards. NZ Med J 1973; 78: 525–8

    CAS  Google Scholar 

  18. Pouyanne P, Haramburu F, Imbs JL, et al. Admissions to hospital caused by adverse drug reactions: cross-sectional incidence study: French Pharmacovigilance Centres. BMJ 2000; 320: 1036

    Article  PubMed  CAS  Google Scholar 

  19. Ebbesen J, Buajordet I, Erikssen J, et al. Drug-related deaths in a department of internal medicine. Arch Intern Med 2001; 161: 2317–23

    Article  PubMed  CAS  Google Scholar 

  20. Buajordet I, Ebbesen J, Erikssen J, et al. Fatal adverse drug events: the paradox of drug treatment. J Intern Med 2001; 250: 327–41

    Article  PubMed  CAS  Google Scholar 

  21. Hilmer SN, Mager DE, Simonsick EM, et al. A drug burden index to define the functional burden of medications in older people. Arch Intern Med 2007; 167: 781–7

    Article  PubMed  Google Scholar 

  22. Le Couteur DG, Bailey L, Naganathan V. Beta-blockers and heart failure in older people. Eur Heart J 2006; 27: 887–8

    Article  PubMed  Google Scholar 

  23. Gallagher P, Barry P, O’Mahony D. Inappropriate prescribing in the elderly. J Clin Pharm Ther 2007; 32: 113–21

    Article  PubMed  CAS  Google Scholar 

  24. Garcia RM. Five ways you can reduce inappropriate prescribing in the elderly: a systematic review. J Fam Pract 2006; 55: 305–12

    PubMed  Google Scholar 

  25. Jano E, Aparasu RR. Healthcare outcomes associated with Beers’ criteria: a systematic review. Ann Pharmacother 2007; 41: 438–47

    Article  PubMed  Google Scholar 

  26. Burr ML, King S, Davies HE, et al. The effects of discontinuing long-term diuretic therapy in the elderly. Age Ageing 1977; 6: 38–45

    Article  PubMed  CAS  Google Scholar 

  27. Myers MG, Weingert ME, Fisher RH, et al. Unnecessary diuretic therapy in the elderly. Age Ageing 1982; 11: 213–21

    Article  PubMed  CAS  Google Scholar 

  28. de Jonge JW, Knottnerus JA, van Zutphen WM, et al. Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema. BMJ 1994; 308: 511–3

    Article  PubMed  Google Scholar 

  29. Walma EP, Hoes AW, van Dooren C, et al. Withdrawal of long-term diuretic medication in elderly patients: a double blind randomised trial. BMJ 1997; 315: 464–8

    Article  PubMed  CAS  Google Scholar 

  30. Nelson MR, Reid CM, Kram H, et al. Predictors of normotension on withdrawal of antihypertensive drags in elderly patients: prospective study in second Australian National Blood Pressure Study cohort. BMJ 2002; 325: 815–9

    Article  PubMed  Google Scholar 

  31. Nelson MR, Reid CM, Kram H, et al. Short-term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in the second Australian National Blood Pressure Study (ANBP2). Am J Hypertens 2003; 16: 39–45

    Article  PubMed  Google Scholar 

  32. Ekbom T, Lindholm LH, Oden A, et al. A 5-year prospective, observational study of the withdrawal of antihypertensive treatment in elderly people. J Intern Med 1994; 235: 581–8

    Article  PubMed  CAS  Google Scholar 

  33. van Kraaij DJ, Jansen RW, Bruijns E, et al. Diuretic usage and withdrawal patterns in a Dutch geriatric patient population. J Am Geriatr Soc 1997; 45: 918–22

    PubMed  Google Scholar 

  34. van Kraaij DJ, Jansen RW, Gribnau FW, et al. Use of diuretics and opportunities for withdrawal in a Dutch nursing home population. Neth J Med 1998; 53: 20–6

    Article  PubMed  Google Scholar 

  35. Straand J, Fugelli P, Laake K. Withdrawing long-term diuretic treatment among elderly patients in general practice. Fam Pract 1993; 10: 38–42

    Article  PubMed  CAS  Google Scholar 

  36. Hansen AG, Jensen H, Laugesen LP, et al. Withdrawal of antihypertensive drags in the elderly. Acta Med Scand Suppl 1983; 676: 178–85

    PubMed  CAS  Google Scholar 

  37. Lernfelt B, Landahl S, Svanborg A, et al. Overtreatment of hypertension in the elderly? J Hypertens 1990; 8: 483–90

    Article  PubMed  CAS  Google Scholar 

  38. Walma EP, Hoes AW, Prins A, et al. Withdrawing long-term diuretic therapy in the elderly: a study in general practice in The Netherlands. Fam Med 1993; 25: 661–4

    PubMed  CAS  Google Scholar 

  39. Nadal M, Wikstrom L, Allgulander S. Once hypertensive, always hypertensive? A three year follow-up after stopping medication. Scand J Prim Health Care 1994; 12: 62–4

    Article  PubMed  CAS  Google Scholar 

  40. Ulfvarson J, Adami J, Wredling R, et al. Controlled withdrawal of selective serotonin reuptake inhibitor drags in elderly patients in nursing homes with no indication of depression. Eur J Clin Pharmacol 2003; 59: 735–40

    Article  PubMed  CAS  Google Scholar 

  41. Campbell AJ, Robertson MC, Gardner MM, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999; 47: 850–3

    PubMed  CAS  Google Scholar 

  42. Curran HV, Collins R, Fletcher S, et al. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 2003; 33: 1223–37

    Article  PubMed  CAS  Google Scholar 

  43. Ballard CG, Thomas A, Fossey J, et al. A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 2004; 65: 114–9

    Article  PubMed  Google Scholar 

  44. Tariot PN, Jakimovich LJ, Erb R, et al. Withdrawal from controlled carbamazepine therapy followed by further carbamazepine treatment in patients with dementia. J Clin Psych 1999; 60: 684–9

    Article  CAS  Google Scholar 

  45. Findlay J, McEwen J, Ballinger BR, et al. Double-blind controlled withdrawal of thioridazine treatment in elderly female inpatients with senile dementia. Int J Geriatr Psychiatry 1989; 4: 115–20

    Article  Google Scholar 

  46. Habraken H, Soenen K, Blondeel L, et al. Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research. Eur J Clin Pharmacol 1997; 51: 355–8

    Article  PubMed  CAS  Google Scholar 

  47. Bridges-Parlet S, Knopman D, Steffes S. Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double-blind, baseline-treatment-controlled pilot study. J Geriatr Psychiatry Neurol 1997; 10: 119–26

    PubMed  CAS  Google Scholar 

  48. Cohen-Mansfield J, Lipson S, Werner P, et al. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Arch Intern Med 1999; 159: 1733–40

    Article  PubMed  CAS  Google Scholar 

  49. van Reekum R, Clarke D, Conn D, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002; 14: 197–210

    Article  PubMed  Google Scholar 

  50. Ruths S, Straand J, Nygaard HA, et al. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. J Am Geriatr Soc 2004; 52: 1737–43

    Article  PubMed  Google Scholar 

  51. Salzman CFJ, Nobel K, Glassman R, et al. Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 1992; 7: 89–93

    Article  Google Scholar 

  52. Horwitz GJ, Tariot PN, Mead K, et al. Discontinuation of antipsychotics in nursing home patients with dementia. Am J Geriatr Psychiatry 1995; 3: 290–9

    Article  Google Scholar 

  53. Minett TS, Thomas A, Wilkinson LM, et al. What happens when donepezil is suddenly withdrawn? An open-label trial in dementia with Lewy bodies and Parkinson’s disease with dementia. Int J Geriatr Psychiatry 2003; 18: 988–93

    Article  PubMed  Google Scholar 

  54. Fair JF. Supervised withdrawal of long-term digoxin therapy. Fam Pract 1990; 7: 56–9

    Article  PubMed  CAS  Google Scholar 

  55. Thapa PB, Meador KG, Gideon P, et al. Effects of antipsychotic withdrawal in elderly nursing home residents. J Am Geriatr Soc 1994; 42: 280–6

    PubMed  CAS  Google Scholar 

  56. George J, Kitzis I, Zandorf D, et al. Safety of nitrate withdrawal in angina-free and hemodynamically stable patients with coronary artery disease. Chest 2003; 124: 1652–7

    Article  PubMed  CAS  Google Scholar 

  57. Lindstrom K, Ekedahl A, Carlsten A, et al. Can selective serotonin inhibitor drugs in elderly patients in nursing homes be reduced? Scand J Prim Health Care 2007; 25: 3–8

    Article  PubMed  Google Scholar 

  58. Chang JT, Morton SC, Rubenstein LZ, et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. BMJ 2004; 328: 680–6

    Article  PubMed  Google Scholar 

  59. Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 2003; 17: 825–37

    Article  PubMed  CAS  Google Scholar 

  60. Gilbert A, Owen N, Innes JM, et al. Trial of an intervention to reduce chronic benzodiazepine use among residents of agedcare accommodation. Aust NZ J Med 1993; 23: 343–7

    Article  CAS  Google Scholar 

  61. Jones D. Weaning elderly patients off psychotropic drugs in general practice: a randomised controlled trial. Health Trends 1990; 22: 164–6

    Google Scholar 

  62. Tata PR, Rollings J, Collins M, et al. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med 1994; 24: 203–13

    Article  PubMed  CAS  Google Scholar 

  63. Fossey J, Ballard C, Juszczak E, et al. Effect of enhanced psychosocial care on antipsychotic use in nursing home residents with severe dementia: cluster randomised trial. BMJ 2006; 332: 756–61

    Article  PubMed  Google Scholar 

  64. Avorn J, Soumerai SB, Everitt DE, et al. A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. N Engl J Med 1992; 327: 168–73

    Article  PubMed  CAS  Google Scholar 

  65. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors: RADIANCE study. N Engl J Med 1993; 329: 1–7

    Article  PubMed  CAS  Google Scholar 

  66. Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol 1994; 22: 955–62

    Article  Google Scholar 

  67. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993 Jul 1; 329(1): 1–7

    Article  PubMed  CAS  Google Scholar 

  68. Gerety MB, Cornell JE, Plichta DT, et al. Adverse events related to drugs and drug withdrawal in nursing home residents. J Am Geriatr Soc 1993; 41: 1326–32

    PubMed  CAS  Google Scholar 

  69. Graves T, Hanlon JT, Schmader KE, et al. Adverse events after discontinuing medications in elderly outpatients. Arch Intern Med 1997; 157: 2205–10

    Article  PubMed  CAS  Google Scholar 

  70. Boockvar K, Fishman E, Kyriacou CK, et al. Adverse events due to discontinuations in drug use and dose changes in patients transferred between acute and long-term care facilities. Arch Intern Med 2004; 164: 545–50

    Article  PubMed  Google Scholar 

  71. van der Velde N, Stricker BH, Pols HA, et al. Risk of falls after withdrawal of fall-risk-increasing drugs: a prospective cohort study. Br J Clin Pharmacol 2007; 63: 232–7

    Article  PubMed  Google Scholar 

  72. Alexander GC, Sayla MA, Holmes HM, et al. Prioritizing and stopping prescription medicines. CMAJ 2006; 174: 1083–4

    Article  PubMed  Google Scholar 

  73. Holmes HM, Hayley DC, Alexander GC, et al. Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006; 166: 605–9

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the support of the Ageing and Alzheimers Research Foundation (a Division of the Medical Foundation of the University of Sydney). The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David G. Le Conteur.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iyer, S., Naganathan, V., McLachlan, A.J. et al. Medication Withdrawal Trials in People Aged 65 Years and Older. Drugs Aging 25, 1021–1031 (2008). https://doi.org/10.2165/0002512-200825120-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/0002512-200825120-00004

Keywords

Navigation