Identification, Management, and Prevention of Polypharmacy in Multiple Sclerosis

The term polypharmacy has been used for centuries to describe the use of multiple medications.¹ In the general population, polypharmacy has been associated with poor medication adherence, increased risk of hospital admission, falls, increased mortality risk, and decreased quality of life.^2,3 Although there is no standardized definition of polypharmacy, most commonly, it describes using 5 or more prescription medications daily.⁴ Polypharmacy is common in North America, being present in 10% to 15% of adults from age 40 to 65 years and 30% to 35% of those aged 65 years or older.⁵ Recent trends indicate that the rates of polypharmacy are on the rise, with a 2.9% average increase in prevalence per year between 1999 and 2018, making this a more pertinent clinical challenge than ever before.⁶

In 2017, the World Health Organization identified polypharmacy as a growing global challenge. This prompted evaluation of prescribing practices in numerous settings, including in multiple sclerosis (MS) care. MS is a progressive, immune-mediated, neurodegenerative disease of the central nervous system of unknown etiology. MS causes a range of symptoms, affecting individuals’ quality of life and placing them at an increased risk of polypharmacy. In addition, MS uniquely affects younger individuals compared with most neurologic conditions, giving ample opportunity for the number of prescription medications to compound as individuals age. This begs the question of how to manage individuals already experiencing polypharmacy and how to prevent polypharmacy altogether. This review will help the practitioner balance the symptomatic management of MS while adhering to the Hippocratic principle to do no harm.

Polypharmacy Risk in MS

Recent literature suggests that polypharmacy in people with MS may result in an increased rate of MS-related hospitalizations,⁷ relapse,⁸ fatigue,⁴ and health care utilization.⁹ Individuals with MS have considerable out-of-pocket expenses for their medications; disease-modifying therapies (DMTs) and medications for symptomatic management are costly. For example, one study analyzing Medicare claims found that individuals who took DMTs consistently throughout the year had annual out-of-pocket expenses exceeding $5,000; the 2014 annual median out-of-pocket cost of for one therapy--dalfampridine (Ampyra; Acorda Therapeutics, Ardsley, NY)---a medication used to improve walking speed in people with MS, was $475.¹⁰

Risk Factors for Developing Polypharmacy in MS

People with MS at risk for polypharmacy include those who are older or have low socioeconomic status, female sex, or comorbidities.⁴ Frequent comorbidities seen in people with MS with polypharmacy include psychiatric illness (eg, depression, anxiety), cardiovascular disease, and autoimmune disease, all of which greatly contribute to the overall drug burden.¹¹ Psychiatric illness within the MS population should not be overlooked; individuals with MS are at a greater risk of developing depression and anxiety and suicide compared with the general population.¹²

Medications Involved in Polypharmacy in MS

One large study found that 66% of individuals experiencing polypharmacy were taking an antidepressant. The next most common medications included antiepileptics (likely used for neuropathic pain [eg, gabapentin]) (47% of individuals), drugs for peptic ulcer disease (41%), lipid-modifying agents (33%), and centrally acting muscle relaxants (27%).⁴ Individuals experiencing polypharmacy were also more likely to fill a prescription for an opioid versus those who were not experiencing polypharmacy (43% vs 14.9%).⁴ DMTs for MS also contribute to polypharmacy, as many of them have side effects or require concomitant medication, such as contraception.

The most dangerous medications taken by individuals with polypharmacy include centrally acting drugs, such as benzodiazepines and gabapentinoids, anticholinergics, and opioids, owing to increased risk of falls, risk of overdose, impaired cognition, and sedation.¹³ Individuals with MS may be more susceptible to being prescribed these medications in an effort to combat symptoms such as pain, spasticity, mood disruption, and bladder dysfunction. One study found that coprescription of different centrally acting drugs in MS was common; for example, combined use of opioids and central nervous system depressants—a potentially harmful combination—was seen in 8.1% of polypharmacy days.⁴

Most polypharmacy studies do not include supplements and over-the-counter medications because they are frequently underreported and difficult to track. More than 70% of the general population takes some form of a dietary supplement every day.¹⁴ Studies suggest that complementary and alternative medicine use may be more common in individuals with MS, suggesting this number may be even greater.¹⁵ Contrary to popular public belief that supplements are natural and therefore safe, supplements carry a substantial risk of adverse drug–supplement interactions, side effects, and toxicity when dosed incorrectly.¹⁴

How Health Care Infrastructure and Culture Affect Polypharmacy

Polypharmacy in the setting of multiple prescribers makes the identification of “prescribing cascades” and medication de-escalation difficult, and individuals being seen by 4 or more physicians are at a greater risk of polypharmacy.¹⁶ The term prescribing cascade has been used since 1995 to describe the initiation of a medication to treat what was thought to be a new condition when it was a side effect of another medication; for example, if a person taking a cholinesterase inhibitor develops urinary incontinence and is subsequently treated with an anticholinergic rather than discontinuing the cholinesterase inhibitor.¹⁷ This can be especially challenging if an individual visits a physician who did not prescribe the instigating drug and is unfamiliar with that drug’s risk profile.

Short appointment times may contribute to the inappropriate use of some prescription medications. One study including more than 4 million individuals found that shorter appointment visits in the primary care setting were associated with a higher likelihood of inappropriate antibiotic prescribing and coprescribing opioids and benzodiazepines.¹⁸

Practical Tips

Management of polypharmacy is nuanced and requires an approach that reflects this. The goal is not to eliminate medication usage, but rather to practice rational prescribing dependent on aligning the individual’s goals with those of the health care team.¹⁶ Neurologists can incorporate procedures into their practice to reduce the incidence of polypharmacy. A team approach, however, may be appropriate and necessary for lasting cultural and organizational change (Figure 1).

Individual-Level Prevention

The easiest way to prevent polypharmacy is to increase awareness of it and prevent it from occurring in the first place. Regular medication review, including asking about supplements and over-the-counter medication usage, is recommended to identify which individuals are experiencing polypharmacy and who would benefit most from a comprehensive medication review. Polypharmacy reduction efforts should be focused on individuals who would benefit most from intervention, including those who are at high risk for falls, people with cognitive decline, those experiencing hyperpolypharmacy (>10 daily medications), individuals receiving palliative care, and people who are not experiencing the full benefit of their drug regimen.¹⁶

Several tools are available that may be helpful in determining which medications to avoid or prioritize de-prescribing in people with MS. The Beers Criteria were developed by the American Geriatrics Society to identify potentially inappropriate medications for older adults. This tool breaks down medications by therapeutic category and organ system to provide recommendations and rationale for use or avoidance. Other resources include the STOPP-START (Screening Tool of Older Persons’ Prescriptions–Screening Tool to Alert to Right Treatment) criteria and the Medication Appropriateness Index. The STOPP-START criteria provide a systems-based approach to medication prescribing, offering alternative suggestions for potentially harmful drugs.¹⁹ The Medication Appropriateness Index (MAI) is a standard 10-question handout used for each medication that facilitates implicit judgment when weighing the risks and benefits of each medication.²⁰ The MAI does not provide medication suggestions. None of these tools is meant to supersede clinical judgment but may be helpful for individualized prescribing and guidance.

Polypharmacy reduction involves much more than simple drug de-escalation. It also requires knowledge of nonpharmacologic interventions neurologists can offer that will not contribute to the drug burden (Figure 2). The most frequently experienced MS symptoms include chronic pain, spasticity, mobility impairment, fatigue, and cognitive impairment.²¹ We highlight a nonexhaustive list of evidence-based nonpharmacologic therapies for some of these symptoms (Figure 2).

Chronic Pain. An estimated 29% to 86% of individuals with MS experience chronic pain. When tolerated, aerobic exercise, aquatic therapy, tai chi exercises, self-hypnosis, and acupuncture were found to be helpful in pain reduction in clinical trials.²¹ There was a lack of high-level evidence supporting the use of yoga or neuropsychological interventions for pain management. It is recommended that clinicians suggest pain treatment interventions on a case-by-case basis.²¹

Mobility Disability. Mobility disability is a common and frustrating consequence of MS. The most robust evidence surrounding this topic suggests exercise training to be the most efficacious rehabilitative approach to mobility disability in those with MS. This includes aerobic exercise, resistance training, and combination exercises. Supervised exercise programs yielded significantly better improvement, attributed to better adherence to the exercise program. Evidence suggests that physical therapy focusing on balance, neuromuscular facilitation, and stretching and mobilization techniques may also improve individual mobility, although the significance was minimal. Gait training may also prove to be helpful, although the evidence for this is somewhat conflicting.²²

Spasticity. Defined as a motor disorder resulting in abnormal muscle contractions, spasticity is experienced by up to 80% of individuals with MS and contributes to chronic pain and disability.²³ Robotic rehabilitation, repetitive transcranial magnetic stimulation, and electric currents paired with physiotherapy have been shown to be helpful in the treatment of spasticity.²⁴

Multidisciplinary Team–Level Prevention

A multidisciplinary team approach is needed for the management of MS. When analyzing the effect of pharmaceutical care in the setting of multidisciplinary teams, a meta-analysis encompassing trials from 2000 through 2018 found that multidisciplinary teams reduced the probability of readmission by 32% and increased individuals’ quality of life outcomes.²⁵ Polypharmacy has been associated with increased risk of hospital admission and decreased quality of life.^2,3

A multidisciplinary MS care team may include neurologists, advanced practice clinicians, pharmacists, nurses, physical therapists, occupational therapists, behavioral health specialists, social workers, and dieticians. All team members should be familiar with both pharmacologic and nonpharmacologic approaches to MS care to prevent polypharmacy. A multidisciplinary approach may limit the aforementioned effects of fractionated health care on polypharmacy.

The addition of a polypharmacy stewardship program has been suggested as a novel concept by a study recently published in The Lancet to address the growing global concern of polypharmacy.¹⁶ This involves a polypharmacy steward, most commonly a pharmacist, working within an interdisciplinary team to identify potentially inappropriate medications and collaborate to find more suitable alternatives. A stewardship program should be as flexible as necessary to work in various health care settings. Some suggestions include a polypharmacy consult service or incorporating a polypharmacy steward within the multidisciplinary MS team.

Institution-Level Prevention

For any change or progress to be made, there must be buy-in from all stakeholders, including senior leadership. A program’s success is vitally dependent upon availability of proper resources (eg, appropriate staffing, adequate time with individuals, financial assistance, technical resources), all of which can be facilitated by support from leadership. There must be accountability for outcomes at all levels to prompt change.

Conclusion

Issues surrounding polypharmacy have been identified as a growing global concern because of the associated risks of adverse health outcomes and effects on physical, emotional, and financial wellbeing. This is especially relevant for practitioners caring for people with MS because of its early onset age and range of debilitating symptoms. The goal of polypharmacy prevention and mitigation is not to reduce medication usage to none but to practice more rational prescribing. Multidisciplinary teams have proven successful in reduction of hospital admissions and increase in quality of life in the general population as well as in MS care. Novel approaches such as instituting a polypharmacy stewardship program may not only provide additional resources, but also hold every level of leadership accountable for prescribing practices. Tackling polypharmacy will require all team members, from the neurologist to senior leadership, to make lasting changes.