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According to the WHO criteria polypharmacy is defined as ”concurrent use of five or more different prescription medication”.1 Polypharmacy is also 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.

In the recent literature, there is a new term of Excessive polypharmacy describing the use of nine different kind of medicines or more in the past 24 h in older population.2 Both polypharmacy and excessive polypharmacy are associated with significant morbidity, mortality, and public health cost.


As patients age or acquire multiple comorbidities, they are prescribed multiple medications, which may put them at risk for ADEs. Such prescribing can be considered potentially inappropriate according to one of a number of variables, including:

  1. Drug-drug interactions, where the administration of 2 or more medications precipitates the adverse event.
  2. 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).

Epidemiology including risk factors and primary prevention

Among the groups vulnerable to polypharmacy are older adults, who carry multiple chronic conditions (5 on average) for which they are prescribed multiple medications. Such comorbid medical conditions, along with the effects of physiologic aging and frailty, make older adults particularly susceptible to drug interactions and ADEs.

In the United States, 60% of those 65 years of age and older receive 5 or more drugs, and approximately 20% receive 10 or more drugs. Almost 1 in 3 older adults living in the community and taking at least 5 medications will experience an adverse drug reaction during a 12-month period. ADEs in older adults account for approximately 10% of emergency department visits and up to 17% of hospital admissions, and the majority of ADE-related emergency hospitalizations are related to supratherapeutic medication effects, such as those involving anticoagulants or hypoglycemic agents.3,4

In the United States, the prevalence of polypharmacy (use of ≥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). This increased prevalence was noticed in 11 drug classes of which the most common were antihypelipidemic agents – increasingly used of statins, antidepressant (both SSRIs and SSNRIs), prescription proton-pump inhibitors and muscle relaxants. Statins use increase can be explained by both its lower price and expanded guidelines for its use, while increased use of antidepressant can be explained by a more proactive approach to treating depression. There is no clear explanation of the increase of prescribed proton-pump inhibitors, other than being cheaper than over the counter PPIs. Increased use of muscle relaxants is unclear, but may be associated with potential misuse or abuse of carisoprodol (Soma)–which has recently been classified as a controlled substance for that reason.5

Interestingly, overall trends in analgesic use were stable–use of COX-2 inhibitors decreased, while use of narcotic pain medications increased from 1999-2000 to 2011-2012. Although this may raise concern for possible misuse or abuse, this trend did plateau after 2003-2004, due likely to increased awareness of prescription opioid drug abuse or misuse.5

The increase in prevalence of polypharmacy cannot be explained by aging population alone, as it has not only been noted in adults over 65, but also in adults 40-64 years of age. A possible explanation is that large-scale policy changes, including the implementation of Medicare Part D, which went into effect in 2006, coincided with the biggest increase.5

Polypharmacy and falls

Multiplicity of medications is associated with an increased likelihood of inappropriate prescribing and ADEs, including falls and declines in nutritional status, functional ability, and cognitive capacity in older adults.

It is interesting that among high risk fallers, the use of two or more FRID (fall risk increasing drugs) is shown to be an independent risk factor for falls, not polypharmacy per se.6

Fall risk increasing drugs (FRID) include:

  1. Opioids
  2. Antipsychotics
  3. Anxiolytics
  4. Hypnotics
  5. Sedatives
  6. Antihypertenives
  7. Dopaminergic

Risk factors for polypharmacy

  1. Multiple medical conditions:

In vulnerable groups, such as older adults, a prescription list of 10 or more medications is easily reached by following practice guidelines for a small number of coexisting medical conditions, thus the term excessive polypharmacy developed especially among cardiac patients.2

  1. Multiple prescribers:

When multiple caregivers 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).

De-prescribing7,8 has been proposed as a way to reduce polypharmacy in frail older people. De-prescribing or reducing the number of regular medications consumed by frail older adults living in residential care showed no significant adverse effects on survival or other clinical outcomes (survival, falls, fractures, hospital admissions, cognitive, physical, and bowel function, quality of life, and sleep).

  1. Institutionalization:

Nursing home residents are particularly vulnerable to polypharmacy, and receive up to 4 times as many prescription items as people who live in their own homes.9,10

  1. Recent hospitalization:

Medicines are started and stopped in-hospital, putting the discharged patient at particular risk for polypharmacy. The number of potentially inappropriate medications globally increases during hospitalization. It’s likely associated with the high numbers of co-morbidities.9,10

  1. Non-adherence:

A variety of factors can result in suboptimal adherence, including poor communication by the prescriber and lack of understanding by the patient; according to 1 study, 11% of older adult hospital admissions are related to medication non-adherence.9,10

  1. Inappropriate prescribing:

Some medications are relatively contraindicated in certain age groups and/or disease states, and patients are prescribed these agents despite available, safer alternatives. Moreover, the exclusion of older adults, or those with multiple medical comorbidities, from many clinical drug trials can make appropriate dosing quite difficult for clinicians to discern.11,12


Prescribing is complicated by altered pharmacokinetics and pharmacodynamics in vulnerable groups, such as older adults.

Pharmacokinetics refers to medication absorption, distribution, metabolism, and elimination.13

  1. Absorption changes related to reduced first-pass metabolism in older adults–such as those resulting from decreased hepatic blood flow and/or gastrointestinal motility–might result in increased absorption of some high hepatic clearance drugs or decreased absorption of active metabolites from pro- drugs.
  2. Distribution changes can stem from age-related alterations in protein binding levels, body-fat to body-water proportion, and other end-organ differences. Decreased plasma albumin levels can lower protein binding (and thus increase the free fraction) of circulating warfarin, phenytoin, naproxen, and other tightly albumin-bound medications; conversely, increased alpha-1-glycoprotein in conditions, such as cancer or inflammatory disease, may decrease the pharmacologically available active free fraction of imipramine, propranolol, and other basic drugs. Aging results in decreased lean body mass and total body water (TBW), with a relative increase in total body fat. Decreased TBW leads to a decreased volume of distribution for hydrophilic medications, such as lithium, ethanol, and digoxin, when unadjusted dosing can result in higher plasma concentrations, increasing the potential for ADEs. Conversely, lipid-soluble medications, such as long-acting benzodiazepines, have an increased volume of distribution, which delays their maximal effects, resulting in accumulation with continued use.
  3. Metabolism of drugs with a high hepatic extraction ratio (e.g., morphine) might have a prolonged half-life in older adults because of the age-related decrease in hepatic blood flow with resulting impairment of hepatic clearance.
  4. Excretion of drugs that are renally cleared may become impaired as a result of age-related or comorbidity-associated declines in kidney blood flow and glomerular filtration rate. Medications, such as non-steroidal anti-inflammatory drugs are implicated as problematic in older adults in part because of their observed toxic effects related to decreased renal clearance.

Pharmacodynamics refers to the physiologic and biochemical effects of the medication.

  1. Increased sensitivity has been described with regard to cardiovascular medications, anticoagulants, benzodiazepines, and general anesthetics.
  2. Proposed mechanisms include altered concentrations of neurotransmitters and end-organ receptors, hormonal changes, and impaired glucose metabolism.
  3. Altered homeostatic mechanisms, such as impaired reflex tachycardia and impaired regulation of temperature and electrolytes, may also result in an increased risk for ADEs.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

There are many consequences of polypharmacy. Aside from the increased direct costs of multiple medications, consequences of polypharmacy can include adverse drug reactions, drug interactions, non-adherence, diminished functional status, and various geriatric syndromes (e.g., falls, urinary incontinence, and cognitive impairment).14

Polypharmacy is sometimes overlooked because its symptoms can be confused with symptoms of normal aging or another disease. Thus, in addition to the situations previously described, problems with polypharmacy may arise when a patient’s signs or symptoms fail to be recognized as adverse effects of medication. In this situation, additional drugs are prescribed to treat the adverse effects of other drugs, resulting in the so-called prescribing cascade.



The key to appropriate prescribing is:

  1. Obtaining an accurate medication list
  2. Inquiring about medication history
  3. Assessing for adverse effects

Brown-bag reviews of the patient’s current medicines should include all prescription and over-the-counter medications. Such reviews provide an opportunity to assess the effectiveness of medications and screen for adverse drug effects.

Medication history should be obtained, where possible, to include:

  1. Past drug reactions
  2. Perceived benefits
  3. Side effects

As previously noted, polypharmacy may manifest with a variety of symptoms thus clinician vigilance is essential in order to respond promptly to medication-related symptoms.

During history taking, diagnoses and indications should be clarified to help guide appropriateness of prescription and ensure accuracy. Patient adherence and health literacy can also be assessed in the history-taking encounter, because these factors influence a patient’s vulnerability to ADEs.

Physical examination

The elements of physical examination, which may be medication-related, are generally guided by history. For example, specific screens for common geriatric syndromes, such as falls, delirium, or incontinence, can be incorporated into the physical examination. Physical findings associated with ADEs and inappropriate medication prescribing include-but are not limited to:

  1. Neurocognitive (e.g., delirium)
  2. Cardiovascular (e.g., orthostasis)
  3. Hematologic (e.g., epistaxis)
  4. Integumentary (e.g., rash)
  5. Liver
  6. Renal
  7. Gait and balance abnormalities

Laboratory studies

Similarly, laboratory studies will be guided by the history obtained. For older patients taking renally cleared medications, such as non-steroidal anti-inflammatory drugs, it is important to remember that serum creatinine alone is not an adequate measure of renal function. Older adults with decreased muscle mass may have serum creatinine levels within the healthy range (usually 0.8-1.3 mg/dL), but in fact have significantly compromised renal function. The Cockroft-Gault formula, which takes into account body weight, may be helpful to account for this phenomenon.

Social role and social support system

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.


Available or current treatment guidelines

Managing polypharmacy is as complex as the medical conditions which often precipitate it; simply counting the number of medications is not always helpful to the individual clinician attempting to treat a patient appropriately. Various criteria have been developed to help inform ascertainment of medication appropriateness.

Explicit criteria are usually based on expert consensus opinion because of the lack of evidence-based data, but it may be the most simple to implement. Examples include Beers Criteria, which was most recently updated in 2012.15

Implicit criteria, such as the Medication Appropriateness Index, help guide the tailoring of medication treatment to the individual patient. While they overcome some of the shortcomings of the explicit criteria, they can be difficult and time consuming to implement.

In Europe, Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) criteria have been used to secure the appropriateness of prescribing in hospitalized older people. However, due to lack of time, poor pharmacological knowledge, being uncomfortable to discontinue or substitute drugs prescribed by other clinicians and skepticism how these actions affect clinical outcomes, many clinicians still have difficulties in applying these criteria in daily practice.16

In elderly population, there are no strict STOPP criteria for using opioids, but it is recommended not to use opioids with tricyclic antidepressant in patients with recurrent falls or chronic constipation, in patients with dementia, or as a first-line pain management.17

Regarding Warfarin use in elderly, no strict STOPP criteria exist as well, but Warfarin should not be used longer than 6 months for the 1st uncomplicated DVT and 12 month for the first uncomplicated PE. Also Warfarin should not be used in elderly patients with bleeding disorders, together with NSAIDs and if used with Aspirin the patients need to be on a PPI or H2-blocker.17

Patient & family education

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. Additionally, physician partnering with pharmacists, nurses and allied health professionals is central to this effort.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

The following 5 basic principles are key to minimizing polypharmacy:

  1. Obtain an accurate medication history.
  2. Assume a new symptom is an adverse drug effect until proven otherwise.
  3. Assess benefits and risks, using clinical judgment and validated prescribing tools.
  4. Reduce medications as feasible; identify and prioritize medications to be targeted for cessation. Medications most implicated in serious adverse events include anticoagulants (e.g., warfarin), hypoglycemics (e.g., insulin or oral agents), opioid analgesics, and digoxin.
  5. Monitor for medication effects in collaboration with the patient, caregivers, and other medical professionals.


Cutting edge concepts and practice

Efforts are ongoing to provide clinicians with more useful, validated tools. Implementation of computerized physician order entry has been shown to reduce ADEs, and computer-aided technologies hold promise in optimizing appropriate prescribing.

Once patient is discharged from the hospital, he or she can be involved in the SafeMed program which is a care transitions program with an emphasis on medication management designed to use low-cost health workers to improve transitions of care from hospital to home for super-utilizing patients with multiple chronic conditions and polypharmacy.18


Gaps in the evidence-based knowledge

Rehabilitation patients have not generally been studied for polypharmacy interventions. Descriptive studies, interventional trials, and quality improvement projects could be utilized to understand and improve medication prescribing and polypharmacy management in physical medicine and rehabilitation.


  1. www.who.int
  2. Walckiers D, Van der Heyden J, Tafforeau J. Factors associated with excessive polypharmacy in older people. Arch Public Health. 2015;73:50.
  3. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57:1331-1346.
  4. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365:2002-2012.
  5. 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.
  6. Cristian A, Thomas J, Nisenbaum M, Jeu L. Practical considerations in the assessment and treatment of pain in adults with physical disabilities. Phys Med Rehabil Clin N Am. 2005;16:57-90.
  7. Zia A, Kamaruzzman SB, Tan MP. The consumption of two or more fall risk-increasing drugs rather than polypharmacy is associated with falls. Geriatr Gerontol Int. 2016. Epub ahead of print.
  8. Gnjidic D, Le Couteur DG, Kouladjian L, Hilmer SN. Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. Clin Geriatr Med. 2012;28:237-253.
  9. Potter K, Flicker L, Page A, Etherton-Beer C. Deprescribing in frail older people. PLoS One. 2016;11(3):e0149984.
  10. Cristian A. Medical management of adults with neurologic disabilities. New York, NY: Demos Medical; 2009.
  11. Geller AI, Nopkhun W, Dows-Martinez MN, Strasser DC. Polypharmacy and the role of physical medicine and rehabilitation. PM&R. 2012;4:198-219.
  12. Hanlon JT, Handler SM, Maher RL, Schmader KE. Geriatric pharmacotherapy and polypharmacy. In: Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. 2010.
  13. Schiff GD, Galanter WL, Duhig J, Lodolce AE, Koronkowski MJ, Lambert BL. Principles of conservative prescribing. Arch Intern Med. 2011;171:1433-1440.
  14. Sera LC, McPherson ML. Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy. Clin Geriatr Med. 2012;28:273-286.
  15. Shah BM, Hajjar ER. Polypharmacy, adverse drug reactions, and geriatric syndromes. Clin Geriatr Med. 2012;28:173-186.
  16. Di Giorgio C, Provenzani A, Polidori P. Potentially inappropriate drug prescribing in elderly hospitalized patients: an analysis and comparison of explicit criteria Int J Clin Pharm. 2016; E pub ahead of printing.
  17. Thomas RE. Assessing Medication Problems in those > or = 65 using the STOPP and START Criteria. Curr Aging Sci. 2016;9(2):150-8.
  18. https://www.ascp.com/articles/potentially-inappropriate-medications-elderly
  19. Bailey JE, Surbhi S, Bell PC, Jones AM, Rashed S, Uqwueke MO. SafeMed: Using pharmacy technicians in a novel role as community health workers to improve transitions of care. J Am Pharm Assoc (2003). 2016;56(1):73-81.

Original Version of the Topic:

Andrew I. Geller, MD, Dale Strasser, MD. Polypharmacy. Publication Date:2012/12/28.

Author Disclosure

Natasa Miljkovic, MD, PhD
Nothing to Disclose