Failure to Reach a Consensus in Polypharmacy Definition: An Obstacle to Measuring Risks and Impacts-Results of a Literature Review

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Failure to Reach a Consensus in Polypharmacy

Denition: An Obstacle to Measuring Risks and

Impacts-Results of a Literature Review

N. Taghy, Linda Cambon, J. M. Cohen, C. Dussart

To cite this version:

N. Taghy, Linda Cambon, J. M. Cohen, C. Dussart. Failure to Reach a Consensus in Polypharmacy

Denition: An Obstacle to Measuring Risks and Impacts-Results of a Literature Review. Therapeutics

and Clinical Risk Management, 2020, 16, pp.57-73. �10.2147/tcrm.S214187�. �hal-03144568�

REVIEW

Failure to Reach a Consensus in Polypharmacy

Deﬁnition: An Obstacle to Measuring Risks and

Impacts—Results of a Literature Review

This article was published in the following Dove Press journal:

Therapeutics and Clinical Risk Management

Najwa Taghy

Linda Cambon

Jean-Marie Cohen

Claude Dussar t

Laboratory P2S (Health Systemic

Process), University of Lyon, University

Claude Bernard of Lyon 1, Lyon, EA4129,

France;

Research Chair in Prevention,

University of Bordeaux, ISPED, Inserm,

Bordeaux Population Hea lth Research

Center, Team Methods for Population

Health Int ervention Research, Bordeaux,

France;

Open Rome, Paris, France,

Laboratory P2S (Healt h Systemic

Process), University of Lyon, University

Claude Bernard Lyon 1, EA4129, France;

Lyon Public Hospices, Central Pharmacy,

Laboratory P2S (Healt h Systemic

Process), University of Lyon, University

Claude Bernard Lyon 1, EA4129, France

Introduction: The risk of polypharmacy is on the rise in most industrialized countries,

threatening to burden their health systems. Although many deﬁnitions exist and numerous

concepts are found in literature as synonyms, the phenomenon of polypharmacy remains

poorly deﬁned. The aim of this literature review is to provide an overview of available

deﬁnitions of polypharmacy, to analyse their convergences and divergences and to discuss

the consequences on the assessment of the problem.

Methods: A literature review was conducted to identify all published systematic reviews on

deﬁnitions of polypharmacy available via Scopus and Pubmed databases. The Assessment of

Multiple Systematic Reviews (AMSTAR) tool was used to appraise the methodological

quality of the selected reviews. Available deﬁnitions and other characteristics were extracted;

summarised in a table and analysed.

Results: Six systematic reviews were identiﬁed. They were published between 2000 and

2018. Three focussed on deﬁnitions of polypharmacy in the elderly; two in the general

population and one in children. The strategy adopted in reviews is more rigorous in the most

recent ones. However, they remain, at best, partially exhaustive. The deﬁnitions found in the

literature used two main approaches, either (i) quantitative, applying varying thresholds and

types of polypharmacy based on the number of medications being taken by the patient (ii)

qualitative, based on the clinical indications and effects of a given drug regimen, with a

growing number of characteristics to describe polypharmacy. The term “inappropriate” is

increasingly associated with polypharmacy especially in studies that aimed to use this

deﬁnition to identify possible solutions for healthcare providers in the ﬁeld related to aging.

Conclusion: This review conﬁrms a high variability and an evolution in the approaches

deﬁning “polypharmacy” in the absence of a consensus following standardized criteria. That

makes it very difﬁcult to estimate and measure the outcomes associated with this phenomenon.

Keywords: polypharmacy, deﬁnition, literature review

Introduction

The increasing life expectancy, the rising prevalence of chronic diseases and multi-

morbidity and the growing range of therapies are currently challenging public

health in most industrialized countries and leading to increased risk of polyphar-

macy. This phenomenon, which is on the rise today, affects the elderly and could

seriously threaten health systems. Despite this, there is no consensus deﬁnition for

polypharmacy. The World Health Organization (WHO) deﬁnes polypharmacy as

“the administration of many drugs at the same time or the administration of an

Correspondence: Najwa Tagh y

University of Lyon, University Claude

Bernard Lyon 1, Laboratory P2 S (Health

Systemic Process), Lyon EA4129, France

Tel +33 633740378

Email najwa.tagh [email protected]

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excessive number of drugs”.

Whether in practice or in

research, this term has numerous meanings and many

terms and concepts are used in the literature interchange-

ably as synonyms for “polypharmacy” . This vagueness in

polypharmacy deﬁnition creates confusion and makes it

difﬁcult to assess the extent of the problem, to measure its

consequences and to search for solutions. In order to

identify and apply relevant knowledge and effective inter-

ventions on polypharmacy, it is necessary to assess exist-

ing discrepancies in the literature. Given that systematic

reviews are recognized as very useful in identifying evi-

dence and basing health care on it,

we conducted an

extensive search of systematic reviews to answer the fol-

lowing question: how is the term “polypharmacy” deﬁned

and how it is used in the literature?

The results of a very recent review were published at

the end of 2017 and provide a very precise quantitative

summary of the existing deﬁnitions for polypharmacy.

using the results of this work and all other systematic

reviews found, our literature review aims to provide an

overview of the different approaches adopted, their evolu-

tion over time, the convergences and divergences of their

results and to discuss their consequences on the evaluation

of the problem.

Methods

A literature review was conducted to ﬁnd all published

systematic reviews on polypharmacy deﬁnitions. Scopus

and Pubmed databases were searched from inception to

December 2018 using keywords: “polypharmacy” and

“deﬁnition”.

Selection of Articles

Inclusion criteria were as followed: (a) systematic reviews

focusing on polypharmacy deﬁnition; (b) systematic

reviews addressing polypharmacy issues and including

also polypharmacy deﬁnitions allowing for relevant data

extraction; (c) publications in English or French.

A ﬁ rst selection was conducted based on titles and

abstracts followed by a second selection on full text. The

Assessment of Multiple Systematic Reviews (AMSTAR)

tool was used to appraise the methodological quality of the

selected reviews.

The 16 elements leading to its assess-

ment criteria provide a reliable basis for evaluating sys-

tematic reviews of randomized and non-randomized

controlled studies.

Some criteria were not relevant for

our study, particularly those related to meta-analyses and

risks of bias (on the table = NA for Not Applicable).

Possible answers were “Yes”“partial Yes”“No” or “NP”

when the information was not provided.

Data Analysis

The selected articles were analysed through a full-text

reading and the following characteristics were extracted:

author, author’s country, year of publication, title, aim and

purpose, review method (consulted databases, keywords,

period), number of studies analysed, concerned popula-

tion. Finally, all elements related to polypharmacy deﬁni-

tion were also extracted in order to analyse convergences

and divergences.

Results

Analyses and results are presented below in four main

sections:

Selection of Articles

Ninety-nine articles were initially identiﬁed; among which 79

were considered irrelevant after titles and abstract reading (not

systematic review, lack of a focus on polypharmacy deﬁnition;

no other relevant deﬁn ition elements; research protocol).

Twenty were selected for full-text reading. Finally, only ﬁve

reviews were selected after full-text reading and one paper

mentioned in the selected reviews was manually retrieved.

Figure 1 illustrates the review ﬂow chart (see Figure 1)

Description of Included Reviews

Five reviews were in English and one in French. They

were published between June 2000 and November 2018.

Of the six reviews selected, three focussed on the elderly

(one on elderly,

one on people aged 65 and over

and one

people aged 60 and over

). Two others deﬁned polyphar-

macy in the general population

3,8

and 1 review, the most

recent, focused on paediatric polypharmacy.

The studies

included in these included reviews were published

between 1985 and July 2017.

Quality Assessment

The methodology used in reviews was analysed using the

AMSTAR grid. However, the score provided by the

AMSTAR tool was not calculated. Instead, available infor-

mation was summarised in a table providing some indica-

tions on the quality of the methodology used in each review

(Table 1). The strategy adopted in these reviews has evolved

and is more rigorous in the most recent reviews. However,

they remain, at best, partially exhaustive.

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Deﬁnition of Polypharmacy

The analysis of the selected reviews provided data on differ-

ent ways in which polypharmacy was deﬁned in the litera-

ture. As the content varied from one review to another

(quantitative and/or descriptive synthesis, table or narrative

text), th e extracted deﬁnition elements have been sum-

marised in a table (See Table 2).

Towards Two Approaches to Deﬁne

Polypharmacy

Among the reviews that we excluded because they were

not systematic, some presented nevertheless interesting

summaries of existing polypharmacy deﬁnitions.

10–13

The

ﬁrst of these, which is important to mention because it is

cited as a reference in most of the works studied, was

----------------------------

---------------------------------

-------------------------------------

242 Records identified

through Scopus Database

107 Records identified

through PubMed Database

99 Titles or abstracts screened

- Sélection of « review » articles

- Duplicates removed

20 Full-text articles assessed for

eligibility

79 irrelevant Titles and /or

abstracts excluded

15 excluded:

- Not systematic review

- Not focus on polypharmacy

definition;

- Not relevant definition

elements;

- Research protocol only.

1 review identified in references

and added by hand searching

Figure 1 Flow chart for review of systematic reviews of polypharmacy deﬁnition.

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Table 1 Quality Assessment Using the AMSTAR Tool

Bakaki

et al

2018

Masnoon

et al 2017

Monégat

et al

2014

Bushardt

et al 2008

Fulton

et al

2003

Veehof

et al

2000

1. Did the research questions and inclusion criteria for the review include the components of PICO? NA

2. Did the report of the review contain an explicit statement that the review methods were established prior to

the conduct of the review

Yes Yes Partial Yes Partial Yes Yes Yes

3. Did the review authors explain their selection of the study designs for inclusion in the review? Yes Yes Yes No No No

4. Did the review authors use a comprehensive literature search strategy? Partial Yes Partial Yes Partial Yes No Partial Yes Partial Yes

5. Did the review authors perform study selection in duplicate? Yes Yes Yes NP NP NP

6. Did the review authors perform data extraction in duplicate? Yes Yes NP NP NP NP

7. Did the review authors provide a list of excluded studies and justify the exclusions? Yes Yes No No Partial Yes Partial Yes

8. Did the review authors describe the included studies in adequate detail? Yes (n=363) Yes (n=110) No (n=34) No (n=11) Yes (n=16) Yes (n=143)

9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that

were included in the review?

10. Did the review authors report on the sources of funding for the studies included in the review?

11. If meta-analysis was pe rformed, did the review authors use appr opriate methods for statistical combination of results?

12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual

studies on the results of the meta-analysis or other evidence synthesis?

13. Did the review authors account for RoB in primary studies when interpreting/discussing the results of the review?

14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed

in the results of the review?

Yes Yes Yes Yes Yes Yes

15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of

publication bias (small study bias) and discuss its likely impact on the results of the review?

16. Did the review authors report any potential sources of conﬂict of interest, including any funding they

received for conducting the review?

Yes Yes No No No No

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Table 2 Deﬁnitions of Polypharmacy

Author/ Year/ Country/ Title /Aim/Purpose Sources/Method/ Period/ Number of Studies Population Polypharmacy Deﬁnitions

Bakaki et al

2018

(USA)

PLoS ONE

Deﬁning pediatric polypharmacy: A scoping review.

To describe deﬁnitions and terminology of pediatric

polypharmacy.

(Conforms to the PRISMA checklist.)

MEDLINE, PubMed, EMBASE, CINAHL, PsycINFO, Cochrane

CENTRAL, and the Web of Science Core Collection databases

were searched for English language articles with the concepts of

“polypharmacy” and “children”. Data were extracted about

study characteristics, polypharmacy terms and deﬁnitions from

qualifying studies, and were synthesized by disease conditions.

From inception to October 2016 and was updated on July 11,

2017

(n= 363 studies included)

Children 324 studies provided numeric deﬁnitions, 131 speciﬁed duration of

polypharmacy, and 162 explicitly deﬁned it.

Over 81%

(n = 295) of the studies deﬁned polypharmacy as two or mor e

medications or therapeutic classes.

The most common comprehensive deﬁnitions of pediatric

polypharmacy included: two or more concurrent medications for 1

day (n = 41), two or more concurrent medications for 31 days (n =

15), and two or more sequential medications over one year (n = 12).

Commonly used terms included polypharmacy , polytherapy,

combination pharmacotherapy, average number, and concomitant

medications.

The term polypharmacy was more common in psychiatry literature

while epilepsy literature fav ored the term polytherap y.

This revie w found 162 studies that offered 203 distinct deﬁnitions of

polypharmacy in the text:

Only 19% (n = 35 outpatient, 3 inpatient) of the text deﬁnitions

provided both a medication threshold number and a period

A list of all 203 text deﬁnitions is available at the journal website

(Continued)

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Table 2 (Continued).

Author/ Year/ Country/ Title /Aim/Purpose Sources/Method/ Period/ Number of Studies Population Polypharmacy Deﬁnitions

Masnoon et al

2017

(Australia)

BMC Geriatrics

What is polypharmacy? A systematic review of deﬁnitions.

To explore the deﬁnitions in existing literature. Additionally, to

explore whether articles differentiated between appropriate and

inappropriate polypharmacy and how this distinction was made.

(Conforms to the PRISMA checklist).MEDLINE (Ovid),

EMBASE and Cochrane.

Grey literature.

Between 1st Januar y 2000 and 30th May 2016

Published in English,

(n=110 studies included)

All A total of 138 deﬁnitions and associated terms. Deﬁnitions were

categorised as:

111 Numerical only (using the number of medications to deﬁne

polypharmacy): a wide range of variability in the deﬁnitions as well as

associated terms (minor , moderate, major), the most commonly

used term was “polypharmacy” but there was variation with regard

to the actual deﬁnition of polypharmacy, which ranged from 2 or

more medications to 11 or more medications. The most commonly

used deﬁnition was 5 or more medication da ily (51 studies). The

second most common deﬁnition was 6 or more medications (10

studies). Only one study deﬁne d polypharmacy as the number of

drug classes used by patient.

15 Numerical with an associated:

Duration of therap y (11 studies): ranged from use of two or

more medications for more than 240 days (“long term use”)to

ﬁve to nine medications used for 90 days or more.

or healthcare setting (4 studies): included the use of ﬁve or

more medications at hospital discharge, and the use of 10 or

more medications during hospital stay.

12 Descriptive (using a brief description to deﬁne polypharmacy) as:

Patients visiting multiple pharmacies to obtain medications; Co-

prescribing multiple medicat ions; Simultaneous and long term use of

different drugs by the same individual; Polypharmacy deﬁnition

ranges from the use of a large number of medications, to the use of

potentially inappropriate medications, medication underuse and

medication duplication; P ot entially inappropriate medications; Use of

multiple medications concurrently and the use of additional

medications to corr ect adverse effects; Use of medications which ar e

not clinically indicated.

More drugs being prescribed or taken than are clinically appropriate

in the context of a patient’s comorbidities. (Some studies used

different wording but conve yed the same deﬁnition ex:

Coprescribing multiple medications and Simultaneous and long term

use of different drugs by the same individual).

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7studiesdeﬁned appropriate or rational polypharmacy, or

recognised the distinction between appropriate and inappr opriate

medications: deﬁned polypharmacy using a brief description only (3

studies) or used a brief description and polypharmacy tools such as

the Be ers criteria and the Medication Appropriateness Index (MAI)

(4 studies). (None of the studies explicitly identiﬁed the need to

distinguish between appropriate and inappropriate polypharmacy

based on the pharmacology of medications involv ed, how they

interact with each other and comorbidities for a speciﬁcpatient).

Only one of the 110 studies included in the review highlighted the

inconsistencies in the deﬁnitions of polypharmacy in the literature

and suggested that polypharmacy be deﬁned as “patients visiting

multiple pharmacies which may be associated with safety concerns

relating to potential outcomes such as medication duplication, drug-

drug interactions and adverse effects”.

Monégat et al

2014

(France)

Questions d’économie de la

Santé

Polypharmacy: Deﬁnitions, Measurement and Stakes Involved

Review of the Literature and Measurement Tests

Based on a review of the literature, different deﬁnitions of

polypharmacy were identiﬁed and the measurement of

polypharmacy was examined according to different thresholds.

The review of the literature was carried out using the Medline

and Gediweb databases.

Completed with research based on references included in

selected articles.

The following key words were used to designate polypharmacy:

“polypharmacy”, “polymedication”, “polyprescription”,

“multimedication”, “multiprescription”.

Inclusion criteria were: articles or literature reviews on the

deﬁnition and measurement of polypharmacy, studies on the

prevalence of polypharmacy (excluding polypharmacy centered

on a single therapeutic class or pathology) and articles in French

or in English.

Between 2000 and 2013

(n= 34 studies included)

All Deﬁned by the World Health Organisation as “the

administration of many drugs at the same time or the

administration of an excessive number of drugs”

Notion of drug misuse: Polypharmacy refers to the

administration of more drugs than clinically necessary.

By extension, polypharmacy is said to be “appropriate” when

the prescription of numerous medications is justiﬁed, and

“inappropriate” when wrongly or indiscriminately prescribed.

According to the time slots used to measure polypharmacy:

Simultaneous polypharmacy: Corresponds to the number

of drugs concurrently taken by a patient on a given day. A

variant of this deﬁnition imposes that the simultaneous use

of numerous medications should be prolonged through

time; at least 60 consecutive days quarterly, for example.

(Continued)

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Table 2 (Continued).

Author/ Year/ Country/ Title /Aim/Purpose Sources/Method/ Period/ Number of Studies Population Polypharmacy Deﬁnitions

Cumulative polypharmacy (also known as multiple

medication): is deﬁned by the sum of different medications

administered over a given period of time. Numerous

studies use a three-month period, the time necessary to

take into account 95% of prescriptions based on the

standard prescription renewal time (three months). Other

periods (six months, twelve months) have also been used.

Continuous polypharmacy: it is similar to cumulative

polypharmacy but limited to medications taken for

prolonged and regular periods. It only takes into account

medications present in two given time periods spaced by

an interval of six months, for example. Or by taking into

account only medications present in the preceding quarter

and the following quarter.

According to a deﬁned thresholds: Numerous thresholds have

been identiﬁed

- Essentially 5 or more medications

- 10 medications or over

- Other thresholds: “5to7”; “8 and over”; Threshold of 8

medications; “6 medications and over”

According to the number of medications administered:

Minor polypharmacy: the administration of 2 to 4 medications –

Major polypharmacy: the use of 5 medications and over.

hyperpolypharmacy or excessive multi-medication: the

consumption of 10 or more medications.

In an article published in 2014:

The consumption of over 10 medications is now

considered as major

20 medications or over is considered excessive.

The consumption of 5 medications or under is now

considered as “non-polypharmacy” or “oligopharmacy”

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Bushardt et al

2008

(USA)

Clinical Interventions in Aging

Polypharmacy: Misleading, but manageable

To identify a consensus deﬁnition for polypharmacy and evaluate

its prevalence among elderly outpatients.

A review conducted within OVID for original articles.

Using the following search terms and phrases: “polypharmacy,”

“elderly,”“geriatrics,”“inappropriate medication,” and “multiple

medication use.”

English language articles available in local holding, which

described “polypharmacy” or the issue of the simultaneous use

of multiple medications in elderly patients, were evaluated.

Discrete deﬁnitions of polypharmacy were identiﬁed and

recorded.

Between January 1997 and May 2007

(n=11 studies included)

Elderly Several different deﬁnitions involved one of the following

concepts (24 déﬁnitions):

Medication does not match the diagnostic (the most commonly

cited, in 4 articles); Many medications; Duplication of

medication; Drug/drug interactions; Inappropriate dosing

frequency (excessive, too low, too long); Medication prescribed

to treat the side effect of another medication (except for case

where there is no other option); Two or more agents with the

same chemical class; Two or more meds to treat the same

condition; Two or more agents with the same or similar

pharmacologic actions to treat different conditions; Minor

polypharmacy = 2–4 meds/Major polypharmacy ≥5 meds; 3, 5

or 6 different medications; Two or more medications; Greater

than 5 medications; Excessive use of medication; Unnecessary

use of medication; Medications prescribed greater than twice

per day; Complicated drug regimen effecting compliance;

Contraindicated in the elderly; Taking an OTC medication, an

herbal product or another person’s medication; Availability of an

equally effective, lower-cost alternative; Patient

misunderstanding of the use of the medication (purpose, how to

take it, side effects possible, toxicity signs, etc.); Dosage does

not reﬂect age/renal/liver status; Improvement after

discontinuation of medication; Diagnosis no longer present.

The term “inappropriate” was part of deﬁnitions used in six

articles.

Some deﬁnitions for polypharmacy place a value on the number

of concurrent medications; the most commonly referenced

number was 6 medications or more.

(Continued)

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Table 2 (Continued).

Author/ Year/ Country/ Title /Aim/Purpose Sources/Method/ Period/ Number of Studies Population Polypharmacy Deﬁnitions

Fulton et al

2003

(USA)

Journal of the American

Academy of Nurse

Practitioners

Polypharmacy in the elderly: a literature review.

To review the body of literature addressing polypharmacy in

individuals aged 60 years and older to (a) determine primary

care providers’ deﬁnition of polypharmacy, (b) explore how

polypharmacy was assessed in primary care, and (c) seek tested

interventions that address polypharmacy.

A systematic review;

Bibliographic databases:

EBSCOHost, InfoTrac, OVID, FirstSearch, and FirstSearch

Deluxe.

The search terms “polypharmacy,”“polypharmacy and elderly,”

“polypharmacy and research,” and “multiple medications”.

Between January 1991 and October 2003

(n=16 studies included)

Elderly

(≥60 years)

●

Multiple deﬁnition are utilized:

- Two or more drugs for 240 days or more

- Concurrent use of two or more drugs

- Use of for or more medications

-Use of ﬁve or more different prescription medications

●

Additional deﬁnitions include regular daily consumption of

multiple medication as well as the use of high-risk medi-

cations and questionable dosing

●

“Untoward iatrogenic sequel of the use of multiple, inter-

acting medications”

●

European studies deﬁned polypharmacy according to the

number of medications taken, whereas the studies con-

ducted in the United states deﬁned polypharmacy

according to whether a medication was clinically indicated

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Veehof et al

2000

(Netherlands)

European Journal of General

Practice

Polypharmacy in the elderly – A literature review.

To d e ﬁne polypharmacy; to determine the extent and nature of

polypharmacy in the elderly; and to discover the problems

which may result from polypharmacy in general practice.

A Medline search from 1985 to 1998 yielded.

Entries: polypharmacy and aged (=65 years and older) in

combination with: adverse drug reactions, drug interactions,

drug combinations.

(n= 143 articles included)

Elderly

(≥65 years)

Deﬁned in two ways in the literature: Quantitative vs

Qualitative.

In quantitative descriptions the emphasis lies mainly on the

amount of drugs, and qualitative descriptions focus on

polypharmacy as a problem.

For instance, polypharmacy deﬁned as the prescription,

administering or use of more drugs than is clinically indicated for

a certain patient.

The term polypharmacy was also applied when several drugs are

used with one of the following characteristics:

●

Drug use with no apparent indication;

●

Use of two identical drugs;

●

Concurrent use of interacting drugs;

●

Use of contraindicated drugs;

●

Use of drugs to treat adverse drug reactions;

●

Improvement after stopping or interrupting medication.

When mentioning polypharmacy some authors describe a

regime in which there is at least one drug that is superﬂuous or

the use of any drug that is not essential to the management of a

medical problem.

When approaching polypharmacy quantitatively, the criterion

often used is the simultaneous use of more than ﬁve drugs (But

it must be remembered that situations exist where the simul-

taneous prescription of several drugs is necessary and has to be

considered effective pharmacotherapy).

For the purpose of this study: polypharmacy means simply the

simultaneous use of two or more drugs; the use of more than

ﬁve drugs is deﬁned as major polypharmacy.

Abbreviations: OTC, over the counter; PIM, potentially inappropriate medication; WHO, World Health Organization.

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published back in 1998 by a general practitioner (R. David

Lee) in the Journal of the American Board of Family

Practice.

This article already identiﬁed polypharmacy

as a serious problem because of the lack of relevant

research data on its prevalence, complications and man-

agement solutions. According to the author, the deﬁnition

of polypharmacy varies from one study to another, making

it difﬁcult to translate research results into useful informa-

tion for primary care. Lee deﬁnes polypharmacy in its

strictest sense as the concomitant use of many drugs and

describes it as a practice that implies the prescribing of

excessive medication. He also introduces two main

approaches that we found in all selected reviews. The

ﬁrst approach focuses on the number of medications the

patient is taking. The authors disagree, however, on the

number of medications and on whether or not to consider

medications over-the-counter drugs or herbal and alterna-

tive medications. The second approach which allows for

an individualized approach to a patient’s drug regimen

focus on the clinical indications and effects of a given

drug regimen, regardless of the number of medications

used. Polypharmacy would therefore imply that more med-

ications are used or prescribed than those that are clini-

cally indicated.

From the ﬁrst review we selected in 2000 to the last one

published in 2018, we ﬁnd this notion of “qualitative

approach vs. quantitative approach” in the deﬁnition of poly -

pharmacy. What changes are the nuances found in the results

of each review; nuances that are a consequence of

approaches and methods that have evolved and that are

different from on review to another according to the purpose

of each (for example: speciﬁc population, more or less in-

depth analysis of the original articles). The progressive gain

of ground in the deﬁnition by increasingly precise concepts

(qualitative approach) as well as the progressive emergence

of notion of inappropriate polypharmacy are also reﬂected in

the comparison of the results of the different reviews.

An interesting approach to deﬁnition by attempting to

measure polypharmacy is found in the French Institute for

Research and Information in Health Economics (IRDES)

systematic review from 2014.

Their results include all the

aforementioned varieties of deﬁnitions (based on thresholds,

on the number of medications or on other related character-

istics) and focus speciﬁcally on time slots to measure poly -

pharmacy. This approach distinguishes several types of

polypharmacy: simultaneous, cumulative (or multiple medi-

cation) and continuous (see Table 2).

As mentioned above, in 2017, an Australian team pub-

lished in the BMC Geriatri c the results of a systemat ic

literature review including 110 articles deﬁning

polypharmacy.

This review describes and quantiﬁes avail-

able deﬁnitions by categories (numerical only; numerical

with an associated duration of therapy or healthcare setting;

descriptive). The vast majority of existing deﬁnitions

(80.4%) are only quantitative; the most commonly used

threshold is ﬁve or more daily medications (51 studies).

Only one study, published in 2011 in the British Medical

Journal deﬁned polypharmacy as the number of drug classes

used by patient.

Nearly eleven percent of studies added the

criterion of dur ation of thera py or healthcare setting to the

numerical deﬁnition. In addition, 8.9% of revised studies had

a descriptive approach to deﬁne polypharmacy while some of

them used different terms when referring to the same deﬁni-

tion. Final ly, this re view identiﬁes studies that deﬁne appro-

priate or rational polypharmacy as opposed to potentially

inappropriate medication. Of the 110 studies included, it

highlights a recent article (2015) that highlights the incon-

sistency in the deﬁnitions of polypharmacy and refers to

situations where “patients visiting multiple pharmacies

which may be associated with safety concerns relating to

potential outcomes such as medication duplication, drug–

drug interactions and adverse effects”.

The last selected review is a sc oping review published by

an American team in November 2018, including 363 articles.

It describes deﬁnitions and terminology of paediatric polyphar-

macy and provides an overview of the wide range of deﬁnitions

associated to the term “polypharmacy” in paediatric studies.

This review’s results are similar to those found in other reviews

concerning the general population: the vast majority of deﬁni-

tions are quantitative; the differenc e is the number of medica-

tions. In over 80% of the reviewed studies, polypharmacy

among children was deﬁned on the basis of two or more

medications or two or mor e therapeutic classes. Commonly

used terms included “polypharmacy”, “polytherapy”, “combi-

nation pharmacotherapy”, “average number”,and“conc omi-

tant medications”.Theterm“polypharmac y” was more

common in the psychiatric literature, while the term “polyther-

apy“ was more frequently found in epilepsy literature.

A Need for a Consensus Deﬁnition to

Enable Action: A Field of Application

Related to Ageing

Between 2000 and 2008, we found three reviews with the

same objective: to identify a consensus deﬁnition for

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polypharmacy in the literature.

5–7

All of them focused on

the elderly. This is quite logical as the elderly are affected

by polypharmacy. The deﬁnitions found in the literature

concern the two approaches described above: (i) quantita-

tive, with varying thresholds and types of polypharmacy

determined by the number of medications (e.g., minor,

major, excessive); (ii) qualitative, with a growing number

of concepts and characteristics to describe polypharmacy,

including treatment duration and many other contextual

elements and concepts (example: Bushardt in 2008 identi-

ﬁed 24 different deﬁnitions,

the most cited being

“Medication does not match the diagnosis”).

The term “inappropriate” is increasingly associated

with polypharmacy, particularly in reviews that aimed to

use this deﬁnition to identify possible solutions for

healthcare providers. Several evaluation tools and var-

ious methods have been developed for this purpose: The

most well known are the Beers’ criteria developed in

1997.

Beers’ criteria help clinicians identify adverse

reactions and medications to be avoided or used with

caution among the elderly. These criteria were included

in several research studies on inappropriate prescriptions

in the late 1990s.

17–20

Other interventions for assess and

control polypharmacy include “brown bag” approach

using mnemonics such as SAIL or TIDE,

or the “10-

step approach”.

The three reviews conducted between 2000 and 2008

identify many variations in deﬁnitions from one school

to another. Some authors note that European studies

often deﬁned polypharmacy according to the number

of medications taken, while studies conducted in the

United States tend to deﬁne polypharmacy according

to the clinical indication of medication.

This qua litative

approach is essential to studies focused on onco-geria-

trics for example. In this multi-morbidity context,

beyond the number of medications prescribed and

used, polypharmacy is deﬁned more broadly than poten-

tially inappropriate medication (PIM) use “Medications

of a speciﬁc drug t ype or class t hat may not be appro-

priate for a given patient because of age or a concurrent

illness/condition”, Medication underuse “Medications

with a c lear beneﬁt for a given illness/condition that a

patient is not taking”, and Medication duplication

“Medications of the same or a similar drug class or

therapeutic effect concurrently being used that may not

be beneﬁcial”.

Discussion

A Lack of Consensus on Polypharmacy

Deﬁnition

This literature review further conﬁrms the lack of standar-

dization in the use of the term “polypharmacy” both, in

research and practice. The WHO deﬁnition (“the adminis-

tration of many drugs at the same time or the administra-

tion of an excessive number of drugs“) is broad enough so

as to allow for the emergence of different deﬁnitions

. The

ﬁrst part suggests an administration of “many” drugs with-

out specifying to which number this excessive nature

corresponds. Moreover, the notion of “same time” raises

the issue of the temporal dimension according to which

polypharmacy is considered and measured. The other part

of the deﬁnition refers to an “excessive number of drugs”

introducing, thus, another notion; that of drug misuse.

literature review conducted by a Canadian team, published

in 1981, seeking to deﬁne “polypsychopharmacy” (poly-

pharmacy in the ﬁeld of psychiatry), had already revealed

a large variability in deﬁnitions in the medical literature.

While being used for more than a century and a half,

this

term has not reached a consensus yet in its deﬁnition.

Instead, the most recent publications reveal a great hetero-

geneity in approaches and the impossibility of establishing

a standard deﬁnition for polypharmacy.

Moreover, although not standardised, these deﬁnitions

have been enriched and reﬁned over time to include new

characteristics and concepts linked to the quality of pre-

scription (appropriate, rational vs. inappropriate), duration

or context of therapy …, etc. This qualitative approach

moves away from stricter deﬁnitions that are limited to the

number of drugs consumed. Nevertheless, the most recent

review shows that more than 80% of the deﬁnitions used

in the literature are quantitative.

Deﬁnition by Measurement: Different

Approaches

Several research studies have focused on the study and

development of indicators and potential tools to reliably

measure polypharmacy. We mentioned the work of IRDES

researchers, which deﬁnes indicators and assesses the tech-

nical feasibility of their calculation.

They compare ﬁve of

the most frequently used measurement tools and test them

on the basis of IMS-Health data to assess the ability of

these indicators to identify polypharmacy. From this

review of the literature, they retained four polypharmacy

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indicators. Three indicators represent simultaneous poly-

pharmacy and one, cumulative polypharmacy. To these,

they added a continuous polypharmacy indicator, also

found in the literature and retained within the PAERPA

program framework.

A table summarizes the name, cal-

culation and sources of each indicator (8, table T).

Two additional publications deal with the same issue.

The ﬁrst one

refers to explicit and implicit instruments,

such as the Beers Criteria, STOPP/START criteria, and

Medication Appropriateness Index, which are common

criteria that can be used to identify high-risk medications

that suggest reconsideration.

It also discusses the rele-

vance of other ways to assess the medication burden in

older adults using tools that consider pharmacological

principles (i.e. dose–response and cumulative effects) and

target-speciﬁc medications such as those with clinically

signiﬁcant anticholinergic effects and sedative effects

(i.e. Anticholinergic Drug Score, Anticholinergic Risk

Scale, Anticholinergic Cognitive Burden Scale, Sedative

Load, and Drug Burden Index). The authors emphasize the

importance of establishing clinically relevant cutoffs for

polypharmacy, meaning that they must be measured and

interpreted according to the clinical context, multimorbid-

ity, patient preferences and goals of care.

The most recent paper in this ﬁeld is a systematic review

and expert consensus study that identiﬁes what they consider

to be the key elements of a measure of prescribing appropri-

ateness in the context of polypharmacy.

Panel members

particularly valued indicators concerned with adverse drug

reactions, contraindications, drug–drug interaction s, and the

conduct of medication reviews. A set of 12 indicators of

clinical importance considered relevant to polypharmacy

appropriateness has been identiﬁed (29, Table 2). This review

concludes by recalling that the use of these indicators in

clinical practice and informatics systems is dependent on

their operationalization and their utility (e.g. risk stratiﬁca-

tion, targeting and monitoring polypharmacy interventions)

requires subsequent evaluation.

No Standard Deﬁnition: An Obstacle to

Measuring Outcomes

This lack of consensus makes it very difﬁcult to estimate

and measure the outcomes associated with polypharmacy.

Several of these reviews aimed at deﬁning polypharmacy

in order to study its prevalence in a given population

(geriatric, onco-geriatric, paediatric or psychiatric) or to

prove and quantify the association between polypharmacy

and its associated consequences (falls, hospitalization,

non-compliance with treatment, increased expenses …,

etc.). The deﬁnition of these parameters is a fundamental

step and a real challenge for researchers interested in

developing adequate solutions based on evidence and pro-

ven methods including recommendations to guide practice

and interventions targeting patients or healthcare provi-

ders. All reviews that attempted to conduct meta-analyses

or to compare the results of previous work share a com-

mon limitation related to the use of different methodolo-

gies from one study/school to another. Several elements

may vary: population proﬁle, threshold deﬁnition (dura-

tion, number), healthcare environment (home, hospital,

institution … ), and speciﬁcities of contexts and health

systems from one country to another.

Results show that the prevalence of polypharmacy in

the elderly can vary from 13% to 92% depending on the

deﬁnition used and the characteristics of the population

studied.

A recent study exploring the correlation between

polypharmacy and falls in a cohort of people over 60 years

old in the United Kingdom, illustrated this variation: using

the threshold of 4 or more drugs (adjusting for socio-

demographic, medical and other lifestyle factors), the

rate of falls is 18% higher among polymedicated people

than among others (IRR 1.18, 95% CI 1.08 to 1.28), while

the use of the threshold of 10 or more drugs was 50%

higher (IRR 1.50, 95% CI 1.34 to 1.67).

The results of

another systematic review that assessed prevalence and

associated clinical signs through variations in polyphar-

macy deﬁnition and mood variation in adults with bipolar

disorder showed a prevalence that varied between 85%

and 36% depending on whether the study used a “permis-

sive” (2 drugs simultaneously) or more “conservative” (4

and more) deﬁnition.

It is also difﬁcult to estimate the cost of polypharmacy

and its burden on health systems. For instance, in Great

Britain, we can have the total number of drugs dispensed

and its evolution (1.08 billion ≈ 19.9 drugs/person in 2015

Vs. 962 million ≈183 drugs/per cent in 2011

); in USA

the cost associated with the management of falls among

people over 65 years old (£6million/day or £2.3 billion/

year for the NHS in 2010

has been estimated in $20

billion in 2006

). However, even if we accept the proven

link between polypharmacy and falls,

35–41

again, the

absence of a standard deﬁnition makes it difﬁcult to pre-

cisely quantify this cost.

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Limitation

The fact that we have limited ourselves to systematic

reviews without studying all the original articles could be

considered as a limitation to this work. But this option was

chosen in order to get an overview of the existing literature

and to be able to assess whether there was a consensus

deﬁnition of polypharmacy.

Conclusion

Published literature reports a high variability in the use of

the term “polypharmacy” in the absence of a consensus

following standardized criteria. In all reviews, we ﬁnd this

notion of “qualitative approach vs quantitative approach”

in the deﬁnition of polypharmacy. The results (existing

deﬁnitions of polypharmacy) were different from one

review to another depending on the purpose and method

of each and have, a fortiori, evolved over time.

Some researchers make trade-offs by choosing a deﬁ-

nition for the purposes of their research. Others are trying

to deﬁne relevant indicators to move towards a precise

measurement of polypharmacy whether comparing the

ability of indicators to identify polypharmacy and evaluat-

ing the technical feasibility of their calculations,

propos-

ing alternative terminologies

or, much more recently,

establishing a standard deﬁnition of the term “polyphar-

macy” based on an index including the many parameters

associated with comorbidity and multi-morbidity.

Research on polypharmacy is moving towards an

increasingly holistic approach. Polypharmacy could be

deﬁned, therefore, within the intersection between its

many etiological or risk factors (health status, general

frailty, comorbid conditions, certain diagnoses, prescribing

cascades, self-medication, inappropriate prescription, etc.);

signiﬁcant demographic factors (age, sex, level of educa-

tion); healthcare environment; and the other factors inﬂu-

encing the number of doctor visits prescribers and hospital

admissions. Paradoxically, this approach brings us further

away from a standard deﬁnition because it deﬁnes several

situations or types of polypharmacy. By combining all

these considerations, some deﬁnitions qualify polyphar-

macy as “appropriate” when “the prescription of numerous

medications is justiﬁed”, and as “inappropriate” when

“wrongly or indiscriminately prescribed”.

25,43

In the

same vein, we can de ﬁne “inappropriate polypharmacy”

as opposed to situations where the use of several medica-

tions would be desirable, justiﬁed and even necessary. This

practice corresponds to the simultaneous administration of

several medications, at least one of which would be inap-

propriate regarding its indications and/or the iatrogenic

risks potentially implied by its administration.

Abbreviations

AMSTAR, Assessment of Multiple Systematic Reviews;

IRDES, Institute for Research and Information in Health

Economics; IRR, Incident Rate Ratio; MAI, Medication

Appropriateness Index; NA, Not applicable; NHS,

National Health Service; NP, Not provided; OTC, Over

the counter; PIM, Potentially inappropriate medication;

WHO, World Health Organization.

Disclosure

The authors report no conﬂicts of interest in this work.

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