Polypharmacy has been variably defined across literature, with the most common definition thus far as “taking 5 or more medications concurrently”.1, 2 Additionally, excessive polypharmacy is a term that has been commonly denoted to mean “taking 10 or more medications concurrently”.1 Polypharmacy can also be defined as the use of potentially inappropriate medications, which increases the risk for adverse drug events (ADEs), the underuse of medications contrary to instructions, and medication duplication, rather than looking at the number of medications prescribed. Polypharmacy is most commonly seen in patients with multiple comorbidities especially in patients with heart failure or cancer. Polypharmacy among COVID-19 patients was also recently reported.3
Polypharmacy is most recognized in older adults with multiple chronic conditions, who are often excluded from trials used to develop clinical practice guidelines.4 Management of multiple chronic conditions, each driven by disease specific treatment guidelines, is a major contributor to polypharmacy, which may put them at risk for ADEs. Polypharmacy may occur secondary to one or more of following etiologies.5
- Drug-drug interactions, where the administration of 2 or more medications precipitates the adverse event.
- Drug-disease state interactions, where the medication adversely impacts a patient’s disease (conversely, where the drug’s metabolism is negatively affected by the patient’s disease state).
- Prescription of potentially inappropriate medications (PIMs) and or inappropriate dosage, especially in older populations
- Failure of deprescribing PIMs and preventative medications with no benefits, given patient’s remaining lifespan or unacceptable treatment burden
- Prescribing cascades (prescribing a medication to manage a side effect of another medication) 6
- Unrecognized/undisclosed over the counter (OTC) and dietary supplements which are significant cause of polypharmacy in patients of all age groups7
The prevalence of polypharmacy varied between 10% to as high as nearly 90% across different patient populations.8 The determinants of polypharmacy included sociodemographic parameters (age, sex, income, and place of residence, ethnicity, behavior), chronic conditions (cardiovascular, metabolic disease, multiple comorbidity status), and the healthcare system.9 Chronic conditions, demographics, socioeconomics and self-assessed health factors were independent predictors of polypharmacy.8 Age is an independent predictor of polypharmacy. As anticipated, the overall prevalence of polypharmacy is greater in older people. A study in Europe reported the overall prevalence for each age group was 25.3% (95% CI 24.6-27.0) for aged 65-74, 36.4% (95% CI 35.4-37.5) for aged 75-84 and 46.5% (95% CI 44.6-48.4) for aged 85 or older. 10 The overall prevalence rates of polypharmacy in women (32.1%; 95% CI 31.3-32.9) and men (32.2%; 95% CI 31.4-33.0) were almost identical.10
Globally studies have shown polypharmacy is on the rise. In the United States, the prevalence of polypharmacy (≥5 prescription drugs) increased from an estimated 8.2% in 1999-2000 to 15% in 2011-2012 (difference, 6.6% [95% CI, 4.4%-8.2%]; P for trend <.001). These trends remained statistically significant with age adjustment.11A large prospective, longitudinal, register-based cohort study involving 1,742,336 individuals aged ≥65 years between 2010 and 2013 in Sweden revealed 44% of the population studied met the definition of polypharmacy (≥ 5 drugs) and 11.7% of excessive polypharmacy (≥ 10 drugs).12 A cross-sectional study in China revealed the prevalence of excessive polypharmacy (≥ 11 medications) was 96.5% in older hospitalized patients aged ≥80 years. 13 A study in Korea including 319,185 participants aged ≥65 years revealed 86.4% taking ≥ 6 medications, 44.9% taking ≥ 11 medications and 3% taking ≥ 21 medications.14 A similar study in Taiwan reported 83.5% of elderly participants were found to have polypharmacy defined as taking ≥ 6 drugs.15
Consequences of Polypharmacy
Polypharmacy has been linked to a broad range of negative consequences for patients and health care system as summarized in Table 1. Polypharmacy increases risk of adverse drug reactions, as well as serious drug-drug and drug-disease interactions, as noted above. Medical impact can be seen in an increased risk of fractures due to increased fall risk, increased risk of renal dysfunction and urinary incontinence, higher frailty. There may be reduced medication adherence by patients, increased hospitalization with longer length of stay, functional declines, impaired ability to perform independent activities of daily living, and increased risk of geriatric syndrome. All of these complications lead to increased health care costs across the system.2, 16-19 Polypharmacy increases risk of falls by 1.5-2 times.20 Additionally, polypharmacy may cause increased mortality.17A recent study reported polypharmacy decreased overall survival in acute myeloid leukemia (AML) particularly among patients aged <60 years old.18
Table 1. Negative Consequences of Polypharmacy2, 6, 16-19, 45
Risk factors for polypharmacy
Age is an independent risk factor for polypharmacy.14 The single most important predictor for inappropriate prescribing and risk of ADEs in older patients is the number of prescribed drugs. 21Prevalence of polypharmacy in cancer population increased from 13% in patients taking 2 medications to 82% in those taking ≥ 7 medications. 22 Of all the chronic conditions, COPD was most strongly associated with both polypharmacy (≥6 medications) and excessive polypharmacy (≥ 11 medications). 23 Other chronic conditions (Table 2) were also significantly associated with polypharmacy (≥6 medications) and excessive polypharmacy (≥ 11 medications) whereas ≥ 85 years, female gender and moderate self-reported health were factors associated only with excessive polypharmacy.23 24 The risk of polypharmacy is higher in cancer patients7 and heart failure populations.25 In young adults, medications for developmental disabilities, chronic pain, metal health, diabetes, heart disease and neurological conditions including stroke usually contribute to polypharmacy.2, 26 Other comorbidities (Table 2) are also associated with increased risk of polypharmacy. Residence at long term care facilities was associated with polypharmacy in older adults.27 It was reported that impaired nutritional status increases risk of polypharmacy.28 OTCs and herbal supplements are often unrecognized but significant cause of polypharmacy in patients of all age groups.7 Lack of connection to a primary care physician is also associated with polypharmacy. When multiple subspecialists prescribe for the same patient, potential interactions may be left undetected. Once a patient starts a medication, it may never be discontinued because of so-called therapeutic inertia, where patients accumulate multiple drugs and incomplete information from the prescriber, resulting in continued consumption of the agent(s). In addition to the patient level, polypharmacy can also occur at the health system level (Table 2). Risk factors for polypharmacy at the patient and the health system levels are summarized in Table 2.
Table 2. Risk Factors for Polypharmacy2, 4, 7, 14, 21, 23, 26-28, 36, 46, 47
Patho-anatomy/physiology of polypharmacy
Aging and associated comorbidities makes elderly prone to polypharmacy secondary to significant changes in drug pharmacokinetics and pharmacodynamics as a result of age-related physiological changes, susceptibility and vulnerability to drug adverse effects.29, 30 The bioavailability of a drug, absorption, distribution, metabolism and excretion of pharmacokinetics can also be modified with aging.31 Age-related pharmacodynamic changes are associated with number, activity and expression of receptors, and with the ability to signal transduction and changes in homeostatic mechanisms.32
Essentials of Assessment
Assessment of polypharmacy and appropriate prescribing should begin with a comprehensive review of past medical history, especially chronic conditions, including COPD, diabetes mellitus, hypertension, depression, heart disease, chronic pain, cancer and heart failure that are associated with increased risk for polypharmacy in older adults.23-25, 33 In young adults, the focus may be more on developmental disabilities, chronic pain, metal health, diabetes, heart disease and neurological conditions, as medications commonly prescribed for these disease states have been shown to contribute to polypharmacy.2, 26 Past surgical history more importantly including fractures, hip/knee arthroplasty, back surgery, cataracts, glaucoma should be reviewed. History taking should include assessment of potential medication side effects, such as lightheadedness, dizziness, syncope, fall, fatigue or poor appetite. History of fall with or without fracture could be suggestive of polypharmacy. Obtaining an accurate medication list and reconciliation of medications including both prescription and OTC is essential for assessment of polypharmacy. Drug allergies, drug reactions and side effects of prior medications should also be obtained. With multiple subspecialists being a risk factor for polypharmacy, it is recommended to find out number of prescribers in addition to number of medications. For those patients with cognitive impairment, it is recommended to assess for safety and accuracy of medication management by discovering who manages patient’s medications. Consequences of polypharmacy may also be reflected by patient’s functional status including activities of daily living, transfers, ambulation, living situation, use of durable medical equipment, caregiver, which should be evaluated.
The elements of physical examination are generally guided by history. For example, specific screens for common geriatric syndromes, such as falls, delirium, and incontinence, can be incorporated into the physical examination. For the purpose of assessment and management of polypharmacy, physical examination should focus on identification and diagnosis of conditions that may increase risk for polypharmacy or be consequences of polypharmacy as discussed below.
- Vital signs: blood pressure to assess for hypotension or orthostatic hypotension; heart rate to assess for any abnormal rate and rhythm; temperature to asses for fever, infection, confusion, medication error and fall
- General appearance (frailty, BMI, cachexia)
- Visual acuity assessment, use of corrective lens and last vision evaluation
- Hearing assessment, use of hearing aids and last hearing evaluation
- Neurocognitive (e.g., dementia, cognitive impairment, delirium)
- Cardiovascular (e.g., orthostasis, lower extremity edema)
- Respiratory (COPD)
- Hematologic (e.g., epistaxis)
- Integumentary (e.g., bruise, rash)
- Liver disease (e.g., hepatomegaly)
- Renal failure (e.g., decreased urine output)
- MSK, gait and balance abnormalities
- Neurological (sensory function, hand tremor): assessment of vision and hearing, sensation to light touch, pinprick, vibration and proprioception and deep tendon reflexes to assess for neuropathy
Laboratory studies are guided by the history obtained and the findings on physical examination. As part of the assessment of risk for adverse effects of polypharmacy in older adults, CBC with differential, CMP, Mg level, phosphorus level, TSH, free T3 and T4, urine analysis could be ordered depending upon the clinical circumstances. It is prudent to add prealbumin level in addition to albumin level included in CMP in order to assess for recent oral intake and nutritional status. Due to drug-nutrient interactions and drug-induced vitamin B12 deficiency34, B12 level should be measured. For patients on warfarin, it is warranted to monitor PT/INR more frequently than usual to appropriately lower its dosage when the patient is concomitantly taking other medications such as antibiotics, antifungal, antiepileptics, duloxetine, etc. Close monitoring of plasma trough level of vancomycin, digoxin, tacrolimus, cyclosporin, or phenytoin is essential in appropriate patients. It should be noted that serum creatinine alone is not an adequate measure of renal function. Older adults with decreased muscle mass may have serum creatinine levels within normal range, but in fact may have significantly compromised renal function as reflected by reduced creatinine clearance index (CrCI), which is calculated using the Cockroft-Gault formula.
Social role and social support system
As above discussed, polypharmacy can occur at the patient level and at the health care system level.2 Awareness and knowledge of polypharmacy among the health care providers and in public is the key to addressing polypharmacy. Judicious prescribing and appropriate deprescribing relies on the partnership between patients, families, caregivers and health care providers. 2, 35 Medication expense (even among those with prescription drug insurance) has been identified as a contributor to suboptimal adherence, which is a risk factor for ADEs.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Judicious prescribing is as important as judicious deprescribing to reduce polypharmacy.2, 36 A medication reconciliation should take place prior to prescribing any new medication in order to identify PIMs and polypharmacy35. Halli-Tierney et al 2 proposed following questions for judicious prescribing: 1). Underlying cause for the issues/symptoms? 2). Indication for new medication? 3). Any nonpharmacological therapies available? 4). Benefits and risks of new medication? 5). Benefits overweighing its risks? 6). The patient’s and caregiver’s goals of therapy? 7). Prescriber’s goal? 8). Patient’s estimated life expectancy when considering age and comorbidities? 9). Is the patient made aware of the decision for a new medication? 10). Patient’s compliance/adherence? 11). Patient’s affordability to the new drug? 12). Timely follow up and monitoring of the effectiveness and adverse drug effects?
Deprescribing is defined as the systematic process of identifying and discontinuing drugs in instances in which existing or potential harms outweigh existing or potential benefits within the context of individual patient’s care goals, current level of functioning, lift expectancy, values, and preferences.21 Criteria/reasons for deprescribing include potential cause of harm due to ADEs or drug-disease interaction, failure to control disease/symptom, resolution of disease/symptom, lack of a valid indication, result of the prescribing cascade (a medication prescribed to treat an adverse effect of another medication), no or questionable benefits of preventative medications, given patient’s remaining lifespan or unacceptable treatment burden.21,35
Several tools including implicit, explicit or mixed approaches have been described to educate and guide clinicians in efforts to reduce polypharmacy.37 The Medication Appropriateness Index (MAI) is an online tool (https://globalrph.com/medcalcs/medication-appropriateness-index-calculator/) and requires providers to make clinical judgements for interpretation and assessment, based on clinical information and patient complexity. MAI is an implicit tool and includes 10 questions that address medication need, optimal therapy for diseases and conditions, medication duplications, appropriateness of dosage, formulation, and duration of treatment, medication and disease interactions, and directions for use.38 Therefore, implicit tools are limited by the physician’s knowledge, experiences, and attitudes and are less reliable than explicit tools in clinic studies.2, 37
On the other hand, explicit tools such as the 2019 American Geriatrics Society (AGS) Beers Criteria®39, STOPP (Screening Tool of Older People’s Prescriptions), and START (Screening Tool to Alert to Right Treatment) STOPP/Screening Tool to Alert to Right Treatment (SMART)5have clear standards/criteria and require no or minimal clinical judgement to interpret but patient complexity is not considered in the decision-making process. 2, 39, 40 The most recent update, the 2019 AGS Beers Criteria® provides a comprehensive list of PIM and drug classes/medications that should be avoided or whose risks overweigh their benefits in older adults in general and in the presence of specific comorbidities, drug-drug or drug-disease interactions.39 Table 3 summarizes common high-risk PIMs/drug-drug interactions that should be avoided in older adults. Common medications that should be avoided or have their dosage reduced based on CrCl are shown in Table 4.
Table 3 Common High-risk Potentially Clinically Important Drug-Drug Interactions in Older Adults 39
Table 4 Common High-risk Medications That Should Be Avoided or Have Their Dosage Reduced based on CrCI in Older Adults 39
The STOPP criteria identify medications that may be inappropriate whereas the START criteria allow to identify alternative medications that may be safer to treat a disease.40 Application of STOPP/START criteria improves clinical outcomes in multi-morbid older people. However, even with well-functioning software for the application of STOPP/START criteria, the need remains for face-to-face interaction between attending clinicians and appropriately trained personnel (likely pharmacists) to explain and qualify specific STOPP/START recommendations in individual multi-morbid older patients.40
The benefits and evidence of efficacy of deprescribing have been documented at the patient, clinician and system level.2, 5, 21, 39 However, there are several barriers to deprescribing at both patient and provider levels.2, 35, 41. Patient-related barriers include fear of adverse drug withdrawal effects, fear of changing the “status quo”, and negative influence to deprescribe medication from family/caregiver/friends. Provider’s fear of adverse drug withdrawal effects or of changing the “status quo”, pressure from clinical practice guidelines to prescribe, difficulty with medication reconciliation, and lack of time, knowledge or skills to deprescribe are provider-related barriers.
Patient & family education
Physicians should identify and prioritize medications to discontinue and discuss deprescribing with the patient/family.2 Educating the patient and family about the indications for medication therapy, as well as instructions for use, is essential to ensuring adherence and minimizing risk for ADEs. In an inpatient rehabilitation setting it is important to engage with your internist/hospitalist for appropriate deprescribing and educate resident physicians and advanced practice practitioners on polypharmacy. Additionally, physician partnering with pharmacists, nurses and allied health professionals is essential to this effort.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Physicians should view deprescribing as a therapeutic intervention similar to initiating clinically appropriate prescribing.2The following 5-step process is recommended for appropriate deprescribing.2, 21 (1) reconcile all medications according to indication; (2) assess the appropriateness of each medication considering the risks and benefits of use; (3) assess each medication for eligibility to be discontinued; (4) prioritize medications for discontinuation; and (5) implement and monitor medication discontinuation. All patients should be evaluated for deprescribing with emphasis placed on clear communication with patients/families/caregivers.
Cutting Edge/ Emerging and Unique Concepts and Practice
Gaps in the Evidence-Based Knowledge
Gaps in the evidence-based knowledge include the definition of polypharmacy, user friendly validated assessment tools, and high quality of evidence for the benefits of deprescribing. The most commonly reported definition of polypharmacy is the numerical definition of five or more medication.1, 21 However, numerical definition does not take the comorbidities into consideration and makes it difficult to assess safety and appropriateness of medication therapy in the clinical setting. In addition, the number of medications alone is not always problematic.42 Evidence is lacking that a structured approach to decreasing the absolute number of medications, as opposed to discontinuing PIMs, improves patient outcomes. 2, 21, 39 Although there are several assessment tools 4,38-40 for judicious prescribing and appropriate deprescribing, more research is needed to fill in the gaps and provide more practical and validated guidelines/tools for frontline clinicians to deprescribe. Deprescribing as a strategy to reduce inappropriate prescribing and polypharmacy is believed to reduce harms associated with potentially inappropriate medications (PIMs). A systematic review reported that deprescribing decreased mortality in nonrandomized studies but did not have significant effect on mortality among randomized studies.43 However, a more recent study reported that deprescribing using the Beers and STOPP criteria was associated with reductions in mortality and number of hospitalized residents in nursing homes.44 Future research investigating prevalence and impact on rehabilitation outcomes of polypharmacy, judicious prescribing and appropriate deprescribing in acute inpatient rehabilitation setting should be considered.
- Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr 2017;17(1):230.
- Halli-Tierney AD, Scarbrough C, Carroll D. Polypharmacy: Evaluating Risks and Deprescribing. Am Fam Physician 2019;100(1):32-8.
- Iloanusi S, Mgbere O, Essien EJ. Polypharmacy among COVID-19 patients: A systematic review. J Am Pharm Assoc (2003) 2021;61(5):e14-e25.
- Molokhia M, Majeed A. Current and future perspectives on the management of polypharmacy. BMC Fam Pract 2017;18(1):70.
- Hill-Taylor B, Walsh KA, Stewart S, Hayden J, Byrne S, Sketris IS. Effectiveness of the STOPP/START (Screening Tool of Older Persons’ potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment) criteria: systematic review and meta-analysis of randomized controlled studies. J Clin Pharm Ther 2016;41(2):158-69.
- Rochon PA, Gurwitz JH. The prescribing cascade revisited. Lancet 2017;389(10081):1778-80.
- Sokol KC, Knudsen JF, Li MM. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther 2007;32(2):169-75.
- Khezrian M, McNeil CJ, Murray AD, Myint PK. An overview of prevalence, determinants and health outcomes of polypharmacy. Ther Adv Drug Saf 2020;11:2042098620933741.
- Guillot J, Maumus-Robert S, Bezin J. Polypharmacy: A general review of definitions, descriptions and determinants. Therapie 2020;75(5):407-16.
- Midão L, Giardini A, Menditto E, Kardas P, Costa E. Polypharmacy prevalence among older adults based on the survey of health, ageing and retirement in Europe. Arch Gerontol Geriatr 2018;78:213-20.
- Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in Prescription Drug Use Among Adults in the United States From 1999-2012. JAMA 2015;314(17):1818-31.
- Morin L, Johnell K, Laroche ML, Fastbom J, Wastesson JW. The epidemiology of polypharmacy in older adults: register-based prospective cohort study. Clin Epidemiol 2018;10:289-98.
- Lai X, Zhu H, Huo X, Li Z. Polypharmacy in the oldest old (≥80 years of age) patients in China: a cross-sectional study. BMC Geriatr 2018;18(1):64.
- Kim HA, Shin JY, Kim MH, Park BJ. Prevalence and predictors of polypharmacy among Korean elderly. PLoS One 2014;9(6):e98043.
- Chan DC, Hao YT, Wu SC. Characteristics of outpatient prescriptions for frail Taiwanese elders with long-term care needs. Pharmacoepidemiol Drug Saf 2009;18(4):327-34.
- Levy HB. Polypharmacy Reduction Strategies: Tips on Incorporating American Geriatrics Society Beers and Screening Tool of Older People’s Prescriptions Criteria. Clin Geriatr Med 2017;33(2):177-87.
- Wastesson JW, Morin L, Tan ECK, Johnell K. An update on the clinical consequences of polypharmacy in older adults: a narrative review. Expert Opin Drug Saf 2018;17(12):1185-96.
- Dhakal P, Lyden E, Muir KE, Al-Kadhimi ZS, Koll T, Maness LJ et al. Prevalence and effects of polypharmacy on overall survival in acute myeloid leukemia. Leuk Lymphoma 2020;61(7):1702-8.
- Davies LE, Spiers G, Kingston A, Todd A, Adamson J, Hanratty B. Adverse Outcomes of Polypharmacy in Older People: Systematic Review of Reviews. J Am Med Dir Assoc 2020;21(2):181-7.
- Ming Y, Zecevic A. Medications & Polypharmacy Influence on Recurrent Fallers in Community: a Systematic Review. Can Geriatr J 2018;21(1):14-25.
- Scott IA, Hilmer SN, Reeve E, Potter K, Le Couteur D, Rigby D et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med 2015;175(5):827-34.
- Goldberg RM, Mabee J, Chan L, Wong S. Drug-drug and drug-disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med 1996;14(5):447-50.
- Jyrkkä J, Enlund H, Korhonen MJ, Sulkava R, Hartikainen S. Patterns of drug use and factors associated with polypharmacy and excessive polypharmacy in elderly persons: results of the Kuopio 75+ study: a cross-sectional analysis. Drugs Aging 2009;26(6):493-503.
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- Beezer J, Al Hatrushi M, Husband A, Kurdi A, Forsyth P. Polypharmacy definition and prevalence in heart failure: a systematic review. Heart Fail Rev 2021.
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Original Version of the Topic
Andrew I. Geller, MD, Dale Strasser, MD. Polypharmacy. 12/28/2012
Previous Revision(s) of the Topic
Natasa Miljkovic, MD, PhD. Polypharmacy. 9/13/2016
Shangming Zhang, MD
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Nicole Swallow, MD
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William Pomilla, MD
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