Reducing Polypharmacy: Prudent Prescribing in Primary Care
Authors: Dean A. Bricker, MD, Assistant Professor of Medicine, Wright State University, Boonshoft School of Medicine, Dayton, OH; and Anne H. Metzger, PharmD, Assistant Professor of Pharmacy Practice, University of Cincinnati, James L. Winkle College of Pharmacy, Cincinnati, OH.
Peer Reviewer: Cynthia Sheppard Solomon, BPharm, RPh, FASCP, President, Sheppard-Solomon Biomedical Consulting, Dayton, OH.
Introduction
Polypharmacy is the simultaneous use of multiple medications. Many authors have defined polypharmacy as the simultaneous use of at least five1 or six medications.2,3 Others have suggested that polypharmacy should not be determined by the absolute number of medications, but rather the use of even a single medication that is not clearly indicated. Yet another alternative describes polypharmacy as the use of one medication to correct the adverse effects of another medication.4 While there are certain disease states in which optimal management often involves multiple medications (e.g., diabetes, HIV, Parkinson's. etc.), polypharmacy generally is discouraged because of the associated risks and unintended consequences.
Polypharmacy is a commonly encountered clinical scenario that has many contributing causes. It can lead to potential adverse consequences, including unnecessary monetary cost, cumulative side effects, poor compliance with critical medications, and increased morbidity and mortality. Furthermore, patients who perceive that they are taking too many medications often have lower quality-of-life scores and increased rates of depression. All practitioners share responsibility for curbing polypharmacy. However, the primary care physician is usually the coordinator of a patient's comprehensive care and may be in the best position to optimize complex medication regimens with assistance from the local pharmacist.
Epidemiology
Multiple Medications. Studies assessing the incidence of polypharmacy have found that community-based elderly patients aged 65 and older use, on average, two to nine medications. A large national study found that two-thirds of elderly U.S. women took five or more prescription medications, and that 12% were taking 10 or more daily medications.5 The overall incidence of polypharmacy appears to be increasing,4,6 due in part to continued expansion of the U.S. population age 65 years and older, now greater than 27 million people. Among Medicare patients, the most frequently prescribed classes of medications include cardiovascular agents, antibiotics, diuretics, opioids, and anti-hyperlipidemics.7 This likely reflects the multiple comorbidities that correlate with aging. The five most common specific medications used by ambulatory elderly women are estrogen products, levothyroxine, hydrochlorothiazide, atorvastatin, and lisinopril.5 For hospitalized patients, polypharmacy often includes proton-pump inhibitors, diuretics, beta-blockers, and opioid analgesics. In the hospital setting, the diseases most closely related to polypharmacy are renal failure, hypertension, diabetes mellitus, and pain syndromes.3
Nonprescription medications and herbal preparations also are part of the ever-growing pharmacopoeia contributing to increased risk and cost. Ninety percent of non-institutionalized elders take at least one over-the-counter medication on a regular basis, and approximately 50% use two to four nonprescription medications.4 Similarly, the use of herbs, vitamins, and minerals is common; 47-59% of elders use vitamins and minerals, while 11-14% use daily herbal supplements.5 Perhaps more concerning, the majority of patients studied did not report herb use to their primary care physicians, increasing the risk for drug-herb interactions (e.g., the risk for bleeding when ginkgo and garlic are combined with warfarin). Equally alarming, only 16% of consumers read non-prescription labels completely, while 10% do not read the label at all, and 44% routinely exceed the recommended dose of nonprescription pain relievers.8
Unnecessary Medications. In addition to evaluating the quantity of medications used, a number of studies have focused on polypharmacy defined as any unnecessary drug use. In their work, Schmader et al applied the Medication Appropriateness Index (MAI), defined as a medication without an indication, one lacking effectiveness, or the presence of a therapeutic duplication. In a population of adults, they found the average number of unnecessary drugs to be 0.65 per person.9 Lipton, et al. showed that up to 60% of elderly patients were taking medications that were suboptimal or lacking an indication.10
Similarly, another study found up to 55% of the elderly took drugs with no indication, 33% took ineffective medications, and 16% had therapeutic duplication.9 In a study of hospitalized elderly veterans, 44% were found to have one or more unnecessary medications at the time of discharge. In 25% of those patients, the culprit medication had been initiated during the hospitalization.4 In these studies, the most frequently prescribed unnecessary medications were gastrointestinal agents, central nervous system agents, as well as nutritional and mineral supplements. Although there is little data on the potential harm from unnecessary medications, it is likely that these regimens resulted in increased drug expenditures.
Presumably "unnecessary medications" are prescribed unintentionally. That is, either ignorance or inattention on the part of the patient or the prescriber somehow resulted in the prescription of an unneeded or inappropriate medication or supplement. Experts believe adverse drug events in ambulatory care can be reduced by electronic prescribing systems with sophisticated decision support to alert clinicians about inappropriate medications or harmful medication combinations. Although such interventions have resulted in modest reductions of inappropriate prescribing, clinicians frequently override alerts. A recent study showed that electronic prescribing generated alerts in 6.6% of prescriptions. Clinicians rejected the vast majority of alerts, accepting only 9.2% of drug interaction alerts and 23.0% of allergy alerts. High-severity interaction alerts were accepted more often (10.4%) than warnings of moderate- or low-severity interactions (7.3 % and 7.1%, respectively). The authors found no difference in alert acceptance among practitioners of different specialties.11
However, not all unnecessary prescribing is unintentional. A recent large survey of U.S. internists and rheumatologists found that at least half of the physicians prescribed placebo treatments on a regular basis. While the largest proportion reported recommending nonprescription analgesics (41%) and vitamins (38%) to their patients, an alarming number reported prescribing antibiotics (13%) and sedatives (13%) when not clearly indicated. Equally controversial were the findings that most physicians believed the practice of prescribing placebo treatments to be ethically permissible and that only a small minority (5%) explicitly described their treatments to their patients as placebos.12
Etiology
Many studies have evaluated potential risk factors for polypharmacy. These risk factors can be categorized as demographic, illness-related, or associated with access to healthcare. Numerous studies have found an increasing incidence of polypharmacy with increasing patient age. While age may be an independent risk factor, most studies show that polypharmacy also strongly correlates with polymorbidity, often associated with aging populations.13 Some studies have shown an increased incidence of polypharmacy among Caucasians, while other studies have shown polypharmacy and potentially inappropriate prescribing to occur more often in women.4 However, the reasons for the latter findings are not entirely clear.
In developed countries, low socioeconomic status and low educational level correlate with increased risk of polypharmacy. One study found that patients with a low educational level were more likely to experience polypharmacy, use three or more psychotropic drugs, and have a greater potential for drug-drug interactions.1 Similarly, a different study assessed elderly patients' knowledge and beliefs about their prescribed medications and found that polypharmacy patients had significantly less understanding about their mediations than patients with simpler regimens. Eighty-four percent of patients had no knowledge about possible adverse effects. Although 93% of patients believed the benefits of their medications outweighed the risks, there was no correlation between the patient's knowledge of indications and side effects and their faith in their medication.14
The use of polypharmacy also has been associated with healthcare access and delivery. For instance, polypharmacy has been linked with low levels of self-rated health, institutionalized living, and the number of visits to a primary care provider per year. A study by Corsonello, et al. demonstrated that polypharmacy increased in incidence following acute hospitalization. This study found that elderly patients acquired, on average, one additional long-term medication at hospital discharge.15
Other studies have demonstrated that the number of medications increases with the number of consultants involved in a patient's care. Frequently, clinicians are reluctant to discontinue a medication prescribed by another physician.16 One area that may play a role but that has not yet been studied is the hypothesis that polypharmacy may be more common when patients use more than one pharmacy.
In 1997 a change in policy by the Food and Drug Administration (FDA) allowed direct-to consumer advertising of prescription drugs on television and in other media. Both the absolute amount and percentage of pharmaceutical advertising expenditure continue to rise.17 While the debate about overall benefit versus harm persists, there is growing concern that direct advertising may lead to potential overuse.18 However, some studies have demonstrated that current advertising practices may help avert underuse of certain classes of medications (e.g., antidepressants). Some consumer advocacy groups and the Institute of Medicine have recommended that the FDA restrict advertising for new prescription drugs for a mandatory waiting period, allowing health professionals to be educated adequately.
Clinical Features
Ideally, the clinician and patient should take preventive measures to protect against polypharmacy. Alternatively, unnecessary medications should be discontinued well in advance of the occurrence of serious adverse drug events or other unwanted consequences. While many patients with existing polypharmacy may not have specific clinical findings, a number of common geriatric syndromes have been correlated with polypharmacy. This presents an opportunity for primary care practitioners to be vigilant in detecting these conditions.
Geriatric Syndromes. Cognitive impairment, imbalance, falls, fractures, urinary incontinence, weight loss, malnutrition, and decline in physical activities of daily living are common geriatric syndromes, and they frequently are associated with polypharmacy in the elderly. Benzodiazepines, antidepressants, and antipsychotics are the medications that most often cause or aggravate these conditions or events.4,19 (See Table 1.)
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Elderly patients also are more susceptible to insomnia, orthostatic hypotension, and constipation, which are the common side effects seen with anticholinergic medications, alpha blockers, and opioids. Patients with long-standing diabetes may be even more prone to these adverse events due to autonomic dysfunction, neuropathy, and vascular disease.20
Polypharmacy is especially common in the elderly, the very population at greatest risk for numerous adverse consequences. In 1991, Beers, et al. published criteria for identifying medications that may be inappropriate for prescription to elderly nursing-home patients.21 Based on expert consensus, the Beers criteria were updated by Fick, et al in 2002. The authors identified a list of medications or classes that generally should be avoided in persons 65 years or older. For instance, the authors recommend avoiding the use of diphenhydamine as a hypnotic because of the substantial risk of confusion and sedation in older patients. The consensus panel also generated an additional list of medications that should not be used in older persons known to have specific medical conditions. An example of potential drug-disease interactions to be avoided is the potential for an alpha blocker to aggravate stress urinary incontinence in an elderly woman. The authors identified 48 specific medications to be avoided as well as 20 disease states that could contribute to drug-disease interactions.22 These are summarized in Tables 2 and 3, respectively.
Consequences. Rollason and Vogt have suggested several adverse consequences possibly caused by polypharmacy.23 These include drug interactions, adverse reactions, non-adherence to medications, aggravation of geriatric syndromes, and increased monetary costs. Polypharmacy also leads to personal and societal fiscal costs, significant risks of severe morbidity requiring acute hospitalization, and the potential for drug-related death.23,24
Drug Interactions. Drug interactions increase with the number of medications taken. Some authors suggest that up to 60% of patients taking multiple medications have drug interactions.23 The incidence of clinically relevant drug interactions is somewhat lower, probably around 5-15%, with the incidence of severe interactions at 3%.23 Drug interactions include not only drug-drug interactions, but also drug-disease and drug-food interactions that sometimes can be clinically problematic. For example, medications with anticholinergic effects may cause adverse drug-disease interactions in a man with prostatism. Similarly, regular consumption of grapefruit juice may alter the metabolism of many statins. While software to check interactions will screen for drug-drug interactions, these alerts most likely will not identify drug-disease and drug-food interactions.
Adverse Drug Reactions. According to the World Health Organization, an adverse drug reaction is any noxious, unintended, and undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. A causal relationship between use of the drug and the noxious event is implied.25 Adverse drug reactions have been correlated with polypharmacy, and this relationship is not one of a linear fashion, but rather one that is exponential. As the number of medications increases, so does the incidence of drug reactions.23 One study found that 35% of outpatients age 65 and older taking five or more medications experienced at least one adverse reaction.26 Most studies examining adverse reactions have focused on the potential, not the actual, occurrence of this outcome. However, one retrospective cross-sectional analysis investigated patients who had actual observed adverse effects to medications. Although most adverse effects were not serious, the patients experiencing more adverse effects were taking 14.4 ± 7.6 medications compared to those in the other group, who had been taking only 8.1± 5.7 medications.27 Adverse drug reactions are thought to cause 1-16% of hospital admissions and may be fatal in up to 0.7% of admissions.25 Additionally, studies have shown that almost half (46.5%) of these are potentially preventable.28 The net result is that adverse drug reactions currently rank as the fifth or sixth leading cause of death in the United States and cost between $37.6 billion and $50 billion annually.16
Non-adherence to Medications. Thirty to sixty percent of consumers are non-adherent to their prescribed medication, and the risk of non-adherence increases as the number of medications increases.29 Accordingly, non-adherence results in the patient not receiving the full benefit of treatment. If the prescriber is unaware of medication non-compliance, he or she may add more medications, resulting in a so-called prescribing cascade. Polypharmacy may be aggravated while adherence to vitally important therapy wanes. The outcomes can range from simple treatment failure to life-threatening consequences.23
Undertreatment. Somewhat related to the issue of non-adherence is another unintended consequence of polypharmacy the potential for undertreatment. An apparent treatment-risk paradox has been reported among patients with complex drug regimens. That is, often patients who are at the greatest risk for disease complications have the lowest probability of receiving the recommended pharmacologic treatment.30 A European study of ambulatory patients found that 43% of polypharmacy patients were undertreated for various chronic illnesses, while only 13.5% of patients taking four or fewer medications had under-treated illnesses. In this study, polypharmacy patients with myocardial infarction, heart failure, and hypercholesterolemia were under-prescribed some common medications, including beta-blockers, ACE inhibitors, and statins.30 Harder, et al. reported underprescribing of statin therapy among diabetic polypharmacy patients; 76% of patients were eligible for statin therapy, while only 51% actually took a statin.31 A possible explanation for these findings is that clinicians may be unwilling to prescribe more drugs to patients with complex drug regimens, perhaps fearing adverse drug reactions or poor adherence. Alternatively, it is possible that patients taking many drugs may be reluctant to add more drugs even when they are clearly indicated.
Cost of Polypharmacy
The financial cost of polypharmacy involves both the direct expenditures for prescription medications as well as significant indirect costs related to hospitalization and treatment of severe adverse drug reactions. The indirect costs of polypharmacy have been estimated to be upwards of $25 billion based on 17 studies between 1976 and 1988.32 In today's healthcare climate, the true cost is likely much higher.
In addition to the costs to the healthcare system, costs to the consumer are high when patients take multiple medications. Prior to the Medicare Prescription Drug Improvement and Modernization Act becoming fully effective in 2006, the average Medicare beneficiary spent an estimated $3,255 annually for prescription medications. Even with the new Medicare drug benefit, the average annual cost per beneficiary was $1,095 in 2006, while the average household income for seniors was approximately $24,500.33
The personal financial impact of multiple medications can lead to other unintended consequences. A Consumer Reports poll found that two-thirds of patients learned about the cost of their prescription at pharmacy pickup, while only 4% had a conversation with their doctor about the cost of a drug. Even more alarming, 28% said they had taken potentially dangerous actions to save money, such as not filling prescriptions, skipping dosages, and cutting pills in half without the approval of their doctor.34
Serious Consequences. A large multi-center, prospective study demonstrated that taking five or more medications was one of several independent risk factors predicting potentially preventable, medication-related hospital admissions.28 A large United Kingdom study found that 10.5% of 1,998 elderly inpatients had adverse drug reactions as their primary reason for hospitalization.35 Another study estimated that 16.8% of hospitalizations of elderly patients in an acute care hospital were due to adverse drug reactions, and 11.4% were due to non-adherence.36 Presumably the hospital admissions due to both scenarios were preventable.36
Solutions
Since the risks are substantial, polypharmacy should be handled like many risk factors for disease. Optimally, polypharmacy should be managed by prevention. If prevention fails, polypharmacy should be identified and treated by discontinuation of unnecessary and ineffective medications well in advance of serious adverse drug events or other unwanted consequences. The mainstays for identifying polypharmacy remain heightened awareness, use of effective electronic alerts, and continued pharmaco-vigilance by the patient, the physician, and the pharmacist in thoroughly reviewing and reconciling the patient's medication regimen at every opportunity.
Primary care providers continue to treat an aging population with multiple disease states. As elderly patients live ever longer, many will continue to require several drugs to treat their conditions. Nevertheless there are several ways to reduce the occurrence of polypharmacy in the primary care population. Most intervention strategies have focused on feedback and education directed to prescribers or patients, or to both simultaneously. Mechanisms for identifying patients at risk and suggestions for change in regimens have ranged from simple computer alerts to pharmacist-initiated feedback. Methods of pharmacist feedback to either patients or prescribers have included e-mails, faxes, phone calls, and letters. In one study, a computer reminder sent to the clinician for patients in an extended care facility on more than 10 medications resulted in a decrease in polypharmacy. In another study, polypharmacy was lessened among patients cared for by resident physicians by providing admitting residents with a medication grid of all medications and administration times.20,37
Prescriber Education and Recognition. Understanding the relevance of polypharmacy is just the first step in combating the problem. Clinicians should practice judicious prescribing by educating themselves on the appropriateness of drug treatments. The best way to prevent polypharmacy is to prescribe the fewest number of medications needed to treat a disease or condition and to reassess the appropriateness of a patient's prescriptions on a frequent and regular basis. Simonson and Feinberg address this issue and provide several useful questions that prescribers can use to guide their medication choices for patients.38 (See Table 4 for a summary of this information.)
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In addition to judicious prescribing, heightened awareness of common drug-drug interactions in the ambulatory setting may help reduce the serious consequences of polypharmacy. Malone, et al., used a standard evaluation tool and an expert panel of pharmacists to identify 25 clinically important drug interactions that are likely to occur in the ambulatory care setting.39 Several of these are listed in Table 5; it should be noted that this is not an exhaustive list of all potential interactions. Some of the most frequently encountered include various warfarin interactions, digoxin plus clarithromycin, methotrexate plus trimethoprim-sulfamethoxazole, and nitrates plus sildenafil. ACE-inhibitors and/or angiotensin receptor blockers combined with diuretics and NSAIDs is yet another clinically relevant drug combination often encountered and that predisposes the patient to pre-renal azotemia. Additionally, remembering to check drug-food and drug-disease interactions may help to prevent adverse drug events and unwanted consequences from polypharmacy.
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Judicious prescribing involves more than the avoidance of drug interactions. In general, prescribing without a diagnosis should be discouraged and, whenever possible, nonpharmacologic treatment alternatives should be considered.32 Furthermore, prescribing medications to treat the adverse effects of other medications should be avoided except when the risk of disease progression, morbidity, or mortality is substantial if left untreated. Awareness of the common drug-drug interactions helps prevent errors that may occur when patients must take several medications to treat their diseases.
One other consideration in prescribing is the cost of multiple medications. Several solutions are available and have been evaluated for cost savings. Interventions to reduce cost include the use of less expensive generic medications, therapeutic interchanges, and combination pill formulations. Using a combination of the suggested solutions can have a large impact on the overall cost to the patient. For example, a study of elderly patients with an average medication cost of $185 per month found that using the interventions above lowered cost by 68% per month.40 Being aware of patients' social challenges and insurance status may allow certain changes in prescribing habits that lower cost. Even patients who have medication insurance coverage may incur large co-payments if taking several brand-name medications. Changing these to less expensive but similarly effective generic medications can reduce cost by a great deal. Prescribing combination pills may help reduce both cost and the overall number of pills the patient must take. The net effect may be improved adherence but sometimes can make dosing titrations difficult. Combination formulations do not eliminate the potential for polypharmacy-related drug interactions.
Multidisciplinary Practice. The involvement of clinical pharmacists in reducing polypharmacy has been addressed in numerous studies. All have found that intervention by a pharmacist can lessen the number of inappropriate medications prescribed. Rollason and Vogt reviewed seven studies measuring the impact of pharmacists on polypharmacy and concluded that review and intervention by a pharmacist with a patient receiving multiple medications significantly reduces the number of medications prescribed.23
As a part of the Medicare Modernization Act of 2003, which established a Medicare prescription benefit program (Medicare Part D), pharmacists can be compensated for performing Medication Therapy Management (MTM). Targeted at Medicare Part D beneficiaries who have multiple chronic diseases, are taking multiple drugs, and are likely to incur a large drug cost related to multiple drugs, MTM was designed to optimize medication use and ultimately improve therapeutic outcomes for individual patients. Pharmacists work collaboratively with the patient's physician, the patient, and his or her other healthcare providers to identify, prioritize, and resolve medication-related problems, while empowering the patient to optimize medication use.41,42
Zarowitz, et al. studied MTM in a group of 195,971 high-risk polypharmacy patients who received their health care from the Henry Ford Medical Group and had health insurance provided by the Health Alliance Plan. Patients were divided into two groups, one of which had its drug therapy modified by a physician and one that had drug therapy modified by a clinical pharmacist in conjunction with the physician. The collaborative team yielded several significant results: overall polypharmacy was decreased by 72%, and the number of patients taking five or more medications was reduced by 36%. Additionally, the physician-pharmacist group had a decrease in the use of multiple benzodiazepines and narcotics of more than 90%, a 73% decrease in patients using three or more oral antidiabetic drugs, and a 96% decrease in the use of sildenafil plus a nitrate. The savings from the reduction in polypharmacy for the physician-pharmacist group was estimated to be more than $3 million.43
Patient Education. One of the most important ways that prescribers can reduce polypharmacy is to educate patients about their medications. Patients should be encouraged to maintain their own list of medications and to bring all their medications into the office when they come for office visits.35 Such diligence is especially important when multiple specialists are prescribing medications. It is also crucial for patients to inform their caregivers about their use of over-the-counter medications as well as dietary supplements. Additionally, encouraging patients to use a single pharmacy as their source for obtaining medications will reduce the risk of polypharmacy and potential serious consequences. Use of a single pharmacy, effective electronic prescribing systems, and electronic medical records with decision support can facilitate both electronic alerts as well as pharmacist input. Today, with marketing techniques such as coupons for new prescriptions and $4 medication lists, using a single pharmacy can be challenging for many patients, but doing so will lower the risk of potentially inappropriate drug combinations.44
Challenges
From the clinician's perspective, when a medication is started it may be difficult to discontinue. Prescribers are concerned about the patient's resistance to change, and patients may be reluctant to stop a familiar medication. Furthermore, clinicians often are unwilling or reluctant to discontinue a medication that another provider has prescribed.16 However, prescribers must understand that it may be appropriate and necessary to discontinue a medication that another clinician has prescribed. Communication and shared decision-making are essential parts of best practice in this regard. With input from the local pharmacist, the primary care clinician coordinating a patient's care is best suited to trim a given patient's complex medication regimen.
Discussion
While it is intuitive to believe that reducing polypharmacy will lead to improved outcomes, evidence demonstrating clinical benefit has been limited largely to studies of inpatient computerized prescribing. Studies investigating the benefits of reducing polypharmacy in the ambulatory setting sometimes have demonstrated successful reductions in the numbers of medications but have not reported fewer adverse drug reactions.11 Nevertheless, we recommend judicious, cost-conscious prescribing and a multidimensional approach to the prevention and treatment of polypharmacy. (See Table 6.) Before prescribing a new medication, the physician should consider the indication, the necessity, the priority, the cost, and the likelihood of adherence, as well as the risk of drug interactions. Furthermore, at each follow-up visit, the clinician should assess medication effectiveness. When medications are unnecessary, ineffective, or not indicated, they should be discontinued.
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Although there is a paucity of data about discontinuing many types of medications, there are some findings from observational and retrospective studies supporting medication withdrawal. For some chronic disease states, benefit may persist after a medication is stopped. For example, a placebo-controlled trial of bisphosphonates demonstrated reduced fracture rates that were sustained for five years after therapy had been discontinued. Whenever a medication is discontinued, there must be careful subsequent monitoring because of potential adverse drug withdrawal events. Such events have been reported to occur in up to one-third of patients stopping medications. Adverse withdrawal events may be averted by identifying potential contributing medications and tapering them over the course of days to weeks.11
Summary
Polypharmacy is a frequently encountered problem in primary care practice. Although there are a number of contributing causes, it is especially common in the elderly, the very population at greatest risk for a myriad of potential adverse consequences. Polypharmacy contributes to drug interactions, adverse drug reactions, geriatric syndromes, and medication non-compliance, as well as the potential for preventable hospitalizations and drug-related deaths. There also are formidable financial implications of injudicious prescribing both on a societal and personal level. A number of interventions have been studied and found to decrease the incidence of polypharmacy. These range from the targeted education of clinicians and patients to the assistance of clinical pharmacists in tailoring complex medication regimens. Computer alerts and ever-increasing decision support may have a positive impact on prescribers and patients. The mainstay for preventing and managing polypharmacy remains heightened awareness of patients at risk. Pharmaco-vigilance is required by the patient, physician, and pharmacist in thoroughly reviewing and reconciling the patient's medication regimen at every opportunity.
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Polypharmacy is the simultaneous use of multiple medications. Many authors have defined polypharmacy as the simultaneous use of at least five or six medications. Others have suggested that polypharmacy should not be determined by the absolute number of medications, but rather the use of even a single medication that is not clearly indicated.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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