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1.  Prevalence and Predictors of Polypharmacy among Korean Elderly 
PLoS ONE  2014;9(6):e98043.
Polypharmacy is widespread in the elderly because of their multiple chronic health problems. The objective of this study was to investigate the prevalence and predictors associated with polypharmacy in a nationally representative sample of Korean elderly individuals.
We used the Korea Health Insurance Review and Assessment Service – National Patient Sample (HIRA-NPS) data from 2010 and 2011. We used information on 319,185 elderly patients (aged 65 years or older) between January 1, 2010 and December 31, 2011 from the HIRA-NPS database. We defined ‘polypharmacy’ as the concurrent use of 6 medications or more per person, ‘major polypharmacy’ as 11 medications or more, and ‘excessive polypharmacy’ as 21 medications or more. The frequency and proportion (%) and their 95% confidence intervals were presented according to the polypharmacy definition. Polypharmacy was visualized by the Quantum Geographic Information Systems (QGIS) program to describe regional differences in patterns of drug use. Multivariate ordinal logistic regression was performed to estimate odds ratios (ORs) and their 95% confidence intervals (CI) to investigate the risk factors for polypharmacy.
Of the Korean elderly studied, 86.4% had polypharmacy, 44.9% had major polypharmacy and 3.0% had excessive polypharmacy. Polypharmacy was found to be primarily concentrated in the Southwest region of the country. Significant associations between polypharmacy and the lower-income Medical Aid population (OR = 1.52, 95% CI 1.47, 1.56) compared with National Health Insurance patients was observed.
Nationwide efforts are needed for managing polypharmacy among Korean elderly patients. In particular, a national campaign and education to promote appropriate use of medicines for the Medical Aid population is needed.
PMCID: PMC4051604  PMID: 24915073
2.  Self-medication with nutritional supplements and herbal over-thecounter products 
In recent years, the popularity increased for nutritional supplements and herbal products. Prescription drugs, but not herbal therapies are paid by health insurances. They are sold over-the-counter (OTC) on the patients’ own expense. However, there are potential risks of self-medication, e.g. incorrect self-diagnosis, severe adverse reactions, dangerous drug interactions, risk of addiction etc. They are often used by patients at their own discretion without knowledge of and control by their physicians. Certain users are at risk of intoxication. Multiple medications taken by older patients increase the risk for adverse drug reactions, drug-drug interactions, and compliance problems for this age group (polypharmacy). Herbals should be discontinued prior to operations to avoid interactions with anesthetics or anticoagulants. Herbal preparations may also be carcinogenic or interfere with cancer treatments. Pregnant women use various OTC preparations. However, in many cases, it is unclear whether their use is safe for mother or baby. Self-medication with herbals is also largely distributed among anxious and depressive patients, and patients with other conditions and symptoms. The popularity of herbal products has also brought concerns on quality, efficacy and safety. Cases of botanical misidentification, contaminations with heavy metals, pesticides, radioactivity, organic solvents, microbials as well as adulteration with chemical drugs necessitate the establishment of international quality control standards. Hepatotoxic effects have been reported for more than 300 plant species, and some commonly used herbs have been demonstrated to interact with Western medication. Health care professionals have a critical responsibility assessing the self-care ability of their patients. Databases are available for pharmacists with information on action, side effects and toxicities as well as herb-drug interactions. There is a need for established guidelines regarding the correct use of nutritional supplements and herbal OTC preparations (phytovigilance). Physicians, pharmacists, and other health care professionals have to counsel patients and the general public on the benefits and risks associated with herbal drugs. Information centers for consumers and general practitioners are needed, and convincing evidence on safety and efficacy of herbal products has to be demonstrated in placebo-controlled, double blind and randomized clinical trials.
PMCID: PMC4131654
botanicals; contamination; complementary and alternative medicine; drug interactions; geriatric; gynecology; insomnia; hepatotoxicity; menopause; nephrotoxicity; over-the-counter; pain; phase I/II enzymes; pharmacognosy; pharmacovigilance; phytochemicals; phytotherapy; phytovigilance; quality control
3.  Polypharmacy in general practice: differences between practitioners. 
BACKGROUND: Polypharmacy, the simultaneous use of multiple drugs, is associated with adverse drug reactions, medication errors, and increased risk of hospitalization. When the number of concurrently used drugs totals five or more (major polypharmacy), a significant risk may be present. AIM: To analyse the interpractice variation in the prevalence of major polypharmacy among listed patients, and to identify possible predictors of major polypharmacy related to the practice. METHOD: Prescription data were retrieved from the Odense Pharmacoepidemiological Database, and individuals subject to major polypharmacy were identified. The age- and sex-standardized prevalence rate of major polypharmacy was calculated for each practice in the County of Funen in Denmark (n = 173), using the distribution of age and sex of the background population as a reference. The practice characteristics were retrieved from the Regional Health Insurance System. Possible predictors of major polypharmacy related to the general practitioners (GPs) were analysed using backward stepwise linear multiple regression. RESULTS: A six-fold variation between the practices in the prevalence of major polypharmacy was found (16 to 96 per 1000 listed patients; median = 42). Predictors related to the practice structure, workload, clinical work profile, and prescribing profile could explain 56% of the variation. CONCLUSION: A substantial part of the variation in major polypharmacy between practices can be explained by predictors related to practice.
PMCID: PMC1313371  PMID: 10343422
4.  Polypharmacy and Falls in the Elderly: A Literature Review 
Nursing and Midwifery Studies  2013;2(2):171-175.
Medications are taken to ease, control or cure ailments. They are effective and safe if used correctly. In the elderly, disorders that occur as a result of ageing, frequently require treatment, resulting in increased use of medications. Polypharmacy is common among the elderly and although it can be therapeutic in nature, is linked to adverse events such as falls.
Evidence Acquisition:
A review of the literature was conducted. English articles in Cinahl, Medline and Healthsource (2000-2012) were searched for links between polypharmacy and falls in older adults aged 65 years old and over. Articles not meeting the age criterion were excluded.
Search terms included falls, polypharmacy, medications, multiple medications, medicines, elderly, aged. A total of 120 articles were retrieved from the Literature search.
Sixteen articles were included in the literature review. Four literature reviews, three observational prospective cohort, three cross-sectional, three case-control, one longitudinal study and two retrospective cohort studies were examined. Many studies were able to demonstrate a link between the number of medications taken and risk of falls however the potential for bias resulting from confounding by indication was high due to study design in many cases.
Polypharmacy as an independent variable has been linked to falls in older people, however there appears to be a stronger link between falls and the type of medications taken (e.g. medications known to increase risk of falls), rather than polypharmacy on its own. Polypharmacy can sometimes be therapeutic and it may be more beneficial to consider terms such as ‘inappropriate prescribing’ or potentially inappropriate medications’ when considering the effects of medication on falls in older adults. Polypharmacy in older people is often viewed in a negative light due to the increased risk of adverse events, including falls. This article examined current knowledge on the characteristics that define polypharmacy, its effect on falls in elderly people and provided recommendations for future research. Further research utilizing prospective and intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidities and fall risk.
PMCID: PMC4228551  PMID: 25414854
Polypharmacy; Falls; Older people; Literature review
5.  Pre-injury polypharmacy as a predictor of outcomes in trauma patients 
One of the hallmarks of modern medicine is the improving management of chronic health conditions. Long-term control of chronic disease entails increasing utilization of multiple medications and resultant polypharmacy. The goal of this study is to improve our understanding of the impact of polypharmacy on outcomes in trauma patients 45 years and older.
Materials and Methods:
Patients of age ≥45 years were identified from a Level I trauma center institutional registry. Detailed review of patient records included the following variables: Home medications, comorbid conditions, injury severity score (ISS), Glasgow coma scale (GCS), morbidity, mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, functional outcome measures (FOM), and discharge destination. Polypharmacy was defined by the number of medications: 0–4 (minor), 5–9 (major), or ≥10 (severe). Age- and ISS-adjusted analysis of variance and multivariate analyses were performed for these groups. Comorbidity–polypharmacy score (CPS) was defined as the number of pre-admission medications plus comorbidities. Statistical significance was set at alpha = 0.05.
A total of 323 patients were examined (mean age 62.3 years, 56.1% males, median ISS 9). Study patients were using an average of 4.74 pre-injury medications, with the number of medications per patient increasing from 3.39 for the 45–54 years age group to 5.68 for the 75+ year age group. Age- and ISS-adjusted mortality was similar in the three polypharmacy groups. In multivariate analysis only age and ISS were independently predictive of mortality. Increasing polypharmacy was associated with more comorbidities, lower arrival GCS, more complications, and lower FOM scores for self-feeding and expression-communication. In addition, hospital and ICU LOS were longer for patients with severe polypharmacy. Multivariate analysis shows age, female gender, total number of injuries, number of complications, and CPS are independently associated with discharge to a facility (all, P < 0.02).
Over 40% of trauma patients 45 years and older were receiving 5 or more medications at the time of their injury. Although these patients do not appear to have higher mortality, they are at increased risk for complications, lower functional outcomes, and longer hospital and intensive care stays. CPS may be useful when quantifying the severity of associated comorbid conditions in the context of traumatic injury and warrants further investigation.
PMCID: PMC3249840  PMID: 22229132
Comorbid conditions; outcome prediction; polypharmacy; trauma outcomes
6.  Clinical Consequences of Polypharmacy in Elderly 
Expert opinion on drug safety  2013;13(1):10.1517/14740338.2013.827660.
Polypharmacy, defined as the use of multiple drugs or more than are medically necessary, is a growing concern for older adults.
Areas Covered
We present information about; 1.) Prevalence of polypharmacy and unnecessary medication use. ; 2.) Negative Consequences of Polypharmacy; 3.) Interventions to improve polypharmacy.
Expert Opinion
International research shows that polypharmacy is common in older adults with the highest number of drugs taken by those residing in nursing homes. Nearly 50% of older adults take one or more medications that are not medically necessary. Research has clearly established a strong relationship between polypharmacy and negative clinical consequences. Moreover, well designed inter-professional (often incuding clinical pharmacist) intervention studies that focus on enrolling high risk older patients with polypharmacy have shown that they can be effective in improving the overall quality of prescribing with mixed results on distal health outcomes.
PMCID: PMC3864987  PMID: 24073682
aged; drug utilization; polypharmacy; suboptimal drug use
7.  Polypharmacy in psychiatric practice in the Canary Islands 
BMC Psychiatry  2004;4:18.
Polypharmacy with psychoactive drugs is an increasingly common and debatable contemporary practice in clinical psychiatry based more upon experience than evidence. The objective of this study was to evaluate the prevalence and conditioners of polypharmacy in psychiatric patients.
A cross-sectional survey was carried out using the Canary Islands Health Service Clinical Records Database. A representative sample (n = 2,647) of patients with mental disorders receiving psychotropic medication was studied.
The mean number of psychoactive drugs prescribed was 1.63 ± 0.93 (range 1–7). The rate of polypharmacy was 41.9%, with 27.8% of patients receiving two drugs, 9.1% receiving three, 3.2% receiving four, and 1.8% of the patients receiving five or more psychotropic drugs. Multiple regression analysis shows that variables sex and diagnosis have a predictive value with regard to the number of psychotropic drug used, being men and schizophrenic patients the most predisposed. Benzodiazepines were the more prevalent drugs in monotherapy, while anticonvulsants and antipsychotics were the more used in combination with other treatment. A questionable very high degree of same-class polypharmacy was evidenced, while multi-class, adjunctive and augmentation polypharmacy seem to be more appropriate.
Almost half of the psychiatric patients are treated with several psychotropics. Polypharmacy is common and seems to be problematic, especially when same class of drugs are prescribed together. Some diagnoses, such as schizophrenia, are associated with an increase risk of Polypharmacy but there is a lack of evidence based indicators that allows for quality evaluation on this practice.
PMCID: PMC471555  PMID: 15236661
polypharmacy; psychotropic drugs; psychiatric patients; monotherapy.
8.  Increasing polypharmacy - an individual-based study of the Swedish population 2005-2008 
An increase in the use of drugs and polypharmacy have been displayed over time in spite of the fact that polypharmacy represents a well known risk factor as regards patients' health due to the adverse drug reactions, drug-drug interactions, and low adherence to drug therapy arising from polypharmacy. For policymakers, as well as for clinicians, it is important to follow the developing trends in drug use and polypharmacy over time. We wanted to study if the prevalence of polypharmacy in an entire national population has changed during a 4-year period.
By applying individual-based data on dispensed drugs, we have studied all dispensed prescribed drugs for the entire Swedish population during four 3-month periods 2005-2008. Five or more (DP ≥5) and ten or more (DP ≥10) dispensed drugs during the 3-month period was applied as the cut-offs indicating the existence of polypharmacy and excessive polypharmacy respectively.
During the period 2005-2008, the prevalence of polypharmacy (DP≥5) increased by 8.2% (from 0.102 to 0.111), and the prevalence of excessive polypharmacy (DP≥10) increased by 15.7% (from 0.021 to 0.024).
In terms of age groups, the prevalence of polypharmacy and excessive polypharmacy increased as regards all ages with the exception of the age group 0-9 years. However, the prevalence of excessive polypharmacy displayed a clear age trend, with the largest increase for the groups 70 years and above. Furthermore, the increase in the prevalence of polypharmacy was, generally, approximately twice as high for men as for women. Finally, the mean number of dispensed drugs per individual increased by 3.6% (from 3.3 to 3.4) during the study period.
The prevalence of polypharmacy and excessive polypharmacy, as well as the mean number of dispensed drugs per individual, increased year-by-year in Sweden 2005-2008.
PMCID: PMC3014875  PMID: 21122160
9.  Multiple medication use in older patients in post-acute transitional care: a prospective cohort study 
Older adults with a range of comorbidities are often prescribed multiple medications, which may impact on their function and cognition and increase the potential for drug interactions and adverse events.
This study investigated the extent of polypharmacy and potentially inappropriate medications in patients receiving post-discharge transitional home care and explored the associations of polypharmacy with patient characteristics, functional outcomes, and frailty.
A prospective observational study was conducted of 351 patients discharged home from hospital with support from six Transition Care Program (TCP) sites in two states of Australia. A comprehensive geriatric assessment was conducted at TCP admission and discharge using the interRAI Home Care assessment tool, with frailty measured using an index of 57 accumulated deficits. Medications from hospital discharge summaries were coded using the World Health Organization Anatomical Therapeutic Chemical Classification System.
Polypharmacy (5–9 drugs) was observed in 46.7% and hyperpolypharmacy (≥10 drugs) in 39.2% of patients. Increasing numbers of medications were associated with greater number of comorbid conditions, a higher prevalence of diabetes mellitus, coronary heart disease, chronic obstructive pulmonary disease, dizziness, and dyspnea and increased frailty. At discharge from the program, the non-polypharmacy group (<5 drugs) had improved outcomes in Activities of Daily Living, Instrumental Activities of Daily Living and fewer falls, which was mediated because of lower levels of frailty. The commonest drugs were analgesics (56.8%) and antiulcer drugs (52.7%). The commonest potentially inappropriate medications were tertiary tricyclic antidepressants.
Polypharmacy is common in older patients discharged from hospital. It is associated with frailty, falls, and poor functional outcomes. Efforts should be made to encourage regular medication reviews and rationalization of medications as part of discharge planning. Whether careful deprescribing improves outcomes in frail patients should be the focus of randomized trials.
PMCID: PMC4158998  PMID: 25214773
polypharmacy; older people; post-acute care; functional outcomes
10.  Using classification tree modelling to investigate drug prescription practices at health facilities in rural Tanzania 
Malaria Journal  2012;11:311.
Drug prescription practices depend on several factors related to the patient, health worker and health facilities. A better understanding of the factors influencing prescription patterns is essential to develop strategies to mitigate the negative consequences associated with poor practices in both the public and private sectors.
A cross-sectional study was conducted in rural Tanzania among patients attending health facilities, and health workers. Patients, health workers and health facilities-related factors with the potential to influence drug prescription patterns were used to build a model of key predictors. Standard data mining methodology of classification tree analysis was used to define the importance of the different factors on prescription patterns.
This analysis included 1,470 patients and 71 health workers practicing in 30 health facilities. Patients were mostly treated in dispensaries. Twenty two variables were used to construct two classification tree models: one for polypharmacy (prescription of ≥3 drugs) on a single clinic visit and one for co-prescription of artemether-lumefantrine (AL) with antibiotics. The most important predictor of polypharmacy was the diagnosis of several illnesses. Polypharmacy was also associated with little or no supervision of the health workers, administration of AL and private facilities. Co-prescription of AL with antibiotics was more frequent in children under five years of age and the other important predictors were transmission season, mode of diagnosis and the location of the health facility.
Standard data mining methodology is an easy-to-implement analytical approach that can be useful for decision-making. Polypharmacy is mainly due to the diagnosis of multiple illnesses.
PMCID: PMC3504540  PMID: 22950486
Polypharmacy; Co-prescription; Anti-malarials; Classification trees; Data mining; Tanzania
11.  Dietary Supplement Polypharmacy: An Unrecognized Public Health Problem? 
Excessive and inappropriate use of medications, or ‘polypharmacy’, has been recognized as a public health problem. In addition, there is growing use of dietary supplements in the United States; however, little is known about the patterns of supplement use. Recent reports in the literature of cases of excessive or inappropriate use of herbal dietary supplements leading to the term ‘polyherbacy’. The clinical vignettes described in this article highlight the need for further research on the nature and extent of multiple and inappropriate dietary supplement use or ‘dietary supplement polypharmacy’. Clinical interviewing and population surveys both address this issue in complementary ways, and provide a further understanding of dietary supplement use patterns.
PMCID: PMC2816386  PMID: 18955288
complementary and alternative medicine; dietary supplements; drug interactions; herbals; polypharmacy
12.  Proteomic Identification of IPSE/alpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs 
Eggs deposited in the liver of the mammalian host by the blood fluke parasite, Schistosoma mansoni, normally drive a T-helper-2 (Th2)-mediated granulomatous response in immune-competent mice. By contrast, in mice deprived of T-cells and incapable of producing granulomata, egg-secreted proteins (ESP) induce acute hepatic injury and death. Previous work has shown that one such ESP, the T2 ribonuclease known as omega-1, is hepatotoxic in vivo in that specific antisera to omega-1 prevent hepatocyte damage.
Methodology/Principal Findings
Using an in vitro culture system employing mouse primary hepatocytes and alanine transaminase (ALT) activity as a marker of heptocyte injury, we demonstrated that S. mansoni eggs, egg-secreted proteins (ESP), soluble-egg antigen (SEA), and omega-1 are directly hepatotoxic and in a dose-dependent manner. Depletion of omega-1 using a monoclonal antibody abolished the toxicity of pure omega-1 and diminished the toxicity in ESP and SEA by 47 and 33%, respectively. Anion exchange chromatography of ESP yielded one predominant hepatotoxic fraction. Proteomics of that fraction identified the presence of IPSE/alpha-1 (IL-4 inducing principle from S. mansoni eggs), a known activator of basophils and inducer of Th2-type responses. Pure recombinant IPSE/alpha-1 also displayed a dose-dependent hepatotoxicity in vitro. Monoclonal antibody depletion of IPSE/alpha-1 abolished the latter's toxicity and diminished the total toxicity of ESP and SEA by 32 and 35%, respectively. Combined depletion of omega-1 and IPSE/alpha-1 diminished hepatotoxicity of ESP and SEA by 60 and 58% respectively.
We identified IPSE/alpha-1 as a novel hepatotoxin and conclude that both IPSE/alpha-1 and omega-1 account for the majority of the hepatotoxicity secreted by S. mansoni eggs.
Author Summary
The flatworm disease, schistosomiasis, is a major public health problem in sub-Saharan Africa, South America and East Asia. A hallmark of infection with Schistosoma mansoni is the immune response to parasite eggs trapped in the liver and other organs. This response involves an infiltration of cells that surround the parasite egg forming a “granuloma.” In mice deprived of T-cells, this granulomatous response is lacking, and toxic products released by eggs quickly cause liver damage and death. Thus the granulomata protect the host from toxic egg products. Only one hepatotoxic molecule, omega-1, has been described to date. We set out to identify other S. mansoni egg hepatotoxins using liver cells grown in culture. We first showed that live eggs, their secretions, and pure omega-1 are toxic. Using a physical separation technique to prepare fractions from whole egg secretions, we identified the presence of IPSE/alpha-1, a protein that is known to strongly influence the immune system. We showed that IPSE/alpha-1 is also hepatotoxic, and that toxicity of both omega-1 and IPSE/alpha-1 can be prevented by first mixing the proteins with specific neutralizing antibodies. Both proteins constitute the majority of hepatotoxicity released by eggs.
PMCID: PMC3201919  PMID: 22039561
13.  Antipsychotic patterns of use in patients with schizophrenia: polypharmacy versus monotherapy 
BMC Psychiatry  2014;14(1):341.
The objective of this study was to characterize real-world treatment patterns in the prescription of antipsychotic polypharmacy (≥2 concurrent antipsychotics) compared with antipsychotic monotherapy for patients with schizophrenia.
This study was a retrospective claims-based analysis of patients (aged 13–64 years) with schizophrenia belonging to an employer-based health plan. Duration of therapy was measured as the number of treatment days over one year following the initial date of antipsychotic therapy. Discontinuation was defined as a 90-day gap in antipsychotic treatment (or in at least one antipsychotic for the polypharmacy group). Logistic regression analyses were used to predict discontinuation within one year. Ordinary Least Squares (OLS) regressions were used to predict duration of therapy (by type of therapy) when controlling for gender, region, number of somatic and psychiatric comorbidities, Deyo-Charlson comorbidity score, and number of psychiatric and somatic medications.
Of the 4,156 patients, 3,188 received monotherapy and 968 received polypharmacy. Mean age was 40 years (37.8 years for polypharmacy vs 40.3 years for monotherapy, p < 0.001). Within one year, 77% of the polypharmacy group and 54% of the monotherapy group discontinued treatment. The average duration of therapy was 163 [SD = 143] days in the polypharmacy group vs 253 [SD = 147] days in the monotherapy group. In both cohorts, patients <25 years had a higher frequency of discontinuations than those ≥26 years. Age and polypharmacy were independent predictors of treatment duration and discontinuation prior to one year.
One quarter of patients with schizophrenia received antipsychotic polypharmacy. Discontinuation was higher in the polypharmacy group. Age and polypharmacy were significant predictors of treatment discontinuation.
PMCID: PMC4264319  PMID: 25433495
Schizophrenia; Polypharmacy; Claims-based analysis; Patterns of use
14.  Optimal medication use in elders. Key to successful aging. 
Western Journal of Medicine  1997;167(4):233-237.
Pharmacotherapy represents one of the most important ways in which the practice of geriatric medicine differs from conventional medical care. The older patients is a major consumer of prescription and nonprescription medications, and proper use of these agents can lead to more cost-effective strategies in reaching optimal health. A key difference in distinguishing appropriate from inappropriate drug use is evident in the themes of polymedicine and polypharmacy. Polymedicine describes the use of medications for an older population for the treatment of multiple co-morbid conditions, while polypharmacy represents a less-than-desirable state with duplicative medications, drug-to-drug interactions, and inadequate attention to pharmacokinetic and pharmacodynamic principles. The purpose of this paper is to outline strategies toward optimal medication use as a key to successful aging. Specifically, we discuss themes of cost-effective prescribing, the role of medication compliance, overuse and underuse of medication, over-the-counter products, alcohol abuse, and preventive medicine. In addition, we discuss policy implications and responsibility for ensuring the high quality of pharmaceutical care. The reader should have a practical understanding of the pertinent issues in geriatric clinical pharmacology and its relationship to successful aging.
PMCID: PMC1304536  PMID: 9348752
15.  A method for calculating adherence to polypharmacy from dispensing data records 
Background Several measures for calculating adherence to one medication from dispensing data records have been proposed, but the nomenclature is inconsistent and computations vary. The same measures, like the medication possession ratio (MPR), have been used for multiple medication regimens, and have tended to over- or under-estimate adherence rates. Objective To demonstrate the impact of varying elements in MPR to a single medication regimen; to define standards for the estimation of adherence to polypharmacy; to propose a new method for calculating adherence to polypharmacy; to face validate it. Setting Face validity of the proposed method. Method Variations in the MPR formula were simulated. Standards for the estimation of adherence to polypharmacy were defined. A new method to calculate adherence to polypharmacy was established. Its face validity with three illustrative cases obtained from a pharmacy refill database was assessed. Main outcome measure Adherence rate to polypharmacy from refill data records. Results MPR to a single medication is operationalized in the numerator and denominator and is influenced by the parameters like observation period, medication gaps, overlap. For polypharmacy, an average MPR is commonly used, which is not accounting for the specificity of multiple medications, and hence overestimating adherence rate. We propose the daily polypharmacy possession ratio (DPPR) as an index of adherence to polypharmacy. It estimates the proportion of time a patient had medication available for use by considering the presence or absence of multiple medications on each day in the observation period. We calculated possession rates from refill histories over 31 months (January 1, 2011–July 31, 2013) for three illustrative patients. The average MPR estimates were 80 % for a patient with 6 medications/20 refill dates, 90 % for a patient with 4 medications/11 refill dates, and 89 % for a patient with 3 medications/17 refill dates. The corresponding DPPRs were 75, 88 and 99 %, indicating overestimations by 5 and 2 %, and underestimation by 10 %, respectively. Conclusion The DPPR accounts for the specificity of polypharmacy including number of medications, medication switching, duplication, overlapping. Research is needed to further confirm the validity of this new index.
PMCID: PMC3890044  PMID: 24293284
Adherence; Compliance; Daily polypharmacy possession ratio; Medication possession ratio; Pharmacy claims; Polypharmacy; Refill data
16.  Synergistic Drug-Cytokine Induction of Hepatocellular Death as an in vitro Approach for the Study of Inflammation-Associated Idiosyncratic Drug Hepatotoxicity 
Toxicology and applied pharmacology  2009;237(3):317-330.
Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.
PMCID: PMC3108859  PMID: 19362101
drug-induced liver injury; adverse drug reactions; pre-clinical assays; information theory; partial least-squares modeling
17.  Polypharmacy in Older Adults with Cancer 
The Oncologist  2010;15(5):507-522.
This paper reviews the adverse outcomes associated with polypharmacy and presents polypharmacy definitions offered by the geriatrics literature, examining the strengths and weaknesses of the various definitions, as well as exploring the relationships among these definitions and what is known about the prevalence and impact of polypharmacy in the geriatric-oncology population.
Learning Objectives
After completing this course, the reader will be able to: Differentiate the multiple definitions of polypharmacy in order to be able to recognize it in your patient population.Discuss the current data available in evaluating polypharmacy specifically in older adults with cancer and incorporate the data in your evaluation of older patients.Summarize the agents or drug classes that may be deemed inappropriate in older adults to avoid prescribing medications for older patients that may lead to adverse drug events.
This article is available for continuing medical education credit at
The definition of “polypharmacy” ranges from the use of a large number of medications; the use of potentially inappropriate medications, which can increase the risk for adverse drug events; medication underuse despite instructions to the contrary; and medication duplication. Older adults are particularly at risk because they often present with several medical conditions requiring pharmacotherapy. Cancer-related therapy adds to this risk in older adults, but few studies have been conducted in this patient population. In this review, we outline the adverse outcomes associated with polypharmacy and present polypharmacy definitions offered by the geriatrics literature. We also examine the strengths and weaknesses of these definitions and explore the relationships among these definitions and what is known about the prevalence and impact of polypharmacy.
PMCID: PMC3227983  PMID: 20418534
Polypharmacy; Cancer; Oncology; Geriatrics; Medications; Therapy
18.  Prevalence of Polypharmacy and Drug Interaction Among Hospitalized Patients: Opportunities and Responsabilities in Pharmaceutical Care 
Materia Socio-Medica  2012;24(2):68-72.
Polypharmacy and drug-related problems (DRPs) have been shown to prevail in hospitalized patients. We evaluated the prevalence of polypharmacy; and investigated relationship between polypharmacy and: symptoms of DRPs, number of drugs and OTC, index of cumulative morbidity, length of exposure to polypharmacy and the number of days of hospital stay among hospitalized patients.
A study was performed in Pharmacies „Eufarm Edal“ Tuzla from 2010 to 2011. Polypharmacy was defined as using ≥ 3 drugs. The total study sample of 226 examiners were interviewed with special constructed questionnaires about DRPs. Experimental study group consisted of hospital patients with polypharmacy (n=166) and control group hospital patients without polypharmacy (n=60). Mann-Whitney test was used to test for significant self-reported symptom differences between groups and cross sectional subgroups, t- test and χ2- test for age, gender and treatment data in hospital.
The prevalence of polypharmacy was 74% among 226 hospitalized patients. The vulnerable age subgroup of hospitalized patients was men and hospitalized patients aged from 46 to 50 years (not geriatric patients). The prevalence of index of cumulative morbidity was 65%. The most common exposures varied by patient age and by hospital type, with various antibiotics, antidepressants, analgesics, sedatives, antihypertensives, flixotide, ranitidine and others. The prevalence of exposure to OTC and self- treatment was 80%. The prevalence of symptoms of drug-related problems were significantly differed among patients of experimental in relationship of control study group patients (P<0.001).
In addition to helping to resolve the above mentioned issues, the results from this study could provide baseline information quantifying the problem of drug- related problems among hospitalized patients receiving polypharmacy and contribute to the formulation and implementation of risk management strategies for pharmacists and physicians in primary care health.
PMCID: PMC3633380  PMID: 23678310
polypharmacy; hospitalized patients; index of cumulative; primary pharmaceutical care.
19.  A population-based study on the association between acute renal failure (ARF) and the duration of polypharmacy 
BMC Nephrology  2012;13:96.
Because of the rapid growth in elderly population, polypharmacy has become a serious public health issue worldwide. Although acute renal failure (ARF) is one negative consequence of polypharmacy, the association between the duration of polypharmacy and ARF remains unclear. We therefore assessed this association using a population-based database.
Data were collected from the Taiwan National Health Insurance Research Database (NHIRD) from 2003 through 2006. The case group included patients hospitalized for ARF during 2006, but not admitted due to trauma, surgery, burn trauma, car accident, transplantation, or infectious diseases; the control group included patients hospitalized without ARF. The cumulative number of days of polypharmacy (defined as more than 5 prescriptions per day) for 1 year prior to admission was determined, with patients further subdivided into 4 categories: less than 30 days, 31–90 days, 91–180 days, and over 181 days. The dependent variable was ARF, and the control variables were age, gender, comorbidities in patients hospitalized for ARF, stay in ICUs during ARF hospitalization and site of operation for prior admissions within one month of ARF hospitalization.
Of 20,790 patients who were admitted to hospitals for ARF in 2006, 12,314 (59.23 %) were male and more than 60 % were older than 65 years. Of patients with and without ARF, 16.14 % and 10.61 %, respectively, received polypharmacy for 91–180 days and 50.22 % and 24.12 %, respectively, for over 181 days. A statistical model indicated that, relative to patients who received polypharmacy for less than 30 days, those who received polypharmacy for 31–90, 91–180 and over 181 days had odds ratios of developing ARF of 1.33 (p<0.001), 1.65 (p<0.001) and 1.74 (p<0.001), respectively.
We observed statistically significant associations between the duration of polypharmacy and the occurrence of ARF.
PMCID: PMC3447669  PMID: 22935542
20.  Long-term antipsychotic polypharmacy: how does it start, why does it continue? 
Background: Antipsychotic polypharmacy remains a widespread and persistent practice, despite a lack of empirical evidence to support its safety and efficacy. This study aimed to assess antipsychotic treatment prior to the initiation of polypharmacy and ascertained clinicians’ reasons for coprescribing long term. We also aimed to determine patterns of antipsychotic coprescription and associated outcome.
Method: Prescription charts across a large mental health trust were reviewed to identify all patients coprescribed two or more antipsychotics excluding clozapine. For those receiving antipsychotic polypharmacy for at least 6 months, electronic patient records were examined to obtain demographic data, documented reasons for initiating polypharmacy and prior prescribing information. Sequence of prescribing, clinical outcome, adverse effects and prescriber considerations to revert to monotherapy were determined.
Results: In all, 38 patients had been receiving two antipsychotics excluding clozapine for longer than 6 months. In 39% of cases patients had been prescribed no or only one antipsychotic before initiation of polypharmacy while 48% had been trialled on clozapine. The most frequently documented reason for coprescribing was that residual psychotic symptoms remained with monotherapy. An improvement in psychotic symptoms was documented in 26% of patients receiving polypharmacy. Prescribers considered stopping polypharmacy in 23 patients.
Conclusion: Antipsychotics were coprescribed largely to improve symptoms and clinical outcome in patients with inadequate response to monotherapy. Polypharmacy was not solely reserved for patients in whom all other therapeutic options had failed. There was some evidence to suggest that patients did benefit from coprescription, albeit at the expense of an increased adverse effect burden. Prospective randomized trials of specific antipsychotic combinations are required to assess the therapeutic utility of this under-researched practice.
PMCID: PMC3736927  PMID: 23983950
antipsychotics; polypharmacy; schizophrenia
21.  Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics 
BMC Psychiatry  2005;5:26.
Antipsychotic monotherapy is recognized as the treatment of choice for patients with schizophrenia. Simultaneous treatment with multiple antipsychotics (polypharmacy) is suggested by some expert consensus guidelines as the last resort after exhausting monotherapy alternatives. This study assessed the annual rate and duration of antipsychotic monotherapy and its inverse, antipsychotic polypharmacy, among schizophrenia patients initiated on commonly used atypical antipsychotic medications.
Data were drawn from a large prospective naturalistic study of patients treated for schizophrenia-spectrum disorders, conducted 7/1997–9/2003. Analyses focused on patients (N = 796) who were initiated during the study on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276). The percentage of patients with monotherapy on the index antipsychotic over the 1-year post initiation, and the cumulative number of days on monotherapy were calculated for all patients and for each of the 3 atypical antipsychotic treatment groups. Analyses employed repeated measures generalized linear models and non-parametric bootstrap re-sampling, controlling for patient characteristics.
During the 1-year period, only a third (35.7%) of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients.
Despite guidelines recommending the use of polypharmacy only as a last resort, the use of antipsychotic polypharmacy for prolonged periods is very common during the treatment of schizophrenia patients in usual care settings. In addition, in this non-randomized naturalistic observational study, the most commonly used atypical antipsychotics significantly differed on the rate and duration of antipsychotic monotherapy. Reasons for and the impact of the predominant use of polypharmacy will require further study.
PMCID: PMC1156914  PMID: 15921508
22.  Long-Term Antipsychotic Polypharmacy in the VA Health System: Patient Characteristics and Treatment Patterns 
Although antipsychotic polypharmacy is being prescribed with increasing frequency, few studies have described patient characteristics and treatment patterns associated with long-term use of this treatment strategy.
By using data from the National Psychosis Registry of the Department of Veterans Affairs, 5,826 patients with schizophrenia or schizoaffective disorder who received long-term antipsychotic polypharmacy (simultaneous treatment with two or more antipsychotics for 90 or more days) during fiscal year 2000 and 39,745 patients who received long-term antipsychotic monotherapy were identified. By using multivariate regression models, patient demographic and clinical characteristics, antipsychotic dosages, and use of antiparkinson and adjunctive psychotropic medications were compared between the two groups.
Patients were more likely to receive antipsychotic polypharmacy if they were younger, were unmarried, had a military service–connected disability, had schizophrenia rather than schizoaffective disorder, or had greater use of inpatient and outpatient mental health services. Patients were less likely to receive antipsychotic polypharmacy if they were African American, had concurrent diagnoses of depression or substance use disorder, or had greater medical comorbidity. For most antipsychotics, dosages prescribed for patients receiving polypharmacy were the same or modestly higher than those prescribed for patients receiving monotherapy. Patients given prescriptions for polypharmacy were more likely to receive antiparkinson medications, antianxiety agents, and mood stabilizers and equally likely to receive concurrent treatment with antidepressants.
Long-term antipsychotic polypharmacy appears to be reserved for more severely ill patients with psychotic symptoms rather than mood symptoms. These patients may experience increased adverse effects as a result of excess antipsychotic exposure.
PMCID: PMC3673552  PMID: 17412850
23.  Association of polypharmacy with fall-related fractures in older Taiwanese people: age- and gender-specific analyses 
BMJ Open  2014;4(3):e004428.
To elucidate the associations between polypharmacy and age- and gender-specific risks of admission for fall-related fractures.
Nested case–control study.
This analysis was randomly selected from all elderly beneficiaries in 2007–2008, and represents some 30% of the whole older insurers using Taiwan's National Health Insurance Research Database.
We identified 5933 cases newly admitted for fall-related fractures during 2007–2008, and 29 665 random controls free from fracture.
Primary and secondary outcome measures
Polypharmacy was defined as the use of fall-related drugs of four or more categories of medications and prescribed related to fall within a 1-year period. Logistic regression models were employed to estimate the ORs and related 95% CIs. The interaction of polypharmacy with age and sex was assessed separately.
Compared with those who consumed no category of medication, older people who consumed 1, 2, 3 and ≥4 categories of medications were all at significantly increased odds of developing fall-related fractures, with a significant dose–gradient pattern (β=0.7953; p for trend <0.0001). There were significant interactions between polypharmacy and age, but no significant interactions between polypharmacy and gender. The dose–gradient relationship between number of medications category and risk of fall-related fractures was more obvious in women than in men (β=0.1962 vs β=0.1873). Additionally, it was most evident in older people aged 75–84 years (β=0.2338).
This population-based study in Taiwan confirms the link between polypharmacy and increased risk of fall-related fractures in older people; and highlights that elderly women and older people aged 75–84 years will be the targeted participants for further prevention from fall-related fractures caused by polypharmacy.
PMCID: PMC3975737  PMID: 24682575
24.  Psychotropic Medication Use and Polypharmacy in Children With Autism Spectrum Disorders 
Pediatrics  2013;132(5):833-840.
The objectives of this study were to examine rates and predictors of psychotropic use and multiclass polypharmacy among commercially insured children with autism spectrum disorders (ASD).
This retrospective observational study used administrative medical and pharmacy claims data linked with health plan enrollment and sociodemographic information from 2001 to 2009. Children with ASD were identified by using a validated ASD case algorithm. Psychotropic polypharmacy was defined as concurrent medication fills across ≥2 classes for at least 30 days. Multinomial logistic regression was used to model 5 categories of psychotropic use and multiclass polypharmacy.
Among 33 565 children with ASD, 64% had a filled prescription for at least 1 psychotropic medication, 35% had evidence of psychotropic polypharmacy (≥2 classes), and 15% used medications from ≥3 classes concurrently. Among children with polypharmacy, the median length of polypharmacy was 346 days. Older children, those who had a psychiatrist visit, and those with evidence of co-occurring conditions (seizures, attention-deficit disorders, anxiety, bipolar disorder, or depression) had higher odds of psychotropic use and/or polypharmacy.
Despite minimal evidence of the effectiveness or appropriateness of multidrug treatment of ASD, psychotropic medications are commonly used, singly and in combination, for ASD and its co-occurring conditions. Our results indicate the need to develop standards of care around the prescription of psychotropic medications to children with ASD.
PMCID: PMC3813388  PMID: 24144704
administrative claims; autism spectrum disorder; commercially insured; psychotropic polypharmacy
25.  Predictors of antipsychotic monotherapy with olanzapine during a 1-year naturalistic study of schizophrenia patients in Japan 
Although expert guidelines for the treatment of schizophrenia recommend antipsychotic monotherapy, the use of antipsychotic polypharmacy is common. This study identified characteristics that differentiate patients with schizophrenia who are treated with olanzapine monotherapy versus polypharmacy in usual care in Japan.
Patients and methods
In a large (N = 1850) prospective, observational study, Japanese patients with schizophrenia who initiated treatment with olanzapine were followed for 1 year. Consistent with past research, antipsychotic polypharmacy was defined as the concurrent use of olanzapine and another antipsychotic for at least 60 days. Switching was defined as discontinuing a prior antipsychotic therapy rather than augmenting the medication regimen. Predictors of antipsychotic monotherapy were based on information available at the time of olanzapine initiation. Baseline characteristics were compared using t-tests and χ2 tests. Stepwise logistic regression was used to identify independent predictors of monotherapy.
Patients treated with olanzapine monotherapy (43.2%) differed from those treated with antipsychotic polypharmacy (56.8%) on demographics, treatment history, baseline symptom levels, functional levels, and treatment-emergent adverse events. Stepwise logistic regression identified multiple variables that significantly predicted monotherapy: older age, shorter duration of schizophrenia, outpatient status, comorbid medical conditions, lower body mass index, no prior anticholinergic use, no prior mood stabilizer use, and switching from a previous antipsychotic (typical or atypical).
Consistent with prior research in Japan, antipsychotic polypharmacy appears to be common in the treatment of schizophrenia. Patients treated with monotherapy could be differentiated from those treated with antipsychotic polypharmacy based on a specific set of demographic and baseline clinical characteristics.
PMCID: PMC3278200  PMID: 22347801
olanzapine; schizophrenia; polypharmacy; quality improvement

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