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Front. Pharmacol. | doi: 10.3389/fphar.2019.00994

Polypharmacy and Nutraceuticals in veterans: 1 partners in crime?

 Tommaso Sciarra1*, Mario Ciccotti1, 2,  Paola Aiello2, 3,  Paola Minosi2, 4,  Diego Munzi1, Cosimo Buccolieri1, Ilaria Peluso3,  Maura Palmery2 and  Florigio Lista5
  • 1Centro Veterani Della Difesa, Ministero Della Difesa, Italy
  • 2Department of Physiology and Pharmacology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy
  • 3Research Centre for Food and Nutrition, Council for Agricultural Research and Economics, Italy
  • 4Istituto Superiore di Sanità (ISS), Italy
  • 5Scientific Department, Army Medical Center, Italy

The presence of multiple chronic conditions (multi-morbidity) is common in veterans, in particular among the elderly (Golchin et al., 2015). Many of veterans’ injuries have been described as poly-trauma clinical triad, which refers to the co-occurrence (Figure 1) of post-traumatic stress disorder (PTSD), chronic pain and traumatic brain injury (TBI). While the concomitant injuries (Figure 1) accompanying TBI may be manifold, including fractures, amputations, burns, spinal cord injury, eye injury, and auditory trauma, the two most prevalent and functionally disabling conditions may be PTSD and chronic pain (Lew et al., 2009). Although it has been recently suggested that treatment with opioids is not superior to treatment with nonopioid medications, including acetaminophen, for improving pain-related function in patients with chronic pain (Krebs et al., 2018), paracetamol pharmacokinetic is affected by nutraceuticals and some plant foods (Figure 1) (Abdel-daim et al. 2018)
Moreover, chronic pain symptoms are often comorbid with psychiatric conditions, such as depression (Runnals et al., 2013), substance use disorders (Figure 1) (Caldeiro et al., 2008), functional disability and growing epidemic of prescription opioid abuse (Wilder et al., 2016). Not only has PTSD been associated with cardiovascular diseases, such as hypertension (Abouzeid et al., 2012), but also with cancer (Boscarino, 2008), type-2 diabetes (Boyko et al., 2010) and poor health, including obesity (Figure 1) (Smith et al., 2015).
As a consequence, the use of five or more medications (polypharmacy) (Figure 1) to control symptoms, in order to prevent both disease complications and the development of new medical conditions, is very common in veterans, so as the accumulation of multiple medications, which represents a critical patient safety issue. In fact, the greater the number of total prescribed medications, the greater the likelihood of prescribing a potentially harmful drug. A suitable polypharmacy can extend life expectancy and maintain quality of life when medicines are prescribed according to the best evidence and their usage is optimized. However, it has been documented that too often polypharmacy can be a detriment in case of inappropriate prescriptions (Soerensen et al., 2016) and potential prescription omissions (Rongen et al., 2016). One possible solution is deprescribing, namely the intentional, proactive, rational discontinuation of a medication that is no longer indicated or for which the potential risk outweighs the potential benefits. The issue becomes more complicated when certain medical guidelines [e.g., those for chronic heart failure (Yancy et al., 2017)] require treatment with multiple medications to achieve the optimal clinical effect.
Furthermore, polypharmacy is sometimes associated with poor clinical outcomes, especially in older adults, including falls, frailty (Figure 1), impaired cognition, increased hospital admissions and adverse drug reactions (Gnjidic et al., 2012). The most worrisome consequence of polypharmacy is the occurrence of therapeutic failures, adverse drug withdrawal events and drug-drug interactions leading to hospitalization. All of these events are associated to similarly negative economic outcomes, such as increased drug cost and costs associated to more frequent usage of health services (Fried et al., 2014).
On the other hand, the impact of some drugs on dietary habit and nutritional status is well documented (Little, 2018; Lappin et al., 2018) It is well known that polypharmacy, malnutrition and sarcopenia are major causes of frailty (Figure 1) and that rehabilitation, nutrition and interventions with mixed outcomes are important to improve disability (Little, 2018; Roberts et al., 2018; Singh et al., 2012; Wakabayashi, 2018).
Despite nutritional supplements can be taken into consideration in malnourished in polypharmacy (Gaddey HL and Holder K, 2014) another phenomenon that should not be underestimated is the trend to use vitamins and nutritional supplements instead of prescription medications. The decision to substitute may be influenced by costs, treatment beliefs and/or health system distrust.
Vitamins and supplements are the most commonly used form of complementary and alternative medicine (CAM) in the United States, especially among veterans (Goldstein et al., 2014). According to a report on the website (US Food and Drug Administration, 2008) many patients use vitamins and supplements in addition to their prescription medications; in fact, nearly 1 in 5 Americans use vitamins and supplements instead of the medications prescribed by their physicians. At the same time, the use of CAM (Figure 1), including acupuncture, deep breathing exercises, massage therapy, meditation, naturopathy and yoga, is growing specifically among patients with chronic conditions and those taking prescription drugs (Gardiner et al., 2006; Nahin et al., 2009). A study of veterans suggested that those who use CAM are more likely to have a greater desire for a holistic approach to health care and distrust of the health system (Kroesen et al., 2002).
Data on the prevalence of vitamins and supplements substitution for prescription drugs showed that 75% of veterans used vitamins and supplements and 18% substituted, which is the same proportion as the general population (US Food and Drug Administration, 2008). Among the subgroup of substituters, 25% substituted for hyperlipidemia medications, whereas 17% did so for anxiety/depression medications and 15% for arthritis/back pain medications. Other common conditions for which patients substituted included hot flashes (15%), diabetes (10%) and hypertension (8%) (Goldstein et al., 2014).
Although the efficacy of herbal preparations and dietary supplements remains controversial, users who are in favor of personal health control often have strong beliefs that herbal preparations and dietary supplements are natural and with fewer side effects (Wu CH, Wang CC, Tsai MT, Huang WT, 2014). Actually, recent US data indicated that the use of a combination of dietary supplement products is most commonly associated with side effects (Austin et al., 2016; Knapik et al., 2016); what’s more, potential interactions can also occur between drugs and herbal/nutritional supplements (Figure 1) (Loya et al., 2009) with significant consequences, such as an increased risk of adverse drug reactions probably due to the induction or inhibition of cytochrome P450 isoenzymes (Hendersn et al., 2002); for example, Hypericum perforatum, known for the antidepressant and sedative activity of its phytocomplex, has the ability to accelerate cytochrome P450 giving multiple interactions with different classes of drugs such as: selective serotonin re-uptake and monoamine oxidase inhibitor (Lantz et al., 1999), warfarin (Jiang et al., 2004), digoxin (Muller et al., 2004), statins (Sugimoto et al., 2001) and all cytochrome P-450 metabolized agents (Markowitz et al., 2003). Moreover, co-administration of Ephedra (Ephedra sinica), which can increase blood pressure and decrease platelet aggregation, and nonsteroidal anti-inflammatory drugs may potentiate the risk of cerebral haemorrhage and gastrointestinal ulcer bleeding (Meng et al., 2014). Possible interactions with drugs have also been suggested for mineral-fortified foods and fruit juices, which are able to influence the bioequivalence of levofloxacine and ciprofloxacine (Neuhofel et al., 2002; Amsden et al., 2003; Wallace et al., 2003).
Accordingly, the Department of Veterans Affairs has dedicated a special section on its website to all the possible interactions between food and drugs, also indicating nutraceuticals (Figure 1) to be taken carefully if you are undergoing a polypharmacy (U.S. Department of Veterans Affairs ).
If on one hand drug–drug interactions are widely recognized as clinically relevant and are included in most pharmacovigilance systems, on the other hand nutrient–drug interactions are still underexplored and their assessment is not part of the clinical routine; even though there is a lot of data to support the presence and relevance of such interactions, indicating that a systematic evaluation would be necessary (Péter et al., 2017). In this sense, we fully agree with the point of view expressed by Péter and colleagues (Péter et al., 2017); in fact, a proper consideration of the nutritional status in the drug action and the assessment of adverse drug effects on the nutritional status clearly requires a paradigm shift towards the inclusion of a nutritional appraisal throughout the stages of drug development and evaluation, ranging from the first phase of experimental work, through clinical investigations, approval and eventually post-marketing surveillance. Spontaneous reporting of adverse drug effects in clinical practice should be stimulated, with special attention to nutrition-related events. Strategies for individual patients should include the development of drug review protocols, and the assessment and integration of nutritional factors and consequences. If possible, clinicians should standardly screen for malnutrition, register measurements of global nutritional status and dietary supplements used.
Particularly, regarding nutritional status Becerra and colleagues (Becerra et al., 2016) reported the association between food insecurity and negative dietary practices among veterans, highlighting the imperative need for health promotion measures focused on a healthy diet in this population, especially those with limited access to healthy food options. In this regard the Department of Veteran Affairs provides guidance to veterans about how a healthy diet, rich in fruits and vegetables, accompanied by movement, can be useful in combating overweight and related diseases (Rutledge et al., 2017). Facilitating healthy diets, physical activity and weight management in the veteran population is an important public health challenge (Figure 1). In fact, a cross-sectional analysis reported that approximately 37 and 33% of women and men veterans are obese, respectively (Das et al., 2005), while others demonstrated higher prevalence of overweight status (Koepsell et al., 2009) and greater waist circumference among veterans (Koepsell et al., 2012) as compared with the civilian population. One potential driving factor for such prevalence of overweight and obesity among veterans may be their dietary practices. In fact, recent studies have found that military service impacts soldiers’ food environment and food security, which then influences eating behavior and food choices both during military service and following discharge (Smith et al., 2009; Wang et al., 2015; Widome et al., 2015). Veterans reported a preference for specific food items, such as burgers and fries, considered to be status foods due to putatively low access during deployment, and such diets high in fat and carbohydrates during military service persisted post service (Smith et al., 2009). Economic analysis has demonstrated that the low cost of high-fat and high-energy-dense foods could further be driving vulnerable populations away from healthier items that usually are more expensive (Drewnowski and Darmon, 2005a, 2005b; Jetter and Cassady, 2006).
A diet high in fruits and vegetables is associated with decreased risk for chronic diseases such as cardiovascular disease, hypertension, diabetes and cancer (Adams, 2006); therefore, it may play an important role in reducing veterans health risks.
In our opinion, although the Mediterranean Pyramid could be the basis for integrative medicine for veterans with disabilities, patient-centred and interprofessional approaches (including physical medicine and rehabilitation clinicians, pharmacists and nutritionists) and interventions are needed in order to prevent malnutrition, self-prescription of CAM and food-drug and/or nutraceutical-drug interactions and to achieve optional rehabilitation (Figure 1) (Ciccotti et al., 2018). Personalized health care for chronic non-communicable diseases that impact quality of life must taken to account gut microbiota, genetic and epi-genetic factors (Peluso I, Abdel-Daim M, Yarla NS, Kamal MA, 2018), as well as moods and hormones involved in stress response (Peluso et al., 2018).

Keywords: Veterans, Polypharmacy (source: MeSH, NML), Nutraceuticals, Food and drug interaction, interprofessional interventions, community based rehabilitation, Non communicable disease

Received: 25 Jan 2019; Accepted: 06 Aug 2019.

Edited by:

Pietro Minuz, University of Verona, Italy

Reviewed by:

Maciej Banach, Medical University of Lodz, Poland  

Copyright: © 2019 Sciarra, Ciccotti, Aiello, Minosi, Munzi, Buccolieri, Peluso, Palmery and Lista. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Tommaso Sciarra, Centro Veterani Della Difesa, Ministero Della Difesa, Rome, Italy,