How polypharmacy affects frailty

KEYWORDS:

• Geriatrics
• deprescribing
• integrated care
• older persons

Polypharmacy and frailty are two geriatric conditions increasingly used in the medical literature for their clinical and public health relevance, especially considering the aging of our societies. However, the study of the relationship potentially existing between polypharmacy and frailty is extremely complex. As usual for age-related conditions, the existence of multiple confounders and the need of embracing new clinical and research paradigms render the field extremely challenging. In this manuscript, it is presented an overlook of the possible mechanisms through which polypharmacy might affect frailty.

The term ‘polypharmacy’ is used in the literature to describe the concurrent use of multiple drugs by a patient, specifically five or more. Polypharmacy can be appropriate and entirely justified [1]. However, it has often given a negative connotation and adopted to capture the detrimental condition defined by the prescription of one or more drugs that are not or no longer needed by the patient [2]. Notably, such polypharmacy has negative consequences on the patient, who is exposed to the risk of adverse drug reactions (ADRs) including falls [3], incident frailty [4], and hospitalization [5]. At the same time, it also affects the sustainability of the public health system via direct (e.g. reimbursement of costs sustained for the provision of useless drugs) and indirect (e.g. hospitalizations due to ADRs) mechanisms. Indeed, even when a drug has no apparent harmful effects, its inappropriate prescription can still be caused detrimental consequences by complicating the patient’s therapy, negatively affecting his/her mood (e.g. making him/her feel sick and vulnerable), and increasing the costs.

Despite polypharmacy is today well recognized as a clinically relevant risk condition [6], it seems highly prevalent (i.e. 26.3–39.9%) [7] and growingly present [8] in community-dwelling older persons. This fact represents a paradox since older persons (especially when frail) are usually excluded from randomized clinical trials, which means from the evidence supporting our clinical and therapeutic choices (i.e. the long-lasting evidence-based medicine issue affecting geriatrics) [9,10].

The clinical complexity of the organism tends to increase with aging. The age-related accumulation of health deficits determines the exhaustion of the organism’s homeostatic reserves [11]. The resulting excess of vulnerability can then pave the way to the onset of adverse outcomes (e.g. hospitalizations, institutionalizations, disability, death) when stressed by endogenous and exogenous triggers. Interestingly, this condition, known as frailty, may represent the lever for shaping a novel way of practicing medicine and taking clinical decisions [12]. Indeed, the concept of frailty has been developed to modernize the obsolete medical approach, too much disease-oriented. Although diseases are necessary in medicine for defining targets of intervention, their definition is growingly felt arguable and somehow disconnected from reality, especially in frail older persons [13]. The categorical definitions of diseases may appear counterintuitive in a medical world tending toward systems biology and personalization of care. Indeed, the time-related, continuous accumulation of health deficits experienced by the organism results in a substantial clinical heterogeneity [14]. Thus, frailty may represent a dynamic, multidimensional measure capturing the continuous nature of biological aging, enriching the standard assessment of the person.

Unfortunately, to date, traditional medicine is still primarily based on the obsolete standalone-disease approach to the patient (Figure 1). This sterile approach automatically leads to the risk that every abnormality is individually considered and treated without the necessary comprehensive evaluation of the person. For every disease, a specific monodimensional solution is assumed. It implicitly introduces a ‘one-fits-all’ behavior in the drug prescription, forcing the standardization of something that cannot be standardized. However, working per silos leads to the unavoidable consequence of adding drugs over drugs to treat every detected abnormality (sometimes in the absence of clinical relevance). This catastrophic mistake becomes particularly evident in frail patients, presenting multimorbidity and living on the edge of extreme vulnerability. A wrong prescription might indeed represent the above-mentioned exogenous stressor precipitating the individual into the adverse outcomes of his/her frailty status. Moreover, the risk–benefit ratio of a specific drug tends to increase when numerous comorbidities and related therapies water the target condition. Therefore, frail individuals may not benefit from the intervention but merely remain exposed to the harmful effects of it.

Figure 1. The standalone-disease approach, typical of traditional medicine, assumes that there is a treatment for each disease. The established relationship between the single disease and its treatment (composed by potentially multiple drugs) is unique and bidirectional: the treatment is taken because of the disease, and the disease is improved by the treatment. The onset of adverse reactions is often managed following the same vertical approach leading to the prescribing cascade

Furthermore, as sketched in Figure 2, the presence of multiple diseases, each theoretically requiring specific treatment, subtly and exponentially increases the number of disease–disease, disease–drug, and drug–drug interactions. Besides explaining why polypharmacy is associated with an age-independent risk of ADRs [15], this clinical approach underestimates the different strengths of the established interactions (among diseases, drugs, and both).

Figure 2. The multiplication of the disease–drug, disease–disease, and drug–drug interactions exponentially increases the clinical complexity. This is further enhanced by the background noise of socio-economic, functional, and environmental factors (dotted box); and the different severity of the diseases (bold font represents severe condition), strength of the drugs (bold font represents high dosage), and established relationships among them (bold lines represents stronger interactions)

Polypharmacy may also represent the first step of the so-called ‘prescribing cascade,’ which is the addition of new therapeutic agents for treating the ADRs of other drugs (e.g. the use of diuretics for reducing the peripheral edema generated by calcium-channel blockers) [16]. In this scenario, the role played by over-the-counter and/or herbal medicinal products should not be overlooked because potentially concurring with the development of ADRs [17]. The fragmentation of care services does not help. The increasing complexity of the individual is frequently addressed in a vertical way by multiple actors who are not used/in the position to exchange among each other adequately. The patient is not the center of the action as it should be, but is called at wandering across different medical settings and specialties in the hope of finding the solution for his/her problems [18]. At the same time, such a detrimental approach often forgets that the priorities of the patient might not be those of the prescribing physician [19]. For example, the age-related increase in the prevalence of chronic and disabling conditions makes the focus on functions much more relevant compared to the treatment of the specific disease(s). The frail individual may not live the presence of a particular diagnosis as a burden but look at the maintenance of autonomy and independent life as a priority [20].

Although the increasing clinical complexity is usually responsible for polypharmacy, an ageism-related exception is noteworthy. In fact, there are reports in the literature showing that frail older persons are excluded from potentially beneficial pharmacological interventions [21], likely due to the stigma of advanced old age. This phenomenon makes the entire matter more complicated because, whereas the general trend is to excessively prescribe in the presence of multimorbidity [22], the opposite might also be true [23]. In other words, it has to be considered the possibility that the absence of polypharmacy might somehow underlie inadequate care in older persons and potentially lead to frailty. Everything is further complicated by the heterogeneous nature of available evidence in terms of clinical setting and adopted operational definitions for the conditions of interest.

Last but not least, it is important to underline how the comprehensive evaluation of the individual with polypharmacy cannot be limited to his/her organism to find the right solution and avoid collateral damages. The therapeutic plan cannot neglect the environment where the person lives. We can design a perfectly sound and evidence-based pharmacological intervention, but it will dramatically fail if we do not consider how, where, and when the person will follow it [24]. For example, functional impairments (e.g. cognitive or vision limitations) and/or access to care services might affect the capacity of the patient to follow the recommendations. Polypharmacy and complicated therapeutic plans will not help in this case, potentially generating confusion, errors, and adverse health-related events.

In conclusion, polypharmacy and frailty are two geriatric conditions that are closely related. A bidirectional relationship links them. If frailty is often seen as the cause leading to polypharmacy, the opposite should not be overlooked. Indeed, the abuse of prescriptions and medical mistakes (usually due to inadequate knowledge of geriatric medicine principles) may dramatically worsen the health status of the aging individual. Never as today, the Hippocrates’ quote Primum non nocere (‘First, do not harm’) has to drive our decisions and the modernization of our care systems toward models that are more person-centered and responsive to the new clinical demands.

Declaration of interest

M. Cesari has declared receiving honoraria from Nestlé for presentations at scientific meetings and as a member of the advisory board. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.