Medicines have adverse effects and the use of multiple medicines, polypharmacy, can be associated with poorer outcomes. Health professionals need to recognise when medicines should be ceased and how to deprescribe. Deprescribing could be considered when there is polypharmacy, adverse drug reactions, ineffective treatment, falls or when treatment goals have changed. If patients are slowly weaned off their medicines, withdrawal and rebound syndromes are usually not serious. A cautious approach to deprescribing includes two principles - stop one drug at a time and wean doses slowly over weeks and months

Banks, Emily

Gnjidic, Donijela

Le Couteur, D

McLachlan, Andrew

Australian Prescriber

English

The Australian National University

182 | Volume 34 | NumBeR 6 | decemBeR 2011 www.austral ianprescriber.comDeprescribingDavid Le Couteur, Professor of Geriatric Medicine,1 Emily Banks, Professor and National Health and Medical Research Council Senior Research Fellow,2 Danijela Gnjidic, Postdoctoral scientist,1,4 and Andrew McLachlan, Professor of Pharmacy (Aged Care)3 1. Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney 2. National Centre for Epidemiology and Population Health, The Australian National University, Canberra 3. Faculty of Pharmacy, University of Sydney and Concord Hospital, Sydney 4. Departments of Pharmacology and Aged Care, Royal North Shore Hospital, SydneySummaryMedicines have adverse effects and the use of multiple medicines, polypharmacy, can be associated with poorer outcomes. Health professionals need to recognise when medicines should be ceased and how to deprescribe. Deprescribing could be considered when there is polypharmacy, adverse drug reactions, ineffective treatment, falls or when treatment goals have changed. if patients are slowly weaned off their medicines, withdrawal and rebound syndromes are usually not serious. A cautious approach to deprescribing includes two principles – stop one drug at a time and wean doses slowly over weeks and months.Key words: drug withdrawal, falls, polypharmacy.(Aust Prescr 2011;34:182–5)introductionThere are many evidence-based guidelines to help clinicians start drug treatment. There is much less evidence to guide clinicians about withdrawing medicines. Several terms have been used for ceasing medicines including deprescribing, withdrawal, discontinuation, pharmacolysis, untrials and prescription pruning. Here deprescribing is used to define the cessation of long-term therapy, supervised by a clinician. when should deprescribing be considered?Good practice requires a regular review of a patient's medicines. These reviews are a good time to consider deprescribing.PolypharmacyThe use of multiple medicines is termed polypharmacy. In older people it is associated with an increased risk of impaired physical and cognitive function, institutionalisation, hospitalisation and death. These associations appear to be independent of the underlying diseases.1 Moreover, studies show that reducing the number of drugs has positive outcomes in older people. A feasibility study to reduce polypharmacy in people over 70 years of age suggested that over half of their medicines could be discontinued. only 2% of the drugs needed to be restarted because the original indication re-emerged. overall there was improvement in cognition and the patients' global health.2 A review of medicine withdrawal studies in older people found that withdrawal was rarely associated with adverse effects.3 After withdrawal of antihypertensive therapy, many patients (20–85%) remained normotensive and withdrawal of psychotropic drugs was associated with a reduction in falls and improved cognition.3 This is further supported by a recent Australian pilot study which confirmed the feasibility of deprescribing in polypharmacy.4 Adverse drug reactionsIt is common sense to stop a drug, or to reconsider its benefit:harm ratio, if it causes a significant adverse reaction. For example, in secondary stroke prevention trials of antiplatelet drugs, up to one in five patients stopped treatment because of adverse drug reactions. Given that clinical trial participants do not always reflect real-life patients, it is likely that a greater number of patients in everyday practice will be unable to tolerate their medicines. Health professionals often have difficulty recognising adverse drug reactions, partly because they are reluctant and unwilling to recognise them and partly because the reactions can be mistaken for symptoms of disease. Falls and cognitive impairment are frequently secondary to adverse drug reactions in older people, yet are often overlooked as simply part of the ageing process.5 Lack of effectivenessFor many drugs it is not possible for any individual clinician to assess effectiveness. This is because many drugs are used to prevent illness or because the number of patients who need to be treated for one to benefit is too large for the effect to be perceptible.6 However, if a drug has no effect on a surrogate outcome (for example blood pressure, cholesterol) or symptoms, then it is pointless to continue therapy because it accrues cost and the risk of harm without any benefit.| Volume 34 | NumBeR 6 | decemBeR 2011 183www.austral ianprescriber.comFallsPolypharmacy and drugs acting on the central nervous system are important risk factors for falls, increasing the risk by around 50%.7 A placebo-controlled clinical trial of withdrawing psychotropic drugs showed that falls were reduced by 66%.8 The number of hip fractures in Australia could be reduced by 10% simply by avoiding the use of benzodiazepines in older people.9 The relationship between cardiovascular drugs and falls is less clear. Antihypertensive drugs are often ceased in older people with orthostatic hypotension and recurrent falls.Terminal illness, dementia or frailtyIt is important to re-evaluate the role of medicines once a patient has entered the terminal phases of an illness, become frail or developed disabling dementia, as there should be a shift in treatment goals. Many preventive therapies such as medicines used to treat hypertension, osteoporosis and hyperlipidaemia take many months and even years before their benefit is established. They have limited value in patients with a short life expectancy. Furthermore the pharmacokinetics and pharmacodynamics of many medicines change with frailty or terminal illness and this impacts on their harm:benefit ratio. Deprescribing will reduce the medicine load and potential adverse effects, while shifting the therapeutic focus to end-of-life issues that are important to the patient.10 what are the consequences of deprescribing?Like all medical interventions, including starting medicines, there are potential harms and benefits in deprescribing. There are several possible outcomes following deprescribing.No obvious change in clinical statusIn many cases there may be no obvious change in the patient after deprescribing. However, patient satisfaction is often increased, the financial cost to the patient and the community is reduced and the risk of future adverse drug reactions and interactions is removed. Resolution of specific adverse drug reactionsFor dose-dependent adverse drug reactions, resolution of the adverse effect will usually coincide with the disappearance of the drug from the blood (3–5 half-lives). However, in some situations, such as delirium, resolution may take much longer than expected on pharmacokinetic grounds.Improvement in function and quality of lifeIn a clinical trial to reduce polypharmacy in older people, the patients' global assessment scale improved in 88% and in most patients cognitive function improved.2 A systematic review concluded that deprescribing can be associated with improvements in cognition and behaviour in patients with dementia, and a reduction in falls.3 Simplification of drug regimens might also improve adherence and reduce medication errors.Withdrawal syndromesWhen deprescribing is undertaken slowly and under medical supervision, clinically significant adverse withdrawal reactions are rare.2,3 Even so, clinicians should be aware of potential problems.Withdrawal and discontinuation syndromesThe most common cause of discontinuation syndromes is the withdrawal of drugs acting on the central nervous system. Most general practitioners will be familiar with the antidepressant discontinuation syndrome commonly seen after ceasing selective serotonin reuptake inhibitors. The symptoms typically occur within one week of ceasing the drug. They are usually mild, and resolve over ten days or less. The abrupt withdrawal of benzodiazepines is associated with a much more serious withdrawal syndrome with confusion, hallucinations and seizures. Abrupt cessation of levodopa is associated with a serious withdrawal syndrome with features of the neuroleptic malignant syndrome, including severe muscle stiffness, autonomic instability and impaired consciousness. In patients who have been taking systemic corticosteroids for more than a few weeks, sudden cessation may sometimes lead to an Addisonian crisis secondary to suppression of the hypothalamic-pituitary-adrenal axis.11,12Rebound syndromesStopping a beta blocker can be associated with rebound tachycardia and hypertension which may aggravate heart failure or ischaemic heart disease. Stopping proton pump inhibitors is associated with hypersecretion of acid and aggravation of gastrointestinal symptoms. Simple analgesics and nasal drops can be obtained without a prescription, but cessation can be respectively associated with rebound headaches and rhinorrhoea.12 Rebound insomnia is common after stopping hypnotic drugs.Unmasking drug interactionsPharmacokinetic interactions should be considered when undertaking deprescribing. For example, if omeprazole is ceased by a patient on a stable dose of warfarin, the INR may decrease because omeprazole had been inhibiting the metabolism of warfarin.Reappearance of symptoms of original disease or risk factorIt is important not to misinterpret a rebound or withdrawal syndrome as a recurrence of the symptoms of the original disease. Surprisingly, clinical trials of drug withdrawal do not 184 | Volume 34 | NumBeR 6 | decemBeR 2011 www.austral ianprescriber.comshow a high incidence of symptoms of the original disease or risk factor reappearing after treatment stops.3 However, if some drugs, for example immunosuppressants, are stopped abruptly the underlying condition may flare up.what is the approach to deprescribing?There is limited clinical evidence to guide deprescribing, but some broad principles can be applied (Fig. 1).2,4,11,12Prepare the patient for deprescribing When starting a drug, explain to the patient that the outcome will be monitored and the drug might be ceased if there is no beneficial effect or a significant adverse effect occurs. Patient expectations can be discussed and managed at this time. This is particularly important for drugs which have Pharmaceutical Benefits Scheme (PBS) continuation criteria (for example  cholinesterase inhibitors for Alzheimer's disease), as the clinician must confirm that there has been clinical improvement in order for PBS funding to continue.Recognise the need for deprescribing The main clues that deprescribing might be useful are polypharmacy, adverse drug reactions (for example falls in older people), lack of efficacy and changes in treatment goals which may be secondary to the onset of terminal illness, dementia or frailty.Prioritise medicines to cease or doses to reduceA cautious approach is to stop or reduce the dose of one drug at a time. This helps to identify which drug might have been causing harm or, if withdrawal symptoms occur, to provide a guide for which drug to consider recommencing. If an adverse drug reaction is suspected, then the implicated drug should obviously be stopped first. If the patient is elderly and taking multiple medicines then there are several possible approaches to identifying the drugs which are suitable for deprescribing, in particular focussing on anticholinergic and sedating drugs.2,13,14 Reducing the dose of a medicine or changing it from regular to 'as needed' might also be an appropriate goal.Wean or taper the dose In many cases, medicines can be ceased abruptly, while for others (beta blockers, benzodiazepines, corticosteroids, opioids, levodopa) sudden cessation can generate serious withdrawal and rebound syndromes. The duration of weaning can vary from days to months and is influenced by factors such as the drug's half-life, the availability of different dose form sizes and scored tablets, as well as the physiological and psychological responses of the patient. For psychotropic medicines, the overall aim might be to reduce the dose by 25% each month, adjusting this according to the patient's response.12,15,16 This Fig. 1General approach to deprescribingPrepare discuss deprescribing at start of therapyrecognise polypharmacy, adverse drug reactions (including falls in older people), lack of efficacy, and change in treatment goals, often due to the onset of terminal illness, dementia and/or frailtyPrioritise one medicine at a time starting with the medicine suspected of causing the adverse drug reaction or consider using risk assessment toolswean always wean central nervous system-active medicines (especially benzodiazepines, opioids), beta blockers, corticosteroids, levodopa typically over weeks and monthsMonitor withdrawal syndromes, discontinuation syndromes, rebound, recurrence of illness, cognition, falls and quality of life| Volume 34 | NumBeR 6 | decemBeR 2011 185www.austral ianprescriber.comis a reasonably conservative regimen that would be suitable for most other prescription drugs if there was concern about withdrawal or rebound. For patients who have taken benzodiazepines for a long time, there might also be a benefit in transferring the patient to an equivalent dose of diazepam, because of its long half-life, then commencing withdrawal. However, for patients who have had a serious adverse drug reaction, then usually the drug should be stopped immediately.Monitor outcomes If a significant withdrawal syndrome or rebound occurs, then the drug could be resumed. Withdrawal could be attempted later at a slower rate. Assess patients for positive outcomes of deprescribing, such as decreased adverse effects and improved function. These benefits will be important for continuing compliance with deprescribing. ConclusionRecognising adverse outcomes or a lack of efficacy requires skill and diligence, particularly in older people taking multiple medications. However, good patient care depends upon the ability of prescribers to evaluate the clinical need for deprescribing and then undertake supervised withdrawal of medicines when appropriate.references1. Hilmer SN, Gnjidic D. The effects of polypharmacy in older adults. Clin Pharmacol Ther 2009;85:86-8.2. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med 2010;170:1648-54.3. Iyer S, Naganathan V, McLachlan AJ, Le Couteur DG. Medication withdrawal trials in people aged 65 years and older: a systematic review. Drugs Aging 2008;25:1021-31.4. Beer C, Loh PK, Peng YG, Potter K, Millar A. A pilot randomized controlled trial of deprescribing.  Ther Adv Drug Saf 2011;2:37-43.5. Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient.  Fundam Clin Pharmacol 2007;21:217-30.6. Le Couteur DG, Kendig H. Pharmaco-epistemology for the prescribing geriatrician. Aust J Ageing 2008;27:3-7.7. Boyle N, Naganathan V, Cumming RG. Medication and falls: risk and optimization. Clin Geriatr Med 2010;26:583-605.8. Campbell AJ, Robertson MC, Gardner MM, Norton RN,  Buchner DM. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999;47:850-3.9. Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people - a review of the evidence.  CNS Drugs 2003;17:825-37.10. Holmes HM. Rational prescribing for patients with a reduced life expectancy. Clin Pharmacol Ther 2009;85:103-7.Self-test questionsThe following statements are either true or false  (answers on page 195)7. Antihypertensive drugs are not suitable for deprescribing because of the risk of rebound hypertension.8. Sudden cessation of long-term use of benzodiazepines may cause hallucinations.11. Woodward MC. Deprescribing: achieving better health outcomes for older people through reducing medications.  J Pharm Pract Res 2003;33:323-8.12. A practical guide to stopping medicines in older people. Best Pract J 2010;27:10-23. www.bpac.org.nz/magazine/2010/april/stopGuide.asp [cited 2011 Nov 8]13. Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, et al. A drug burden index to define the functional burden of medications in older people.  Arch Intern Med 2007;167:781-7.14. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US  consensus panel of experts. Arch Intern Med  2003;163:2716-24.15. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R.  Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction 2009;104:13-24.16. Lader M. Pharmacotherapy of mood disorders and treatment discontinuation. Drugs 2007;67:1657-63.Conflict of interest: none declaredThe December issue of NPS RADAR reviews the evidence and place in therapy for: asenapine (Saphris) for schizophrenia or bipolar 1 disorder (acute mania or maintenance) indacaterol (onbrez), a once daily beta2-agonist for chronic obstructive pulmonary disease ticagrelor (Brilanta), an oral antiplatet for acute coronary syndrome oxycodone-with-naloxone controlled-release tablets (Targin) for chronic severe pain.Read the full reviews at www.nps.org.au/radar

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