research article on medication adherence

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• Review Article
• Published: 27 March 2023

Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems

• Tsvetelina H. Baryakova   ORCID: orcid.org/0000-0002-3484-9227 1 ,
• Brett H. Pogostin   ORCID: orcid.org/0000-0002-1462-4442 1 ,
• Robert Langer   ORCID: orcid.org/0000-0003-4255-0492 2 &
• Kevin J. McHugh   ORCID: orcid.org/0000-0001-6801-4431 1 , 3  

Nature Reviews Drug Discovery volume  22 ,  pages 387–409 ( 2023 ) Cite this article

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• Drug delivery
• Outcomes research
• Pharmaceutics

Poor medication adherence is a pervasive issue with considerable health and socioeconomic consequences. Although the underlying reasons are generally understood, traditional intervention strategies rooted in patient-centric education and empowerment have proved to be prohibitively complex and/or ineffective. Formulating a pharmaceutical in a drug delivery system (DDS) is a promising alternative that can directly mitigate many common impediments to adherence, including frequent dosing, adverse effects and a delayed onset of action. Existing DDSs have already positively influenced patient acceptability and improved rates of adherence across various disease and intervention types. The next generation of systems have the potential to instate an even more radical paradigm shift by, for example, permitting oral delivery of biomacromolecules, allowing for autonomous dose regulation and enabling several doses to be mimicked with a single administration. Their success, however, is contingent on their ability to address the problems that have made DDSs unsuccessful in the past.

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Introduction.

More than half of the world’s population takes at least one drug each day, and the demand for pharmaceuticals is only expected to increase as the global disease burden continues to grow 1 . The benefits that a drug seemingly affords in a highly controlled setting, however, will not translate to real-world use if patients do not take their medication as prescribed. Poor medication adherence is the most common reason for disparities observed between results obtained in randomized clinical trials (RCTs) and real-world outcomes 2 , 3 and remains pervasive; estimates of non-adherence are around 50% for chronic illnesses 4 , 5 . In the United States alone, poor adherence is responsible for an estimated 125,000 deaths per year, a figure comparable with the number of deaths caused by colorectal cancer, breast cancer and prostate cancer combined 6 , 7 . Poor adherence is also estimated to cause 10% of all hospitalizations and underlie $100–300 billion of avoidable health-care costs annually owing to wasted medicine, unnecessary diagnostic procedures and excessive health-care provider utilization 8 , 9 , 10 . Rates of non-adherence are especially high among older people, who are more likely to require complicated treatment plans and suffer from cognitive and/or functional impairments (for example, dysphagia) that impede their ability to administer certain types of medication 11 . Owing to a globally ageing population and a worldwide shift in the general disease burden from acute to chronic conditions, the adverse effects of non-adherence are only expected to increase 12 .

The key reasons for poor adherence are patient forgetfulness, anxiety about treatment-associated adverse effects, low motivation due to a perceived lack of efficacy, poor health literacy and aversion to the health belief model, and stigmatization 4 , 8 . Other factors that may play a role include high prescription costs and insufficient patient–provider communication. Besides negatively impacting the health of an individual, pervasive non-adherence can have a pernicious effect on the health of a community, especially as it pertains to communicable diseases. For example, failing to complete a vaccination schedule or a course of antibiotics or antivirals as prescribed can lead to the emergence of a resistant strain of a contagious bacteria or virus. Vaccine refusal has been implicated in outbreaks of varicella, measles and pertussis, among others 13 .

Improving adherence is recognized as one of the most impactful and cost-effective strategies for improving the health of the general population, yet it has not garnered the same attention as other approaches for improving wellness 4 . A mere 1% increase in drug utilization among individuals enrolled in Medicare and Medicaid in the United States is estimated to result in a $3 billion reduction in national health-care spending (0.2% of the total Medicare and Medicaid budget in 2020 (ref. 14 )) 15 , 16 . Traditional health-care provider-mediated strategies for improving adherence by educating and empowering patients have produced inconsistent and often underwhelming results 17 (Box  1 ). These interventions are often too complex, requiring health-care infrastructure and/or some extent of personalization, to be cost-effective at scale. Drug delivery systems (DDSs) are promising technological alternatives that can mitigate the logistical factors negatively impacting real-world adherence. DDSs are formulations, systems or technologies used to modulate the release of a drug in the body over time and/or target the drug to a particular tissue or cell type. The first DDS, a sustained-release system delivering dextroamphetamine, was approved in 1952 (Box  2 ). A timeline describing the development of several key DDSs — with an emphasis on those that did (or are expected to) improve medication adherence — is provided in Fig.  1 .

This timeline illustrates examples of several key delivery technologies and drug delivery systems (DDSs) developed between the 1950s and the 2020s, many of which have improved or are expected to improve patient adherence. Several technologies currently in development that may be featured in future DDSs are also included. ADHD, attention deficit hyperactivity disorder; GLP1RA, glucagon-like peptide 1 receptor agonist; HIV, human immunodeficiency virus; IUD, intrauterine device; PrEP, pre-exposure prophylaxis.

In this Review, we first overview the fundamentals of DDSs and the mechanisms by which they can improve adherence. We then summarize the impact that DDSs have had on patient adherence across four disease and intervention types: chronic, relapsing–remitting, acute and prophylactic. Finally, we discuss the lessons that can be learned from several novel DDSs that failed to realize broad commercial success.

Box 1 Traditional interventions for improving adherence and ways to measure adherence

Traditional strategies aimed at improving adherence include both direct and indirect methods. Examples of traditional, direct strategies for improving adherence include providing educational materials and monetary incentives, conducting motivational interviews and performing regular check-ins. Indirect strategies include strengthening patient–provider relationships and improving community-wide health literacy 243 . Unfortunately, there is no consensus on the efficacy of these strategies in improving medication adherence and there is evidence that their implementation can result in anywhere from a worsening to a significant improvement in rates of adherence and/or outcomes 4 , 6 , 126 , 244 , 245 , 246 . An analysis of data from 17 high-quality randomized clinical trials (RCTs) investigating the effect of various interventions on adherence with a low risk of bias 247 revealed improvements in both medication adherence and clinical outcome in five studies, albeit only to a modest extent 17 . Moreover, each strategy that improved adherence consisted of a complex, multifactorial scheme, such as educational intervention from a health-care provider, rigorous counselling and/or daily treatment support.

Adherence assessments can be made using multiple methods, which can make it more difficult to compare findings between studies. In order of decreasing fidelity and cost, methods for measuring adherence include direct measures (for example, periodically measuring the concentration of a drug in a patient’s blood or urine), electronic monitoring (for example, employing a ‘smart’ container capable of sensing when medication is retrieved), secondary database measures (for example, reviewing prescription refill records), tablet counting and clinical assessment/self-reporting 243 , 248 . If using an electronic monitoring device, researchers can also gain insight into several different definitions of adherence: taking adherence (the percentage of device openings relative to the prescribed number of doses), regimen adherence (the percentage of days with the correct number of device openings per day) and timing adherence (the percentage of device openings occurring within a prescribed interval).

The two metrics most widely used to quantify adherence are the medication possession ratio and the proportion of days covered (PDC). The medication possession ratio is defined as the proportion of days’ supply obtained over a period of interest and is used approximately six times as often as the PDC 10 . The PDC is the proportion of days that a patient has access to their medication over a period of interest. In most instances, a patient with a medication possession ratio or PDC ≥ 0.80 is considered ‘adherent’ 249 . Medication persistence, defined as the duration of time from treatment initiation to discontinuation, is another useful measure of medication-taking 250 .

It is important to note that studies often overestimate adherence owing to various confounding factors. These include ‘white coat’ adherence (patients are more adherent when under surveillance or near a clinical visit) and the ‘healthy-adherer effect’ (patients who are more adherent are also more likely to engage in health-seeking behaviour and may have better, treatment-independent outcomes). One meta-analysis considered 51 studies in which adherence to oral medications was monitored via an electronic monitoring device 30 . The studies that blinded patients to electronic monitoring, implemented longer follow-up periods and had a randomized trial design were associated with inferior adherence rates. As all three of these strategies are expected to increase the fidelity of the collected data, this supports the notion that adherence overestimation occurred.

Box 2 A brief history of drug delivery systems

The earliest drug delivery systems (DDSs) were developed during the 1950s–1970s/1980s when researchers mostly sought to control the pharmacokinetics of oral and transdermal drugs. The first DDS, the Spansule sustained-release system, was approved in 1952 and consists of a gelatin capsule containing granules of the stimulant dextroamphetamine coated with a layer of natural waxes that dissolve in a composition and thickness-dependent manner 251 , 252 , 253 . Taking one Spansule capsule thus results in pharmacokinetics comparable with taking two or three immediate-release doses over the course of 12 h. Transderm Scop, the first systemic transdermal DDS, was approved in 1979 and delivers scopolamine across the skin via passive diffusion to treat nausea and vomiting. The device was recently discontinued for reasons unrelated to its efficacy or safety, but generic versions remain available. As of 2018, there were approximately 200 sustained-release oral preparations and 50 transdermal patches (both new products and generic versions) on the US market 254 .

Researchers developing the second generation of DDSs from the 1970s/1980s to the 2010s sought to improve and expand the use of these systems to achieve more consistent drug release rates, deliver comparatively more delicate biologics (for example, proteins, peptides and nucleic acids), utilize ‘smart’ materials capable of automatic or manual regulation and/or achieve tissue-specific targeting 255 . It was initially believed that large macromolecules could not withstand loading into polymeric microparticles but, in 1976, several proteins, including soybean trypsin inhibitor, lysozyme and alkaline phosphatase, were successfully encapsulated in non-inflammatory polymeric vehicles and released in a biologically active state over the course of months 256 . Thereafter, Lupron Depot, a formulation of poly(lactic-co-glycolic acid) microspheres encapsulating leuprolide acetate — the first long-acting injectable of its kind — was approved by the US Food and Drug Administration (FDA) in 1989 for the palliative treatment of prostate cancer. Its approved indications have since expanded to include treating endometriosis, anaemia owing to uterine fibroids and precocious puberty. Following an initial burst release, this system is capable of providing sustained release of leuprolide acetate for 1–6 months, depending on the formulation. Doxil, the first liposomal formulation of a small molecule (doxorubicin), was approved in 1995 and 13 other liposomal technologies have followed since 257 .

Building upon the innovations of the two prior generations, third-generation DDSs (2010s–present) are being developed to last longer and, where desirable, use less invasive technologies capable of delivering cargo with tightly controlled spatial and temporal precision. DDSs are also being employed to deliver new classes of drugs, such as nucleic acids for gene regulation and whole cells for cell-based immunotherapies 22 , 258 . Onpattro was the first RNAi therapeutic approved by the FDA in 2018; it was shown to reduce the production of the protein transthyretin in patients with hereditary transthyretin amyloidosis. rVSV-ZEBOV was the first viral vector-based vaccine approved for human use against Ebola in 2019. Most recently, Comirnaty and Spikevax were the first mRNA vaccines approved for COVID-19 vaccination in 2021.

Overview of drug delivery systems

Controlled-release DDSs can be classified by numerous characteristics including their route of medication administration (for example, oral, transdermal, intravenous, intramuscular, subcutaneous, transmucosal; Fig.  2 ), the device type (for example, injectable microparticle depot, extended-release oral formulation, intravaginal ring) or the drug release profile afforded by the system (pulsatile, first-order, sustained, zero-order or stimuli-responsive).

a , US Food and Drug Administration (FDA)-approved examples of drug delivery systems (DDSs) grouped by route of administration (oral, intramuscular, transdermal, subcutaneous, intraocular, intranasal, intrauterine and transmucosal (pulmonary, sublingual, buccal, intravaginal and rectal)). b , Pharmacokinetic profiles showing the plasma concentration of a drug following a single dose, based on the type of release. Traditional, non-DDS formulations of parenteral and oral drugs result in rapid clearance of drug from the blood, whereas some DDSs can prolong the duration over which the drug concentration remains within the therapeutic window without increasing the peak drug concentration. In the case of pulsatile release, DDSs can also allow for multiple, pre-programmed release events mimicking bolus doses of drug following a single administration.

DDSs are especially useful when the active pharmaceutical ingredient (API) has dose-limiting side effects, a narrow therapeutic window and/or a short half-life that makes maintaining the proper drug concentration difficult. Examples of DDSs that have been developed to address these issues include the liposomal formulation of the cardiotoxic chemotherapeutic doxorubicin (Doxil), a subcutaneous injectable microparticle suspension of somatotropin, a protein with a half-life of 20–30 min following intravenous injection 18 (Nutropin Depot) and an extended-release oral formulation of the anticonvulsant drug phenytoin, which has a therapeutic index of only two (Phenytek capsules) 19 . In other instances where the payload is too fragile to survive in the body over therapeutically relevant timescales without a suitable carrier (for example, nucleic acids), a DDS such as a lipid-based nanoparticle may be required.

Chemical modifications and microenvironment modulation are two additional paradigms for improving the pharmacokinetics of an API. The former entails changing the physicochemical properties of a drug to create a new molecular entity 20 , 21 , and the latter entails changing the immediate vicinity of the drug to increase its solubility, stability and/or modulate the resulting immune response 22 . Although these additions may be included as part of a DDS formulation, they do not, by themselves, meet the definition of DDS used in this Review. Instead, we focus on platform technologies that can be applied to more than one API.

Limitations

Formulating APIs in DDSs is not a one-size-fits-all approach, however, and there are limitations common to certain classes of DDSs that are worth noting. For example, surgically implanting a device requires an invasive procedure and, in some instances, frequent monitoring by a health-care professional. This is also true for some state-of-the-art DDSs in preclinical development, including responsive particle systems that require external stimuli such as ultrasound or focused light to release cargo in a targeted manner, or systems that utilize instrument-mediated modes of cell transfection for gene therapy (that is, electroporation or biolistic (gene gun) delivery). Some classes of DDSs may be more likely to malfunction than their traditional alternative(s) owing to added device or usage complexity. Certain devices may also be less accessible owing to limited demand, scant coverage by insurance providers, a lack of enabling infrastructure, limited awareness among patients and providers, and/or costly premiums, especially in low and middle-income countries. These drawbacks, however, are arguably true of all nascent technologies and should diminish as further development and cost optimization enables broader adoption. Finally, some patients may express apprehension or outright refusal in favour of traditional, ‘tried and true’ methods of medication administration, depending on factors such as the severity of their disease and the device’s route of administration and usability 23 .

Design considerations

Generally, there are several key design considerations that DDS development should abide by depending on the device’s intended disease target(s). Given that patients with chronic conditions are likely to use it on a frequent (often, daily) basis, reliability, affordability and ease of use generally take priority. Factors including the size of the device (if used externally), the ease of administration and the severity of rapidly onset side effects, if any, can affect its perception among patients and its clinical utility. For relapsing–remitting conditions, it may additionally be beneficial to design a device capable of accommodating medically recommended changes in treatment owing to variable disease progression. The design considerations for DDSs used to administer prophylactic medication are similar to those for DDSs intended for use in patients with chronic and relapsing–remitting conditions, given the similarity in dosing duration requirements; however, device discretion may additionally carry more weight for some prophylactic drugs, such as pre-exposure prophylaxis (PrEP) and contraceptives. Where applicable, all non-surgically implanted DDSs intended for long-term use would benefit from monitoring capabilities to track patients’ adherence and the device effectiveness. The design considerations for DDSs used to treat acute conditions include those mentioned above, but there may be additional considerations given the time-sensitive nature of the condition (as is the case with an acute infection). These may include the speed of drug delivery and the portability of the device.

Improving patient acceptability and adherence

DDSs can improve the pharmacokinetics of an API and/or enable alternative delivery routes, potentially allowing for a reduction in dosing frequency and/or abatement of adverse effects. Some DDSs can also allow for added discretion, benefitting patients who feel embarrassed by having to regularly store and take pills. These improvements, among others, can enable patients to overcome barriers to adherence such as forgetfulness, premature discontinuation and stigma-related aversion. Below, we discuss seven major ways in which DDSs can improve adherence.

Reduced dosing frequency

Patients prefer to take a drug less often and are, accordingly, more adherent when their treatment regimen aligns with their preferences 24 , 25 , 26 , 27 , 28 . There is strong evidence to support a significantly higher rate of adherence to drugs taken once daily versus those taken multiple times per day for various conditions, including bisphosphonates (BPs) for osteoporosis, angiotensin-converting enzyme inhibitors for hypertension and sulfonylureas for type 2 diabetes (T2D), among many others. On a more granular level, there is evidence to support both the notion of an inverse, monotonic relationship between dosing frequency and adherence 29 as well as a subtle or insignificant difference between adherence rates for drugs taken multiple times per day 30 , 31 . In one meta-analysis, adherence rates to oral medications used to treat chronic diseases across three definitions of adherence (taking, regimen and timing; Box  1 ) were found to be progressively lower for regimens requiring administration of two, three and four doses per day compared with once-daily dosing regimens, with the disparity growing more pronounced as the stringency of the adherence definition increased 30 . In another analysis, adherence rates among patients with asymptomatic chronic diseases taking once-daily medications were significantly higher compared with rates among those taking twice-daily or thrice-daily medications 26 .

In contrast to immediate-release formulations such as capsules and intravenous injections, extended-release DDSs release a drug over a longer period of time, enabling less frequent dosing. Three common types of extended-release formulation, either for oral delivery or parenteral implantation/injection, are matrix, reservoir and osmotic-controlled systems (Fig.  3 ). Each system is capable of achieving delivery times of 12–24 h (if taken orally) or, potentially, years (if implanted parenterally) but is subject to trade-offs, including the rate and precision of drug release and ease of manufacturing. Some reservoir systems additionally consist of multiple types of particle, each made of biodegradable polymers of a different composition and/or thickness that allow for burst release of a drug at different times — a so-called pulsatile DDS 32 . These systems constitute a promising platform for addressing adherence issues with multi-dose vaccines. These are often associated with low rates of completion due, in part, to the burden of visiting a health-care provider multiple times, an adherence barrier that is heightened in low-resource settings 33 , 34 .

a , Reservoir-based systems. These consist of a hollow, drug-filled core encapsulated by a degradable polymer. Over time, the polymeric shell degrades in a composition and thickness-dependent manner to release the drug. Using multiple types of shell allows for a fraction of the drug to release at a certain time. This technology can be used in capsules or as part of a microparticle depot suspension in oral and parenteral delivery systems, respectively. b , Osmotic pump-based systems. These systems are often used for extended-release oral delivery and consist of a water-permeable, insoluble polymer laden with drug and, often, a so-called expandable ‘push’ layer encapsulated in a hard coating. Exit holes are drilled through the coating to expose the polymer to the outside. Over time, water infiltrates the capsule and causes both layers to expand, pushing drug out through the exit holes. c , Matrix-based systems. These systems consist of drug embedded within a water-permeable, soluble monolithic matrix. Over time, water infiltrates the matrix (often, in the form of a tablet) and causes it to degrade, enabling drug release. These types of system are most often used in extended-release oral formulations. d , Matrix-based systems with a rate-limiting membrane. These consist of a drug-laden matrix core surrounded by a semi-permeable membrane that limits the rate of drug release, enabling pseudo zero-order delivery. This technology is often found in non-degradable, long-lasting implants, such as intrauterine devices (IUDs) and intravaginal rings. e , Transdermal/transmucosal systems. The three types of system shown here are iontophoretic devices, transdermal patches and microneedle array patches. Iontophoretic devices achieve delivery by creating an electric field that efficiently shuttles charged moieties across the skin barrier. Transdermal patches allow for passive delivery of molecules smaller than 500 Da. Finally, microneedle array patches penetrate the skin to deliver drug directly into the cutaneous layer.

Other extended-release DDSs include near zero-order delivery systems such as intravaginal rings, osmotic pumps, actuated pumps and implantable microchips, which are capable of providing a steady rate of drug release over a period ranging from hours to years 35 . Finally, nano-formulations, such as liposomes and dendrimers, can help extend the circulating time of a drug or improve its deposition characteristics, thereby increasing the therapeutic duration of the drug and reducing its required dosing frequency.

Avoidance of first-pass metabolism and accelerated onset of action

The bioavailability of oral drugs is limited by hepatic first-pass metabolism, leading to variability in the rate and extent of absorption. DDSs that avoid first-pass metabolism by using a parenteral route — such as intravenous, subcutaneous, intramuscular, transdermal, intranasal, sublingual or buccal administration — to deliver a drug directly into the bloodstream or the target site enable comparatively less material to achieve the same therapeutic effect in a well-controlled manner. They also enable a faster onset of action compared with oral delivery, which can be crucial for adherence; if patients do not immediately feel a lessening of their symptoms, they may stop taking their medication before it has a chance to exert its intended effect.

Intranasal DDSs enable a drug to access the brain via the olfactory or trigeminal nerves, bypassing hepatic first-pass metabolism, harsh gastrointestinal conditions and the blood–brain barrier to elicit the desired therapeutic effect within minutes instead of hours 36 , 37 . So-called nose-to-brain delivery systems are typically used to deliver classes of drugs such as anti-seizure medications, migraine medications, cholinesterase inhibitors and antidepressants 38 , 39 .

Rapid improvement of depressive symptoms is critical in patients with severe depression who are acutely suicidal. Accordingly, studies have shown that the short-term effects of antidepressants are predictive of long-term results 40 , 41 . Esketamine is an anaesthetic drug that is used to treat patients with treatment-resistant depression and has a quicker onset of action than traditional antidepressants. The oral bioavailability of esketamine, however, is only 8–11% and the rate of absorption appears to vary considerably between patients, possibly owing to factors such as stomach contents and gut motility 42 . In those taking oral esketamine, significant changes are often detected only 2–6 weeks after treatment initiation 43 . Intranasal esketamine (Spravato), in comparison, has a much higher bioavailability (46–54%) and is fast-acting, reaching a peak plasma concentration 20–40 min after dosing and lessening depressive symptoms as quickly as 4 h after the first dose.

Mitigation of concentration-dependent adverse effects

Experiencing adverse effects or anxiety about potential adverse effects is a major deterrent to patient adherence 44 , 45 , 46 . A high plasma concentration of certain drugs, including glucagon-like peptide 1 receptor agonists (GLP1RAs), cholinesterase inhibitors and BPs, immediately after dosing is directly correlated with the onset of gastrointestinal adverse effects such as nausea, diarrhoea and vomiting. Accordingly, these side effects are reported less frequently by patients taking long-acting formulations of these drugs than those taking short-acting formulations 47 , 48 , 49 , 50 . For patients with epilepsy, taking consecutive doses of immediate-release antiepileptic drugs (many of which have short half-lives and narrow therapeutic indices 51 ) results in large peak-to-trough fluctuations, which may increase the risk of both seizures and concentration-dependent toxicity 52 . Extended-release formulations of antiepileptic drugs such as phenytoin (Dilantin) and valproate (Depakote ER), in comparison, are associated with improved tolerability, offer significant improvements in quality of life and can mitigate the effects of missed or delayed doses 53 .

Besides short-term adverse effects, there are other risks associated with repeated exposure to high concentrations of some drugs. These include an increased risk of developing resistance (as is the case with some antibiotics and antivirals) or developing tolerance and physical dependence (as is the case with opioids) 4 , 54 . Extended-release formulations have the potential to mitigate many of these issues by minimizing the peak-to-trough fluctuations in plasma drug concentration, enabling it to stay below toxic levels and within the therapeutic window. Because the drug metabolism rate is typically a function of concentration, these formulations have the added benefit of enabling less total drug to achieve the same therapeutic duration, potentially reducing the burden on the liver and kidneys.

Lowered barrier to continued use

Long-acting DDSs can offer a lowered barrier to continued use, benefitting patients who would otherwise prematurely stop taking a medication for the various reasons discussed below.

Patients taking fast-acting drugs may begin to feel better within a short period of time after initiating a course of medication and, considering their problem solved, fail to continue taking it as a result. This phenomenon is prevalent during the remission phase of various relapsing–remitting diseases, such as inflammatory bowel disease (IBD), relapsing–remitting multiple sclerosis and asthma. Premature discontinuation is also common in patients taking a course of antibiotics for an acute infection, which may increase the risk of developing antibiotic resistance.

Patients may also prematurely stop treatment if taking a drug with a delayed onset of action, as is common for antidepressants, antipsychotics and some immunosuppressants. In the case of depression, premature medication discontinuation contributes to its undertreatment and is a risk factor for developing a treatment-resistant form of the disease 55 .

Finally, patients may prematurely discontinue a drug because of its short-term side effects. Some treatment regimens for chronic diseases, such as interferon therapy in the treatment of multiple sclerosis or chronic hepatitis C, often result in flu-like symptoms that typically diminish over time 56 , 57 . The initial, acute onset of these symptoms is a deterrent to patient acceptability 58 , with the number and severity of symptoms inversely correlated to adherence 59 , 60 , 61 . Patients who are taking naltrexone for a substance use disorder can also initially experience unpleasant withdrawal symptoms during the first phase of treatment that can last for up to 2 weeks, depending on the substance. This often leads to premature discontinuation, a phenomenon that is common among patients receiving treatment for a substance use disorder 62 .

Reduced pain

Needle phobia is estimated to affect one out of every five people, and those afflicted are more likely to avoid medical treatment involving needles, including vaccination 63 , 64 . This fear is estimated to be the primary reason for non-compliance with recommended paediatric immunization schedules in 7–8% of cases 65 and may account for as many as 10% and 16% of all individuals expressing COVID-19 (ref. 66 ) and influenza vaccine hesitancy 63 , respectively.

Nasal and oral vaccines are alternatives to vaccines delivered via intramuscular injection with a hypodermic needle. In a survey of parents whose children had received vaccines via both intranasal administration and intramuscular injection, a significantly larger percentage found the intranasal formulation to be more well tolerated and generally regarded it as more favourable 67 . However, oral vaccines are limited by challenges associated with oral delivery, such as withstanding the harsh conditions of the gastrointestinal tract and achieving sufficient absorption across the intestinal mucosal barrier despite a short residence time 68 . For these reasons, although they can provide mucosal immunity and are highly acceptable to patients (≥90%), oral vaccines are often unable to confer systemic immunity 69 .

Transdermal microneedle array patches (MAPs) are a type of DDS in preclinical development that deliver drugs to the epidermis or upper dermis, avoiding the cutaneous pain receptors found in the lower dermis and allowing for painless drug delivery. Injections with micro-sized needles are also less likely to cause serious skin irritation, redness or swelling and present a lower risk of infection than standard intramuscular injections 70 . Studies have shown that patient acceptability of MAPs is high, with 70–90% reporting that they would prefer to use a MAP rather than receive an intramuscular injection with a hypodermic needle 71 , 72 , 73 , 74 .

Increased cost-effectiveness

High out-of-pocket medication costs are a deterrent to patient adherence, especially in resource-limited settings 75 , 76 , 77 , 78 . DDSs have the potential to reduce the total amount of drug required to achieve a therapeutic effect by controlling the drug’s systemic concentration and rate of clearance. From a financial perspective, this benefit might be greatest for controlled-release DDSs delivering costly biologics. For example, anti-VEGF biologics are highly effective in the treatment of ocular diseases such as macular degeneration and macular oedema but are relatively expensive, and lowering the out-of-pocket costs of these treatments has been shown to significantly improve adherence 79 . Intravitreal bolus injections of the anti-VEGF treatments ranibizumab and aflibercept are annually estimated to use 160 and 190,000 times more drug, respectively, than that which a zero-order DDS would require 80 . If cost was to scale linearly with dose size, this translates to an estimated annual saving of approximately $10,000 for both treatments when formulated in a DDS, which is likely to far exceed the fabrication costs of such a device 81 . Moreover, controlling release over an extended duration could reduce the number of times a physician needs to administer the drug, requiring fewer doctor’s visits and reducing costs.

MAPs can also achieve dose sparing of vaccines, often requiring only 1–10% of the antigenic material that would be required in a subcutaneous or intramuscular injection due to the efficient activation of skin-resident antigen-presenting cells 82 , 83 . They may also have the potential to be stored outside the cold chain and/or self-administered, further lowering costs and improving accessibility.

Destigmatization

Stigma plays an important role in treatment acceptability and adherence for various conditions, including neuropsychiatric disorders, epilepsy, attention deficit hyperactivity disorder (ADHD) and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) 84 , 85 , 86 , 87 , 88 .

Patients with ADHD may need to take as many as eight immediate-release methylphenidate tablets a day. This can be a source of stigma and embarrassment, especially among children who need to take one or more doses during the school day 88 , 89 . Several extended-release formulations of methylphenidate have been developed, including the osmotic controlled-release oral delivery system Concerta XL. This DDS, which consists of an immediate-release coating of methylphenidate encapsulating an extended-release osmotic pump system, produces a quick onset of action and avoids the rapid development of tolerance, extending the drug’s duration of efficacy to 10–12 h. Accordingly, results from RCTs suggest that this system leads to higher satisfaction and treatment adherence among patients over traditional immediate-release formulations 90 , 91 .

Individuals taking antiretrovirals for HIV/AIDS prophylaxis or therapy face a unique combination of stringent adherence requirements 92 , 93 and a high rate of stigmatization, leading them to prefer comparably invasive, long-acting DDSs (for example, injectable suspensions and intravaginal rings) over short-acting oral drugs and pericoital microbicides 94 , 95 , 96 . In a survey of individuals receiving oral antiretroviral therapy, more than four fifths reported that they would definitely or probably try an injectable long-acting extended-release formulation if the dosing frequency was reduced to once monthly or better 97 . Accordingly, the two long-acting injectable antiretroviral therapies recently approved by the FDA have both been shown to be more effective in clinical trials over an oral PrEP alternative, ostensibly due to a demonstrable improvement in patient adherence 98 , 99 , 100 .

Trends in adherence by disease type

Adherence rates and auspicious DDS intervention strategies vary by disease type. In this section, we discuss the effects that implementation of a DDS and/or treatment modification attainable with a DDS have had on adherence in four categories of diseases and treatments: chronic, relapsing–remitting, acute and prophylactic interventions. These four categories broadly encompass most conditions that are currently treatable/addressable using DDSs and that substantially contribute to disability-adjusted life years lost worldwide. For example, cancer, diabetes, hypertensive heart disease and major depressive disorder alone (all discussed below) were collectively responsible for an estimated 15% of disability-adjusted life years lost in 2019 (refs. 101 , 102 , 103 , 104 ). In each section, we begin by discussing the impact that clinically approved DDSs have had on patients afflicted with that particular disease type and, where applicable, conclude with a brief discussion of promising DDSs in preclinical development. For further reference, a comparison of traditional versus DDS/long-acting formulations for the same API is provided in Table  1 .

Chronic disorders

Adherence rates across chronic conditions are variable, but generally straddle 50% 4 . Across several conditions including hypertension, hypercholesterolaemia and heart disease, the risk of mortality in non-adherent patients is approximately twice that of adherent patients 105 and rates of adverse outcomes are 1.5-fold to 5.4-fold higher 106 .

The potential of DDSs to improve adherence in patients with chronic conditions depends on the characteristics of the disease, the established treatment regimen and the administration parameters of the DDS. Given the low-level persistent nature of diseases such as osteoporosis, glaucoma and hypertension, long-acting injectables or implants might effectively promote adherence. In patients with a disease that can be well managed but for which no long-acting treatments currently exist, such as T2D, a DDS capable of making a seminal advancement (for example, enabling oral delivery or autonomous function) may be necessary in order to achieve widespread adoption. By contrast, for patients living with an often-debilitating disease with few treatment options, such as cancer, marginal improvements are much more meaningful and patients may be more willing to tolerate a DDS that produces adverse effects in exchange for added efficacy. For those with neuropsychiatric disorders, faster time to onset, a reduced barrier to continued use (usually in the form of an injectable or implantable DDS) and increased discretion are key characteristics.

Diabetes differs from many other chronic conditions in that it currently requires very frequent self-monitoring and intervention. Accordingly, poor adherence levels in patients with T2D are associated with an increased risk of hospitalization, complications, cerebrovascular disease and death 107 .

Several insulin analogues are commonly prescribed to patients with T2D: rapid-acting (lispro, aspart and glulisine), short-acting (regular human insulin), intermediate-acting (neutral protamine hagedorn) and long-acting (detemir and glargine). Each offers a trade-off between their onset and duration of action 108 . Although there is little information regarding the differences in rates of adherence between patients using different types of insulin, there is evidence that patients are more satisfied with rapid-acting analogues owing to the increased flexibility of dosing 109 .

Non-insulin oral and injectable antidiabetic agents, such as biguanides, sulfonylureas and GLP-1RAs, are also prescribed to some patients. There are multiple formulations of GLP-1RAs taken via subcutaneous injection twice daily, once daily or once weekly 110 . Persistence rates among patients with T2D taking a once-weekly GLP-1RA formulation are consistently reported to be higher than for those taking once-daily or twice-daily formulations, likely owing, in part, to a lower incidence of nausea and vomiting 111 , 112 , 113 , 114 .

Inhalable insulin was developed in the late 1990s and early 2000s as a non-invasive alternative to subcutaneous injected insulin. In clinical testing, inhalable insulin was found to have comparable efficacy and a quicker onset of action compared with subcutaneously injected insulin 115 . Owing to the ease of administration and convenience, patient satisfaction and acceptance was consistently reported to be higher with inhalable insulin, especially in patients whose T2D was poorly controlled by lifestyle changes and oral therapies 116 . However, some patients experienced side effects such as a dry cough, a mild decrease in pulmonary function and/or variable rates and extents of insulin absorption 116 , 117 . These reasons, among others, led to the eventual market failure of inhalable insulin despite its initial promise 118 , 119 .

Patients with T2D are likely to understand that their condition will require near-constant surveillance and generally prefer to use less painful, short-acting insulin delivery systems for hourly maintenance of their blood glucose levels. There may be a paradigm shift in the treatment of this disease owing to two categories of novel DDSs currently in preclinical development. The first are oral delivery technologies, including an ingestible, self-righting device that can inject insulin painlessly across the gastric mucosa 120 , a spring-actuated microneedle injector that acts on intestinal tissue 118 and a reversible intestinal permeation enhancer 119 . These still constitute short-acting systems that will likely require repeated daily dosing, but have the potential to change which route of administration is considered acceptable. The second are stimuli-responsive DDSs, including some MAPs 121 and hydrogels 122 , that can autonomously sense a patient’s blood glucose and deliver the appropriate amount of insulin directly into vascularized tissue. Both types of system have the potential to help patients with T2D overcome the current challenges that impede their adherence: frequent self-monitoring and intervention, and an invasive mode of delivery due to the poor oral bioavailability and gastrointestinal permeability of antidiabetic drugs.

Across various cancer types, patients tend to prefer oral chemotherapeutics over their parenteral counterparts (for example, in-clinic intravenous infusions and provider-administered injections) when these treatments are presented as options with equivalent efficacy 123 . Accordingly, home-based chemotherapies have historically resulted in increased patient satisfaction and adherence 124 , 125 . However, patients with cancer and other life-threatening illnesses are generally less willing to accept almost any reduction in efficacy or increase in toxicity, perceived or real, in exchange for an increase in convenience. Patients are sometimes also willing to tolerate more severe side effects and/or a greater number of side effects in exchange for relatively modest increases in efficacy 126 . In a scenario-based survey of treatment preferences among women with breast cancer, 25% of patients preferred a monthly, inpatient intramuscular injection, 63% preferred a daily tablet and 13% had no preference. However, women’s preference for injections increased from 25% to 61% and 75% when they were told to imagine a scenario where the monthly injection produced fewer hot flashes or where two monthly injections administered in the same session improved efficacy, respectively 127 . In another scenario-based survey of treatment preferences, approximately 70% and 74% of patients taking palliative chemotherapy were unwilling to accept the added convenience of taking a tablet at the expense of a lower response rate or shorter response duration, respectively 128 . One quarter and one third of patients thought that a mere 5% reduction in efficacy or one less month of response duration, respectively, was not worth the improved convenience of oral delivery. Finally, in one randomized crossover trial that employed both a scenario-based survey and a satisfaction questionnaire, 95% of patients with metastatic colorectal cancer who expressed a treatment preference initially preferred an oral therapy (capecitabine) and 5% preferred an inpatient or outpatient intravenous infusion of 5-fluorouracil/leucovorin. After receiving both types of treatment, however, the preference rate for the oral regimen dropped to only half of patients who received an outpatient intravenous infusion regimen and to two thirds of patients overall. Those who preferred the infusions generally did so because they experienced fewer side effects 129 .

Cancer therapies in preclinical development include particle formulations (for example, liposomes and polymeric nanoparticles) of chemotherapeutics such as paclitaxel, docetaxel and 5-fluorouracil, with or without active targeting moieties. By prolonging the elimination half-life of the drug and preferentially increasing its uptake in the desired cell population, these systems have the potential to reduce the required dosing frequency and mitigate side effects traditionally associated with non-specific chemotherapeutics and immunotherapeutics. Similarly, in situ cross-linkable hydrogels and non-degradable polymeric implants can be injected or implanted into the site of interest (when the location of the tumour burden is known) to form a slowly depleting depot that delivers drug in a localized fashion. These systems may be especially useful when the site of interest is a cavity made accessible due to a recent surgical intervention.

Osteoporosis

Bone antiresorptive agents, such as BPs and oestrogen, are first-line therapies for osteoporosis. Poor adherence, which is estimated to occur in between one third and one half of patients with osteoporosis, can significantly increase the risk of fracture and is correlated with inferior health outcomes and increased health-care costs 130 . Rates of treatment discontinuation are also high; up to three quarters of patients will discontinue a daily treatment regimen within the first year 131 . Reasons for discontinuation often include a low risk perception and/or the onset or fear of adverse effects associated with taking BPs (for example, upper gastrointestinal issues and an increased risk of oesophageal cancer) 50 . Upper gastrointestinal adverse effects occur in between one third and one half of patients taking oral BPs and remain the most commonly cited reason for treatment discontinuation. Reducing the dosing frequency has been shown to consistently improve adherence and persistence in patients taking BPs 132 , 133 , 134 , 135 , 136 . Two studies found that more than four out of five women with osteoporosis preferred once-weekly over once-daily BPs and believed it would help with adherence or would prefer to take it in the long term 132 , 133 . Accordingly, a higher percentage of patients were able to achieve full adherence when taking once-weekly BPs compared with once-daily BPs over a combined 8-week period 133 . Adherence and persistence were even higher among patients taking once-monthly BPs compared with those taking once-weekly BPs 135 .

DDSs in preclinical development for osteoporosis include parenteral hydroxyapatite-containing scaffolds and injectable or implantable depots 137 , 138 . These formulations may be able to address the common barriers to adherence by minimizing the need for patient intervention, abating fluctuations in dose and/or avoiding the gastrointestinal tract entirely.

Hypertension/cardiovascular disease

Poor adherence to antihypertensive therapy is associated with an increased risk of adverse outcomes, including death 106 , 139 , 140 . Adherence rates for common cardiovascular medicines have been reported to range from 21 to 71% 141 . There are several extended-release formulations of antihypertensive drugs, including nifedipine, propranolol and metoprolol/hydrochlorothiazide, which are capable of sustained drug release over 12–24 h and are taken either once or twice daily. It has consistently been shown that a reduction in the dosing frequency of chronic oral cardiovascular disease medication is associated with a significant improvement in all three types of adherence (taking, regimen and timing) 28 , 142 , 143 . However, because many cardiovascular medications are taken prophylactically and do not usually produce an immediately noticeable effect, many patients undervalue their importance 141 .

Catapres-TTS is a transdermal patch containing the antihypertensive medication clonidine. In one study, 87% of surveyed patients with mild to moderate hypertension viewed the patch as a more convenient monotherapy option as compared with previously used oral alternatives. Moreover, 65% were able to achieve better treatment adherence when using the patch and physicians deemed it a satisfactory or highly satisfactory option for 80% of their patients 144 . For these reasons, transdermal clonidine has explicitly been recommended to patients who have difficulty adhering or are otherwise intolerant to standard oral antihypertensive medications. Several additional DDSs are in clinical trials for the treatment of atherosclerosis and other ischaemic diseases, including nanoparticle and liposomal formulations 145 .

Ocular disorders

Adherence among patients is negatively impacted by inaccurate beliefs about the efficacy of the medication and severity of the disease if left untreated. This is especially prevalent in patients with glaucoma as there are not usually clear markers of disease progression and the disease often causes a gradual worsening of vision that is difficult to perceive over short periods of time. Adherence rates among patients with glaucoma have been reported to be approximately 50%, and poorly adherent patients tend to exhibit higher intraocular pressure, more severe visual field loss and are more likely to go blind 146 .

Using topical eye drops is generally considered to be the most convenient and safe approach for treating ocular conditions, including glaucoma, and generally leads to the highest patient acceptability. However, as many as nine out of ten patients are unable to properly instil eye drops 147 , 148 , leading to an increased risk of under-medication or over-medication and, potentially, resulting in poor outcomes and unnecessarily high treatment costs. Long-acting DDSs, including clinically available injectable depots, refillable devices and in situ-forming hydrogels, are promising strategies to improve medication adherence, mainly because they minimize the need for frequent drug administration. Sustained-release ocular implants, in particular, are able to limit the adverse effects associated with both systemic exposure and the high concentrations associated with frequent intraocular injections of immediate-release drugs 149 . Examples of these systems include Vitrasert, a non-degradable poly(vinyl alcohol)/poly(ethylene vinyl acetate) implant that delivers ganciclovir and is used to treat viral retinitis in patients with AIDS; Iluvian, an injectable, non-degradable poly(vinyl alcohol)-based implant that delivers fluocinolone acetonide to treat diabetic macular oedema; and Ozurdex, an injectable, biodegradable poly(lactic-co-glycolic acid) implant that delivers dexamethasone for up to 6 months and is used in the management of uveitis 150 . Ocusert is a pilocarpine reservoir surrounded by two rate-controlling membranes that a patient inserts into their own eye socket and is capable of releasing drug at a zero-order rate for 7 days to treat glaucoma and other eye conditions. The conventional alternative, pilocarpine eye drops, needs to be administered four times per day. Given that this dosing scheme results in local concentrations that frequently fall outside the therapeutic window, patients taking these eye drops often experience more adverse effects, including blurred vision and fluctuations in intraocular pressure, than patients taking Ocusert 151 . This system has not achieved widespread adoption, however, partially owing to the difficulty of device insertion, resulting eye irritation and premature device ejection.

Patient acceptability of and adherence to ocular injectables and implants is generally high, provided that the system can provide sustained release over a sufficiently long duration. In a small-scale survey, patients who underwent cataract surgery received a single injection of compounded ophthalmic pharmaceuticals in one eye and followed a regimen of self-administered eye drops for up to 4 weeks in the other. There was no significant difference in outcome efficacy or self-reported pain severity between treatments, but more than 90% of patients preferred the long-lasting injection over frequent administration of eye drops 152 .

Several DDSs in preclinical development for ocular delivery aim to deliver biologics (for example, antibodies, neurotrophic factors and even stem cells), in the form of injections or intravitreal implants. Others include MAPs that offer the same benefits as intravitreal injections but potentially fewer risks, degradable polymeric nanoparticles that mitigate the need for a removal procedure and hydrogels and refillable port delivery systems that, following implantation, allow patients to obtain refills in a comparatively non-invasive manner at a provider’s office 153 .

Major psychiatric disorders

It is estimated that about half of patients with a major psychiatric disorder are non-adherent 154 , owing to factors including negative attitudes towards medication and/or a perceived lack of efficacy, high rates of side effects and perceived stigma. The average amount of time it takes for conventional antidepressants to take effect and achieve a full response is 14 days and 20 days, respectively 41 . Given the extreme risks associated with a prolonged latency period (including an increased risk of suicide), a quicker and sustained onset of action has been correlated with improved long-term outcomes 155 . In contrast to oral DDSs, intranasal DDSs are capable of bypassing the gastrointestinal tract and blood–brain barrier and directly reaching the brain. This type of delivery enables a rapid, localized onset of action with convenient self-administration as compared with other, fast-acting parenteral medications (for example, intravenous infusions). Intranasal esketamine (Spravato) was approved by the FDA in 2020 for the treatment of depressive symptoms in adults with treatment-resistant depression and/or major depressive disorder. In clinical trials, Spravato was shown to act quickly, lessening depressive symptoms in some patients in as quickly as 4 h and exhibiting an acceptable safety profile. In the long term, approximately half of the experimental group taking both Spravato and a standard-of-care oral antidepressant achieved clinical remission of depression after 25 days compared with one third of the placebo arm receiving only the standard-of-care oral antidepressant 156 , 157 .

Risperdal Consta is an intramuscular injection of a degradable microparticle depot containing risperidone, an antipsychotic medication used to treat schizophrenia and other mental disorders. The injection can be given every 2 weeks and is especially recommended for those who exhibit poor medication adherence to oral antipsychotics. This DDS has been shown to result in significant behavioural improvements among patients who switch 158 , 159 and is expected to be more cost-effective than oral alternatives in the long term by preventing avoidable hospitalizations and other types of health-care spending 160 .

Substance use disorder

For individuals with a substance use disorder, effectively managing symptoms requires good adherence to medication over a prolonged period. Herein, DDSs have the potential to replace daily oral therapies, which are associated with notoriously poor adherence and persistence rates; for example, more than three quarters of patients discontinue oral naltrexone treatment within 6 months 62 . Probuphine is an FDA-approved subdermal implant capable of releasing the partial opioid agonist buprenorphine over 6 months. Given its poor oral bioavailability, no oral alternative of this drug exists, and it is often given as a sublingual tablet. The implant was developed largely to address issues with patient non-adherence and medication misuse. In a RCT setting, this system was significantly more effective than a placebo implant 161 and non-inferior to daily sublingual buprenorphine, with 86% of patients receiving buprenorphine implants and 72% receiving sublingual buprenorphine maintaining opioid abstinence over a period of 6 months. An extended-release injectable suspension of naltrexone (Vivitrol) taken monthly has also been developed to address adherence issues associated with daily oral therapy. Vivitrol has been shown to result in a small but significant improvement in adherence and to be as effective as or more effective than oral naltrexone for relapse prevention in individuals with alcohol use disorder 162 , 163 , 164 , 165 . This system is also indicated for use in individuals with opioid use disorder, and a naltrexone-releasing implant (DLP-160), also capable of delivering the drug over 6 months, is in clinical development. In one clinical trial, 53% of patients receiving the naltrexone implant and an oral placebo were able to remain in treatment without relapse over 6 months, as compared with only 16% of patients receiving a placebo implant and oral naltrexone 166 .

Relapsing–remitting disorders

Relapsing–remitting disorders are characterized by periods of remission interspersed with occasional flare-ups. Compared with patients with chronic, symptomatic disorders, patients with relapsing–remitting disorders are more likely to exhibit disease denial and less likely to actualize the benefits of taking their medication during symptom-free periods 167 , 168 , 169 , 170 .

The rates of adherence among patients with relapsing–remitting disorders are generally poor but vary widely, with underlying reasons that tend to be complicated, multifactorial and difficult to fully address. Although the main reason for non-adherence is still forgetfulness, patients are more likely to consciously become non-adherent to their medication during symptom-free periods owing to a low perceived risk of consequences. Accordingly, patients that are well-informed, self-empowered and believe in the positive benefits of their treatment tend to exhibit higher rates of adherence 170 , 171 . Still, there are no long-acting treatment options for the diseases discussed below and developing long-acting DDSs that patients can administer less than once per week (for example, a depot injection or implant) may be valuable to some, especially in instances where the aforementioned intervention strategies are infeasible or ineffective.

Inflammatory bowel disease

The long-term risks of poor adherence in patients with IBD include an increased risk for colorectal cancer, a fivefold greater risk of recurrence and an increased risk of hospitalization and surgery 172 , 173 . Oral mesalazine is the current standard of care for the induction and maintenance of remission in patients with ulcerative colitis, the most common form of IBD 174 . Rates of patient adherence to ‘conventional’ regimens of oral mesalazine (taken multiple times per day) are generally poor, with adherence estimates around 40% 172 . The most commonly cited reason for non-adherence among patients with IBD is forgetfulness 167 ; despite this, retrospective analyses on adherence with extended-release mesalamine taken once daily have produced mixed results. Studies have concluded that adherence with once-daily mesalamine is significantly better than 175 , 176 , slightly better than 172 , 177 or no different to 178 , 179 , 180 adherence with mesalamine taken multiple times per day. There is also evidence to suggest that adherence and persistence in patients with ulcerative colitis are not significantly affected by factors associated with treatment, such as drug formulations and dosing frequency, especially with longer durations of use 181 . There does seem to be a meaningful role for more conventional strategies, such as audio-visual reminder systems, patient education and effective patient–provider communication 167 , 182 , 183 . Still, multiple methods often need to be deployed concurrently with some amount of customization in order to achieve meaningful results. Because the factors underlying poor adherence to IBD treatment are complex, it may be difficult to develop a one-size-fits-all DDS or interpersonal intervention strategy for the disease.

One of the most prominent types of DDS for IBD in preclinical development are nanoparticle-based systems that target the mucus layer or intestinal epithelium. Of these, responsive systems whose degradation is triggered by an altered disease state (for example, changes to pH and microbiome composition) are also under investigation 184 . Other DDSs in development include probiotic bacteria ‘factories’ that produce immunomodulatory recombinant or endogenous proteins. All have the potential to enable a significant reduction in required dosing frequency when compared with the current standard of care.

Relapsing–remitting multiple sclerosis

Reported adherence rates to disease-modifying therapies (DMTs) for relapsing–remitting multiple sclerosis are variable, with estimates ranging from 36 to 87% 169 , 185 . Good medication adherence has consistently been shown to produce better outcomes, including a reduced risk of relapse, a reduced risk of hospitalization and optimized cognitive abilities 57 , 186 .

One third of patients with relapsing–remitting multiple sclerosis who report missing an injection of the DMTs interferon-β (IFNβ) or glatiramer acetate cite injection-related reasons (for example, pain at the injection site) as the cause 185 . In addition to obviating the need for injections, oral DMTs (mainly fingolimod, dimethyl fumarate, teriflunomide, siponimod and cladribine) are more likely to produce fewer adverse effects such as flu-like symptoms 187 . Despite this, there is inconsistent evidence as to whether adherence and/or persistence are higher among patients taking oral DMTs or those taking injectable DMTs. When compared with patients who self-inject DMTs, it has been reported that those taking oral fingolimod were more adherent and persistent 187 . Similarly, those taking oral dimethyl fumarate were reported to exhibit improved adherence that correlated with an increase in perceived effectiveness and a decrease in (predominately gastrointestinal-related) adverse effects 188 . By contrast, a larger retrospective study considering self-injectable DMTs and three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) reported that the route of administration did not appear to affect patient behaviour, with approximately half of patients in both groups considered adherent or persistent 189 . In another meta-analysis, the reported 12-month adherence rates among patients taking oral DMTs were significantly higher than among those taking injectable DMTs (53–89% versus 47–77%). However, there was no significant difference in persistence, with the mean discontinuation over 12 months being 11–33% for oral DMTs and 15–50% for injectable DMTs. Potential sources of variability in outcomes between the studies under consideration include inconsistencies in protocols, methodology and data analysis, including adherence thresholds and definitions of discontinuation 190 .

DDSs in development for multiple sclerosis include IFNβ nanoparticles intended for intranasal administration 191 . These particles were created with the intention of circumventing the blood–brain barrier and delivering IFNβ directly to the brain. By avoiding the premature degradation that IFNβ would experience upon entering systemic circulation (as is the case following intramuscular, subcutaneous or intravenous administration), lower concentrations of the drug can be used. Accordingly, this system’s comparatively non-invasive and easy delivery strategy and ability to mitigate concentration-dependent side effects are expected to improve adherence among its users.

Owing to the episodic nature of asthma, many patients feel that it does not impact their day-to-day lives and tend to underestimate the importance of long-term treatment. Patients are also more likely to adjust dosing according to their own perceived disease burden. Rates of adherence to inhalable asthma medication across multiple classes are reported to range from 30 to 70% 184 , 192 . Predictors of adherence to long-term inhaled therapies include regular appointments with a provider and positive beliefs about the medicine and its intended effects 192 . A reduction in dosing frequency could also play a beneficial role 193 , 194 , 195 . DDSs for asthma currently in preclinical development include alternatives to dry powder inhalers such as liposomes, microspheres and polymeric micelles. These systems have the potential to reduce the dosing frequency by enhancing deposition efficiency and reducing the rate of clearance from the lungs 196 , 197 .

Acute illnesses

In general, there is an inverse correlation between treatment duration and adherence rate. Although patient adherence is generally higher in acute illnesses requiring short-term treatment, there remains a substantial opportunity to improve current outcomes 198 . For example, one third of patients are estimated to not be fully adherent when taking a short course of antibiotics and one quarter save leftover antibiotics for future use 199 .

Tuberculosis

In 2020, an estimated 10 million people became sick with tuberculosis 191 . The current standard-of-care treatment regimen for tuberculosis in adults is a 6-month course of oral antibiotics. It is estimated that 20–50% of patients do not complete their tuberculosis treatment regimen within a 2-year period 200 . Intervention strategies such as health education and direct supervision have generally proven ineffective at improving adherence and those that have shown some efficacy, such as monetary incentives, are feasible to implement only in an extremely limited capacity 200 . Simplifying and/or shortening treatment times, in comparison, is expected to significantly improve adherence rates 198 , 201 , 202 , 203 , 204 . Recently, a phase III RCT achieved a breakthrough in showing that an abridged 4-month antibiotic regimen was non-inferior to the standard 6-month regimen 205 .

Inhalable, antibiotic dry powder drug formulations are currently under investigation to improve tuberculosis treatment compared with oral, short-acting antibiotics. These systems are advantageous because they are able to achieve a high localized concentration of drug in the lungs and, potentially, reduce the risk of systemic toxicity. This may also allow a reduction in the dose amount, dosing frequency and/or treatment duration, thereby reducing the likelihood of developing multidrug-resistant tuberculosis. Liposomes are one such carrier that have been extensively investigated in the context of pulmonary delivery, including for tuberculosis. Although studies have shown that these systems — particularly those with large payload capacities 206 — can provide sustained release and improve the pharmacokinetic profile of antibiotics, efforts are underway to address critical challenges, such as the co-loading of all drugs currently prescribed as part of conventional tuberculosis treatment 207 , 208 .

Prophylactics

High adherence to contraceptives and antiretroviral therapies is crucial for their efficacy given that a single instance of non-adherence could lead to unintended pregnancy or HIV transmission. Accordingly, the documented usage of long-acting contraceptives and HIV PrEP formulations provides insight into how intervention-free DDSs can maximize adherence and improve patient satisfaction and outcomes. Vaccines are a form of prophylaxis for which several long-term DDS options (for example, transdermal and microneedle patches, intranasal sprays and injectable pulsatile-release microparticles) intended to reduce administration frequency are in clinical development 209 , 210 .

In general, patients have benefited from discrete, long-acting and comparatively invasive formulations of contraceptives and HIV PrEP over shorter-acting oral alternatives. In the near future, DDSs offering additional benefits (for example, fewer side effects, dual-drug delivery or an even longer duration of action) that emerge in this space, along with the first long-acting vaccine options of their kind, are expected to further improve the health of patients and communities.

Contraceptives

Contraceptive DDSs include transdermal patches, intravaginal rings, intramuscular injectables, subdermal implants and intrauterine devices (IUDs). The latter two fall into the category of long-acting reversible contraception (LARC) as they can be removed on-demand prior to drug depletion. LARCs take the matter of adherence out of the hands of the patient almost entirely for the duration of their use (up to 3 years for an implant, 3–7 years for a hormonal IUD and 10 years for a copper IUD). Although all of the aforementioned contraceptive methods generally have a theoretical failure rate of <1% with perfect use, only IUDs attain this in practice. In comparison, the reported annual failure rates are approximately 1–2% for injectables and implants and 2–9% for non-LARC methods (tablets, patches and rings) 211 , 212 , 213 . Accordingly, it has been reported that the risk of contraceptive failure is 20-fold higher among those using tablets, patches or rings as compared with LARCs 211 . Continuation rates with IUDs are also generally higher; 12-month continuation rates are reported to range from 80 to 89% for IUDs, from 68 to 83% for implants and from 49 to 73% for the tablet, patch, ring and depot injection 214 , 215 , 216 . Moreover, the rates of satisfaction appear to mirror the rates of continuation and it has been reported that more than four fifths of women using a LARC were still using their chosen method after 12 months of use, in comparison with half of women using a non-LARC method 214 .

The principles underlying modern contraceptives have remained the same for nearly 60 years as focus has largely been placed on making marginal improvements to hormonal strategies in women that are known to be effective. The future of contraceptive DDSs is towards various non-hormonal strategies in women and both hormonal and non-hormonal strategies in men. Accordingly, DDSs will likely be required to successfully deliver small molecules or delicate biologics to target locations. An example of the latter are anti-sperm antibodies capable of rapidly binding and immobilizing sperm in the female reproductive tract. These drugs must be formulated in a device, such as a vaginal film or suppository (for short-term delivery) or ring (for longer-term delivery), in order to remain stable and biologically active throughout both storage and use 217 . Novel DDSs such as these have the potential to improve contraceptive effectiveness, in part by mitigating or eliminating the negative side effects conventionally associated with hormonal approaches and encouraging adherence.

HIV pre-exposure prophylaxis

Stigma against HIV/AIDS is one of the most commonly reported barriers to adherence to prophylactic or therapeutic antiretroviral therapy 218 , 219 . Non-adherence is the strongest predictor of antiretroviral therapy failure and is strongly associated with an increased risk of mortality 92 , 93 . Poor adherence is also one of the primary reasons behind subpar clinical trial outcomes that have found oral PrEP to be ineffective or poorly effective. For example, in the Preexposure Prophylaxis Initiative (iPrEx) trial, daily dosing of emtricitabine and tenofovir disoproxil fumarate was initially found to reduce HIV transmission by only 44% overall 220 ; however, when a retrospective analysis was limited to the approximately 18% of participants who were adherent (having a plasma tenofovir diphosphate concentration consistent with taking four or more doses per week 221 ) or highly adherent (having a plasma tenofovir diphosphate concentration consistent with taking seven doses per week), the risk reduction increased to an estimated 96% and 99%, respectively 222 . Similar findings have been reported in other trials that initially reported an underwhelming rate of efficacy for oral PrEP drugs 223 .

In 2022, the FDA approved two injectables for HIV/AIDS prophylaxis and treatment: a long-acting injectable formulation of the prophylactic cabotegravir (CAB-LA) that is taken every 2 months 98 , and a therapeutic combination of CAB-LA and long-acting rilpivirine taken monthly 99 . In phase III testing of the former, patients were given either active oral Truvada and inactive CAB-LA (placebo) or inactive Truvada (placebo) and active CAB-LA. The rate of partial adherence or better among participants in the latter group was higher as determined via blood analysis. In phase III testing of CAB-LA and long-acting rilpivirine, an overwhelming majority — 91% of patients — preferred the long-acting injectable to the oral daily dosing regimen at the end of the year-long trial 100 . This is in alignment with results from previous, scenario-based surveys in which participants have signalled an interest in a long-acting alternative to oral PrEP and believed it would improve their adherence 97 , 224 , 225 .

Many DDSs currently in preclinical development for HIV are focused on increasing the duration of release for existing PrEP drugs. One class of examples are subdermal/subcutaneous implants for the extended release of drugs such as islatravir, tenofovir alafenamide, emtricitabine and cabotegravir 226 , 227 . Efforts are also underway to create novel dual-acting systems that can offer both contraception and protection against HIV 228 .

Multi-dose vaccines

The main barriers that parents face when vaccinating their children, aside from misconceptions about the safety of vaccines and the threat of vaccine-preventable illnesses, are forgetfulness and difficulty in tracking vaccinations 229 , 230 . Vaccines that require fewer doses and/or a shorter treatment time are associated with higher rates of completion across multiple age groups 222 , 231 , 232 . For example, among female patients who initiate HPV vaccination, only one third complete the vaccine regimen, and of these only two thirds receive all three doses within a valid time frame 233 , 234 , 235 . Switching to a two-dose or one-dose regimen, both of which have been shown to be effective, is expected to significantly improve adherence 236 , 237 , 238 .

Given that a majority of vaccines are administered via intramuscular injection, needle phobia is also an addressable issue that affects immunization compliance 63 . MAPs, a class of DDSs for single-dose or multi-dose vaccinations currently in preclinical development, can painlessly deliver a vaccine across the skin barrier into the epidermis or upper dermis using significantly less antigenic material than would be required for an intramuscular injection 82 , 83 . Tolerability studies have shown that 70–90% of participants would prefer using a MAP over receiving an intramuscular injection with a hypodermic needle 71 , 72 , 73 . There is also evidence to suggest that the added convenience of a self-administered vaccine option in the form of a MAP could improve vaccination coverage among vaccine-hesitant individuals 74 .

Vaccinations are different from many other types of health-care intervention in that at-home vaccination options usually do not exist and patients must visit a provider (or vice versa) in order to receive a dose. Long-acting DDSs, such as injectable pulsatile-release microparticles capable of mimicking a bolus dose multi-injection vaccine regimen, have the potential to combat under-immunization due to patient forgetfulness or negligence, or, as is often the case in the developing world, limited access to health-care providers and resources 239 , 240 .

To have the greatest impact, DDSs must be developed in a way that aligns with the needs of patients, clinicians, pharmaceutical companies and payers. Whereas patients and clinicians typically want to achieve the best health outcomes with the fewest side effects (which should factor in the patient’s ability to adhere to the prescribed dosing regimen), pharmaceutical companies seek profit and payers aim to balance cost and patient benefits. DDSs have the potential to provide value for all stakeholders. For patients and clinicians, superior efficacy, improved convenience and reduced side effects can make DDSs valuable options. For companies, DDSs have the potential to capture an additional share of the market due to patient preference, to rescue drugs that have failed in clinical trials or to extend the effective patent lifetime for existing drugs to maintain an advantage over emerging generics. Historically, a large emphasis has been placed on developing and bringing a new drug to market whereas relatively minimal effort has been placed on developing DDSs for existing drugs with addressable flaws in their pharmacokinetic profile or route of administration. A shift in this strategy, reflecting an improved appreciation for the critical role of patient adherence, could allow insurance providers and pharmaceutical companies alike to assess the benefits of DDSs more accurately and make their development more commercially attractive (Box  3 ).

The nature of the existing disease treatment should be considered when creating a novel DDS. For example, patients who have taken the same medication for years may have become accustomed to the side effects and, therefore, be less receptive to a new route of administration. At present, most clinically approved DDSs are oral extended-release formulations owing to the generally high patient acceptability of this delivery route and ease of manufacturing; however, there are some limitations with this approach, such as a limited duration of action due to a short gastric residence time. Parenteral administration of injectable depots and implantable devices still constitutes a viable option for greatly reducing the required dosing frequency and improving adherence. These systems have the added benefit of being more readily compatible with biological drugs, which have gained a large share of the market over the past decade.

Novel DDSs currently in clinical or preclinical development have the potential to initiate a paradigm shift and redefine what constitutes an ‘acceptable’ treatment option in the near future. Examples of these potentially paradigm-shifting technologies include ingestible systems that make biologics orally bioavailable and/or provide sustained API release over 1 week or longer, sense-and-respond systems that autonomously regulate the concentration of a drug in circulation to minimize the need for manual intervention and pulsatile-release systems that mimic multi-dose regimens with a single injection (Fig.  4 ).

Medication adherence could be improved by systems that enable oral delivery of biologics, autonomously regulate the concentration of a drug in circulation or mimic a multi-dose dosing regimen with a single injection. a–c , Examples of systems in each category include the self-orienting millimetre-scale applicator (SOMA), which injects insulin across the gastric mucosa and leads to near zero-order release for hours (panel a ); the glucose-responsive microneedle (GR-MN) insulin patch consisting of an array of polymeric needles that reversibly swell under hyperglycaemic conditions and collapse when blood glucose levels return to normal to modulate insulin release (panel b ); and core shell poly(lactic- co -glycolic acid) (PLGA) microparticles synthesized via the stamped assembly of polymer layers microfabrication method capable of releasing active pharmaceutical ingredient cargo in discrete bursts at pre-programmed intervals (panel c ). Part a adapted with permission from ref. 120 , AAAS . Part b adapted from ref. 121 , Springer Nature Limited. Part c is adapted from ref. 34 , CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ).

Despite their advantages, DDSs still face logistical hurdles that can stymie their translation from bench to bedside, even after obtaining regulatory approval. Case studies of DDSs that have been removed from the market — inhalable insulin (Exubera and Afrezza) (Box  4 ), long-acting injectable human growth hormone (Nutropin Depot) (Box  5 ) and several iontophoretic devices (LidoSite, Ionsys and Zecuity) (Box  6 ) — highlight three lessons learned. First, an initial demonstration of safety is paramount to the ultimate translational success of a DDS; even if a once-flawed DDS is fixed after its initial launch or is quickly supplanted by an improved device, the perceived lack of safety among patients and clinicians can still negatively affect sales of the device and devices similar to it in the future. Second, the logistical challenges associated with large-scale manufacturing, which are typically greater for a DDS than for a stand-alone drug, should be appreciated and addressed early on to prevent potentially fatal consequences. Last, the DDS must fill an unmet or poorly met clinical need in the context of real-world use. Iontophoretic devices, for example, have thus far mainly focused on the treatment of acute symptoms such as migraine headaches, or been used to achieve dermal analgesia in a doctor’s office. In both scenarios, patient adherence is already high and viable oral and passive transdermal drug alternatives exist 241 , 242 . Moving forward, these devices may prove more commercially and clinically successful if their unique attributes are leveraged to fill a clinical gap that affects patient adherence. For example, iontophoretic devices currently in development are capable of delivering drugs into ocular tissue and directly into tumours, both of which are difficult environments to penetrate or require invasive means to do so. Thus, the types of challenge that have prevented the widespread use of once-promising DDSs are worth considering when translating new DDSs; each should be engineered to address the most pressing challenges facing the current standard-of-care treatment for the relevant disease target(s) to increase the likelihood of achieving meaningful clinical adoption.

Box 3 Creating a paradigm shift from developing new drugs to developing novel drug delivery systems

Currently, only about 10% of new chemical entities that enter phase I clinical trials achieve US Food and Drug Administration (FDA) approval 259 , with the majority dropping out of the clinical pipeline owing to issues with pharmacokinetics, efficacy and safety 260 . An analysis of new chemical entities that failed in phase II or phase III clinical trials between 2013 and 2015 found that three quarters of these trials were discontinued, in part, owing to efficacy and safety concerns due to poor pharmacokinetics and a narrow therapeutic window, respectively 261 . These issues can often be addressed by formulating a drug in a controlled-release system, suggesting that a stand-alone drug that has previously failed in clinical trials could be clinically viable when combined with the proper drug delivery system (DDS).

A DDS that has the added benefit of significantly improving patient adherence can often constitute a favourable value proposition compared with the development of a new drug. For example, hypertension-related health expenditures are one of the largest costs paid out by public insurance in the United States 262 . Antihypertensive medications are taken by more than two thirds of US adults 263 and are estimated to cost an average of $336 annually per patient 264 . Patients who are non-adherent to these hypertension medications are at a significantly higher risk for related morbidity and mortality 265 . Of the 91.7 million people taking hypertension medications in the United States 263 , 14.4% (13.2 million) are completely non-adherent 266 . In 2014, non-adherence resulted in 350,000 preventable hospitalizations at an average cost of $16,623 per patient, amounting to $5.9 billion in avoidable medical spending 267 . Thus, a DDS that enables these 13.2 million high-risk patients to achieve full adherence could cost up to 133% more annually ($784 total) than the standard treatment option to account for the financial benefit of avoiding unnecessary hospitalizations. This opportunity for significant cost savings is often not well conveyed to or fully appreciated by payers and providers who make these systems available to patients 268 . Accordingly, there is a need to instate a more holistic cost–benefit analysis when ascertaining whether the added benefits of a DDS justify the increased cost.

Box 4 Market failure of inhalable insulin

In the years leading up to its market approval, inhalable insulin generated great interest and was widely heralded as a system with the potential to revolutionize diabetes treatment 269 . However, the only two inhalable insulin products to be commercialized, Exubera and Afrezza, have both experienced underwhelming market success. The Exubera device became the first US Food and Drug Administration (FDA)-approved inhalable insulin system in 2006, but was taken off the market just 1 year later 270 . The device was obtrusive and non-intuitive, requiring patients to convert from the often-used subcutaneous insulin ‘units’ to the non-intuitive milligrams 271 . Additionally, some patients who used Exubera presented with pulmonary side effects, such as a decline in lung function and/or increase in insulin antibodies, which were not as common in those taking subcutaneous insulin 272 . This development, in conjunction with the perceived notion that inhalable insulin slightly increased the incidence rates of lung cancer among smokers, led to the addition of a boxed warning on the prescription and increased apprehension among both patients and health-care providers 270 .

The only other product of this kind to emerge since the market failure of Exubera is MannKind’s Afrezza, which claimed a share of just 0.1% of the diabetes market 1 year after its launch in 2014 (refs. 270 , 273 ). Although the drug is still available and its contemporary market sales are showing an upward trend, inhalable insulin sales still account for less than 1% of total treatment visits for insulin and significantly less than 1% of the diabetes drug market 274 . Despite being a smaller and more intuitive device than Exubera, Afrezza still offers relatively inflexible dosing options 275 , leading clinicians to strongly encourage patients on Afrezza to continuously monitor their glucose levels. This requirement offsets the benefits of increased convenience and adds to the cost of disease management 275 , 276 . Additionally, Afrezza has a similar safety profile to Exubera and produces a persistent cough in more than one quarter of patients 277 . The fear of inhalable insulin posing a possible carcinogenic risk in general has also carried over from Exubera, despite the lack of any definitive clinical evidence 271 . The culmination of these factors, in addition to its high cost — which is more than twice that of injectable rapid-acting insulin 278 — has led most insurance companies to list Afrezza as a non-preferred brand, imposing higher co-payments on patients and stymying interest and accessibility 270 .

Box 5 Market failure of long-acting injectable human growth hormone

Recombinant human growth hormone (rhGH) is typically administered daily via subcutaneous injection in patients with growth hormone deficiency. Nutropin Depot, a twice-monthly injection of microspheres containing rhGH, was approved by the US Food and Drug Administration (FDA) in 1999 (refs. 279 , 280 ). Unfortunately, the added convenience of less frequent dosing with this drug delivery system (DDS) was partially offset by the need to deliver large volumes of the viscous formulation via multiple injections with a large-bore needle, which led to pain and left a visible bump on the (often, paediatric) patient’s skin for an extended period of time 281 . As is the case with most biodegradable microparticle depot formulations, Nutropin Depot also produced a large initial burst, releasing 22% of the total loaded rhGH in the first 24 h, and caused frequent injection site reactions 282 , 283 . Additionally, the bioavailability of rhGH administered via Nutropin Depot was 33–55% lower than that of rhGH administered via subcutaneous injection, requiring that 15% more rhGH was used and significantly increasing the cost of treatment 284 . Finally, manufacturing Nutropin Depot involved a complex and cost-intensive cryogenic freeze-drying process intended to preserve the activity of the encapsulated rhGH 285 . In 2004, the product comprised only $16 million (5%) of Genentech’s total growth hormone sales, but cost $4 million to manufacture and was discontinued 281 , 286 .

Box 6 Market failures of various iontophoretic devices

Although iontophoretic devices are capable of quicker and more controlled dosing over passive transdermal formulations, many of these devices were ultimately unsuccessful owing to high costs and safety concerns 287 . LidoSite, an iontophoretic patch that delivers lidocaine, was discontinued in 2008 after only 2 years on the market. This device was capable of producing dermal analgesia six times faster than alternatives, but the treatment was more than ten times as expensive as the standard buffered lidocaine injection 288 , leading to depressed demand 289 , 290 . Similar devices, such as Lidopel and Iontocaine, were also removed from the market owing to limited demand in 2005 and 2011, respectively 289 , 291 .

Ionsys was approved for use in 2006 for the transdermal delivery of fentanyl to manage postoperative surgical pain. Clinical evaluation of the drug delivery system (DDS) found that it was effective and well tolerated 292 , 293 , yet it was removed from the market twice (temporarily in 2008 and permanently in 2017) owing to manufacturing quality concerns. The high technical complexity of the device made quality control difficult and expensive, and a corroded electronic component that could lead to the inadvertent delivery of a fatal dose of fentanyl was identified in a batch of the product shortly after its launch 290 . In a similar vein, reports of patients being burned and scarred by the Zecuity patch, a single-use iontophoretic device used to deliver migraine medication, led the manufacturer to temporarily suspend sales and launch an investigation in 2016, just 3 years after the initial approval of the device in 2013 (refs. 289 , 294 ). These safety concerns, in combination with the high cost of the device and marginal improvement in therapeutic efficacy over comparable low-cost alternatives, led to the permanent withdrawal of the product from the market in 2020 (refs. 294 , 295 ).

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Acknowledgements

K.J.M. was supported by the National Institutes of Health (NIH) (R35 GM143101). T.H.B. (Grant No. 2236422) and B.H.P. (Grant No. 1842393) were supported by the National Science Foundation (NSF). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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R.L. holds numerous patents and holds equity and consults for companies that operate in the drug delivery arena; complete details for R.L.’s competing interests can be found online ( https://www.dropbox.com/s/yc3xqb5s8s94v7x/Rev ). K.J.M. is an inventor on several patents and patent applications in the area of drug delivery (US20190076631A1, WO2019018301A1, US10960073B2, US 63/213,082), and was also formerly a paid consultant for Particles for Humanity, a public benefit corporation.

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Baryakova, T.H., Pogostin, B.H., Langer, R. et al. Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat Rev Drug Discov 22 , 387–409 (2023). https://doi.org/10.1038/s41573-023-00670-0

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• Volume 26, Issue 4
• Medication adherence interventions and outcomes: an overview of systematic reviews
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• Nina C Wilhelmsen 1 ,
• Tommy Eriksson 1 , 2
• 1 Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences , Norwegian University of Science and Technology (NTNU) , Trondheim , Norway
• 2 Department of Biomedical Sciences, Faculty of Health and Society , Malmö University , Malmö , Sweden
• Correspondence to Dr Tommy Eriksson, Clinical Pharmacology, Laboratory Medicine, Lund University, Lund 221 00, Sweden; tommy.eriksson{at}mah.se

Objective To present evidence for healthcare-provided medication adherence interventions on clinical, economic and humanistic outcomes among patients.

Methods Literature search of systematic reviews in Medline, Embase and CINAHL (2007–2017), validation of quality using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses questionnaires and, finally, extraction, combination and tabulation of results for included studies.

Results From eight systematic reviews with medium to high AMSTAR 2 score, 37 randomised controlled studies involving 28 600 participants were extracted. Patient education and counselling showed some positive effects on medication adherence. Patient education also showed some positive effects on morbidity, healthcare utilities and patient satisfaction. Counselling had some benefit on mortality and healthcare utilisation. Simplifying doses was shown to have some benefit on morbidity and patient satisfaction. Interventions delivered by pharmacists and nurses showed a better result in improving adherence and outcomes than interventions delivered by general practitioners.

Conclusions Some interventions were found to have positive effect on adherence and outcomes, but no single strategy showed improvement in all settings. For future research patients should be screened for non-adherence to reveal both if they are non-adherent and type of non-adherence, as well as bigger sample sizes and longer duration of follow-up.

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https://doi.org/10.1136/ejhpharm-2018-001725

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Introduction

Every new method of drug treatment being implemented in healthcare has to be proven effective, both when it comes to costs and clinical effects. It has preferred to use the most efficient intervention that provides a maximum of benefit for a minimum of costs. Providing good healthcare service is dependent on the utilisation of available knowledge and experience, and the use of new knowledge simultaneously as outdated practice ceases. In addition, there should be a local, regional or national agreement about what is considered good or preferred service performance.

Systematic reviews are one of the key tools for achieving evidence-based healthcare for providers and healthcare decision makers, so the systematic reviews should provide the accurate and the best available evidence on the topic of interest. 1 Systematic reviews of several randomised trials are seen as the ‘gold standard’ 2 and provide the highest level of evidence. 3

Healthcare providers are responsible for choosing the right treatment for each patient, and that requires professional skill in searching for, assessing and using evidence-based information in clinical practice. 4 This approach is called evidence-based medicine, meaning that provided healthcare is supported by high-quality evidence, does more good than harm and provides the greatest benefit for the patients. 5

Drug therapy is important in protecting, maintaining and restoring people’s health, 6 and has therefore an important priority in the resources used in healthcare. Since medications are critical to prevent and treat disease, 7 we must ask what happens when medications are not taken properly, that is, when adherence is low.

Adherence is defined as: ‘The extent to which the patient’s behaviour matches agreed recommendations from the prescriber.’ 8 WHO stated in 2003 that adherence to long-term therapies was as low as 50% in the general population, and even much lower in low/middle-income countries. 9 A Cochrane review stated that people who are prescribed medication for self-administration only take half of their prescribed dose, and many stop taking their medication entirely without informing their provider. 10 Many patients who continue taking their medication do not do it consistently as prescribed. There is also an increasing number of self-administered treatments available, making improved adherence even more important.

Adherence to medication is an essential component of health outcome, 9 11 so by increasing medication adherence we can also improve patient outcomes. 10 Even the most carefully chosen and optimal medication can be rendered ineffective by insufficient adherence. 9 11 Failure of medication adherence leads to substantial worsening of disease, death and increased healthcare costs. In other words, non-adherence affects both the individual patients and the healthcare system. 9 12 Studies have shown that patients with good adherence to treatment had both a lower rate of mortality 13–15 and a lower rate of hospital admissions than patients with poor adherence to treatment. 13 16 17 WHO states, ‘increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.’ 9

Donabedian’s theoretical framework for evaluating quality of care consists of three approaches: structure, process and outcome. The structure represents the conditions under which care is provided, the process represents the activities that constitute healthcare and the outcome represents the changes in the health status. 18 It is suggested that good outcome is a result of a structure that promotes a good process, 19 and that any efforts to improve the approaches in the triad must be seen in the light of care and needs of the patients. 20 In the ECHO model, the outcomes of medical care are classified along three general dimensions: clinical, economic and humanistic. 21 The assertion of this study is that: healthcare professionals with their education and skills represent the structure. The process represents what is done in the patient-healthcare professional interaction (eg, interventions to improve medication adherence), and the outcome is the clinical, humanistic and economic outcomes measured because of the adherence intervention.

With this background, the aim of the study was to present evidence for healthcare-provided medication adherence interventions on clinical, economic and humanistic outcomes among patients.

Literature search

After initial search, a search strategy was built using relevant text words and their synonyms, and opposites, in addition to terms found going through the controlled vocabulary in the databases: MeSH (in Medline), Emtree (in Embase) and CINAHL Subject Headings (in CINAHL). The final searches (performed 22 December 2017) were restricted to year published (2007–2017), English language and systematic reviews. A detailed description of the search is given in online supplementary appendix 1 . The Cochrane Library itself was not searched. Relevant articles found in the initial search were crosschecked for ensuring that they also were included in the final search strategy. Articles were screened for inclusion and exclusion criteria on title and abstract. Full text was assessed on articles not excluded by title and abstract. The purpose of the literature search was to find systematic reviews that matched the inclusion criteria. If all the studies in a systematic review did not match, individual studies in the systematic review were extracted. Also references from the systematic reviews selected for quality assessment were screened.

Supplemental material

Inclusion criteria.

Included studies were systematic reviews that contained medication adherence interventions, and one or more of the predefined outcomes (mortality, morbidity, healthcare utilisation, healthcare costs and patient satisfaction/quality of life). The systematic review had to include at least two randomised controlled trials (RCT) that matched the inclusion criteria. The RCTs extracted from systematic reviews had to have a sample size of at least 60 participants in each group to have enough power to detect an absolute difference. 10 Finally, the studies must be evaluated as of moderate or high in methodological quality.

Exclusion criteria

Systematic reviews only reporting medication adherence, surrogate endpoints and not the predefined hard endpoints were excluded. Studies had to have a description of medication adherence interventions, not only results of interventions. Studies where the interventions were very complex and had multiple components not only regarding medication adherence (eg, diet, exercise, and so on) were excluded. Studies were also excluded if not all participants used medication. Cochrane reviews targeting several mixed components, and not only medication adherence, were excluded if they reported low or very low evidence (Grading of Recommendations Assessment, Development and Evaluation) by the authors, even if they scored high on A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Assessment of study quality

PRISMA and AMSTAR 2 are validated tools for assessing quality of systematic reviews. They were used according to instructions 22 23 on 32 systematic reviews. Ten of them were also evaluated by a coresearcher for validation. The PRISMA checklist was used to assess the reporting characteristics, meaning the quality of reporting, and the AMSTAR 2 checklist was used to assess the methodological quality of the systematic reviews. Methodological quality was given highest weight for studies to be included, only studies with moderate to high quality were included.

PRISMA is a reporting guidance with a 27-item checklist. The PRISMA statement is used by authors to ensure a clear, complete and transparent systematic review. 22 The checklist contains seven sections/topics with the associated questions. The answers were given very much rigour as to where in the systematic reviews they were found, meaning that they had to be found where they were supposed to be due to the checklist. The answer ‘yes’ was denoted as page number, figure or table where the item was found. A ‘no’ or ‘not applicable’ was denoted as ÷. When summarising, all the ‘yes’ was given 1 point, making the potential total score 27.

AMSTAR was published in 2007, 24 and has been widely used for assessing methodological quality of systematic reviews 25–27 of both Cochrane and non-Cochrane overviews of healthcare interventions. 28 AMSTAR was recently updated to AMSTAR 2, and now consists of a 16-item online tool for evaluating systematic reviews as high, moderate, low or critically low of methodological quality. 24 Although AMSTAR 2 was not intended to generate an overall score, it was used with that purpose for this report, to find the systematic reviews with the highest quality. Based on the original AMSTAR tool, a score range was made for ranking the systematic reviews into critical low (0–4 p), low (5–8), moderate (9–11) and high (12–16). Two researchers evaluated the studies separately. Any disagreement was resolved through discussion to reach consensus about the final score.

Summarising evidence

The evidence is based on the data that were presented in the systematic reviews for each of the included RCTs. Individual RCTs were not assessed and evaluated through the primary sources, only from the systematic reviews they were included in.

The evidence of the interventions was interpreted on the reported CIs and the p values of the RCTs in the systematic reviews. Studies were evaluated based on statically significant results on the predefined outcomes. For risk ratio, relative risk, OR, risk difference and relative rate the ‘no effect’ cut-off was set at 1, meaning that if the CIs crossed 1, the interpretation was that the results were not statistically significant. For absolute risks and mean differences, the ‘no effect’ cut-off was set on 0, meaning the interpretation was not statistically significant if 0 was within the CI of the results. 29

Literature search and inclusion

The database search identified a total of 854 studies ( figure 1 ). After initial screening and full-text reading 32 studies remained for inclusion before quality assessment. A detailed description of studies excluded before quality assessment is provided in online supplementary appendix 2 .

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Flow diagram of studies found, assessed, excluded and included. AMSTAR, A Measurement Tool to Assess Systematic Reviews; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Quality assessments

Many of the systematic reviews did not have a clear PICO (population, intervention, comparator group, outcome) in their research questions or inclusion criteria. This could be because the studies included in the systematic reviews already had elements of it, for example, RCTs having control groups. An accessible protocol was missing in many systematic reviews. In the PRISMA checklist, studies received a positive score when information was provided about the existence of a protocol, but if the protocol was not found (searching PROSPERO database), there was consequently lack of score in the AMSTAR 2 checklist. There was also a lack of a clear explanation of which study designs that were selected in most of the systematic reviews. Many of the systematic reviews did not provide a full search strategy and did not search for grey literature. Almost all systematic reviews reported that study selection and extraction were done in duplicate. Most of the systematic reviews not being Cochrane reviews did not provide a list of excluded studies and the reason for exclusion. The Cochrane reviews had the most detailed description of the studies included. Almost every systematic review described a satisfactory technique for assessing risk of bias in individual studies but there was often a lack of reporting funding of individual studies. Consequently, systematic reviews including meta-analysis were given a higher score due to the amount of questions addressing meta-analysis. Heterogeneity was reported in most of the SR because of its nature in the intervention and measurements of outcome. Overall there was reported funding of systematic reviews and conflict of interests. As presented in table 1 , more than half of the systematic reviews assessed had a low or critically low quality. Fourteen had moderate to high quality, and eight of those were selected for inclusion and consensus assessment. A detailed description of the studies excluded after quality assessment is provided in online supplementary appendix 3 .

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Results from AMSTAR 2 checklist evaluation

Table 2 gives the PRISMA and AMSTAR 2 scores from two evaluators and the consensus scores. A detailed description of the result of the assessment is given in online supplementary appendix 4 .

Included systematic review with PRISMA and AMSTAR 2 score

Summary of evidence

The eight systematic reviews included in this report were published between 2014 and 2018. Five of them were Cochrane reviews. Thirty-seven RCTs published between 2000 and 2016 involving 28 600 patients were extracted from the systematic reviews. The studies included mostly adult patients of various ages. The group sample size ranged from n=63 to n=3260. Follow-up time ranged from 12 weeks to 2 years. Table 3 shows an overview of the outcomes reported in the RCTs extracted from the systematic reviews. Characteristics of each systematic review and the results of the RCTs extracted from them are presented and tabulated in online supplementary appendix 5 .

Overview of outcomes extracted from the RCTs in the included systematic reviews

The results from the tables representing the RCTs from each systematic review, presented in detail in online supplementary appendix 5 , are summarised across the systematic reviews, representing intervention type and outcome type. Table 4 shows the studies where a positive, negative or mixed effect on outcomes was reported. This table does not include the intervention effect on adherence. These are presented in online supplementary appendix 5 . A detailed description of the results based on intervention type is given in online supplementary appendix 6 and based on effects on outcomes in online supplementary appendix 7 . A detailed reference list is given in online supplementary appendix 8 .

Summary of adherence intervention type and effects on outcomes. Based on detailed description of each study in online supplementary appendix 5

The most frequent intervention type reported was patient education, delivered by pharmacists or nurses. Improvement in adherence was reported in most of the studies where patient education was provided. For counselling there was improvement in half of the studies. In studies where the intervention was delivered by pharmacists who prescribed medication, it was uncertain whether the intervention had any effect on adherence. In all the studies where physicians were the interventionists, the intervention failed to show improvement in adherence.

Reminder interventions, direct observed treatment, web-based programmes and interventions performed by physicians failed to show statistically improvements in outcomes. Simplified dosing, patient education and counselling with and without pharmacists prescribing showed mixed effects among the outcomes. There was evidence that patient education had a positive effect on morbidity and patient satisfaction. Counselling had a positive effect on mortality and healthcare utilisations. Morbidity was also reduced when pharmacists prescribed medication. Since most of these improvements were based on the results of only one RCT, the evidence is weak.

The results of the studies with counselling intervention showed a reduction in mortality and healthcare utilisation, and improvements in adherence were mixed. Patient education showed an increased patient satisfaction and some benefits on mortality and healthcare utilisation, while patient education in addition to pharmacist prescribing medication showed decreased morbidity. Educational intervention had mostly a positive effect on adherence. Simplification of dose showed some improvement in morbidity and patient satisfaction, and a mixed effect on adherence. However, no intervention was shown effective across all the outcomes of interest in this study, indication that choice of intervention should be in concordance with the type of challenges the patient has with adherence.

How the adherence was measured is not without importance, as the methods can have unintended impact on the results, for example, under-reporting or over-reporting in patient self-reports, electronic medication monitors that record opening of the medication container but do not in fact record if the medication is being taken by the patient, and so on. However, this was not the focus in this report and is not reported.

There are several limitations in this study. Only systematic reviews that achieved a moderate to high AMSTAR 2 score were included in this report. There could have been individual studies of high quality within the lower quality systematic reviews that were missed because of the quality assessment. A major limitation is that bias in the individual RCTs was not assessed. However, bias has been assessed by the authors of the systematic reviews. There was some degree of incomplete reporting of data. This could be caused by selective reporting, but it was not examined.

The literature search for this report was restricted to systematic reviews published the last 10 years (2007–2017), although two systematic reviews from 2018 were included that were found by a non-comprehensive Google search of systematic reviews published in 2018. Language was restricted to English, so this report is prone to language bias, with a chance of missing potential studies published in non-English language journals. This search did not aim for unpublished studies (‘grey literature’), but some of the systematic reviews had included unpublished studies in them.

Some studies may have been excluded because of indistinct reporting of the intervention. Studies reporting only ‘health care professionals’ as interventionists were excluded. Because this report was restricted to interventionists being pharmacists, nurses or clinicians, the results of this report may be skewed against middle or high-income countries, since low-income countries were more likely to use non-healthcare professionals as lay or community workers as interventionists.

There was no systematic review that gave a full match with the aim and inclusion criteria for this report, instead individual RCTs that matched the inclusion criteria were extracted from the systematic reviews. Likewise, meta-analysis in the systematic reviews could not be used, making the power in clinically and statistically significance weaker as single RCTs were extracted. Overall the studies were heterogeneous in population type, intervention type and length, and which outcomes that were measured. There was a considerable difference in how the adherence was measured, and what was considered ‘good adherence’. Some of the studies were complex and had several components in their intervention, because of this there was a degree of overlap between the studies, so it was difficult to divide them in a rigid manner.

Another limitation by using individual studies from systematic reviews, and not the primary source itself, is the possibility of misreading by the authors of the systematic reviews. Any interpretation, correct or incorrect, will follow further if the author is not interpreting the result from the individual studies by him or herself. The primary studies were added so they can be found, they were not assessed by the author of this report.

This study was planned as an MSc project in Pharmacy. Three students performed similar studies on different interventions aimed at improving important outcomes. In this study, the student (NCW) performed all activities supervised by TE. The quality assessment was also performed by one costudent researcher. As this report was mainly conducted by a student, not having the same amount of expertise and knowledge in the field as professional researches have, it is more exposed to flaws. The researcher did not have any training in quality assessment of systematic reviews before the work with this report was performed but gained experience through the process. This could have caused some variation in how the first quality assessments were considered compared with the last quality assessment. However, consistency was strived for, and it involved changes in some of the previous quality assessments.

This report can be interesting for several readers. For healthcare decision makers, this report gives an insight into which interventions and interventionists have shown to improve adherence and/or clinical, economic and humanistic outcomes or not. In other words, what type of intervention resources are reasonable to invest in. For researchers who are planning to do similar studies, new studies can be based on the studies in this report. For healthcare professionals who want to enhance their awareness and knowledge about adherence interventions, and want to use them in their practices. Finally, this report is also interesting for patients and consumers of medications by gaining awareness of the challenges insufficient adherence can lead to.

Some interventions were found to have positive effect on adherence and outcomes, but no single strategy showed improvement in all settings. For future research, patients should be screened for non-adherence to reveal both if they are non-adherent and type of non-adherence, as well as bigger sample sizes and longer duration of follow-up.

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EAHP Statement 6: Education and Research.

Contributors This study was planned as an MSc project in Pharmacy. The student (NCW) performed all activities supervised by TE in MSc report. Based on the MSc report we have written this manuscript together.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

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CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management — Innovations and Opportunities

Weekly / November 17, 2017 / 66(45)

Andrea B. Neiman, PhD 1 ; Todd Ruppar, PhD 2 ; Michael Ho, MD, PhD 3 ,4 ; Larry Garber, MD 5 ; Paul J. Weidle, PharmD 6 ; Yuling Hong, MD, PhD 1 ; Mary G. George, MD 1 ; Phoebe G. Thorpe, MD 7 ( View author affiliations )

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Adherence to prescribed medications is associated with improved clinical outcomes for chronic disease management and reduced mortality from chronic conditions ( 1 ). Conversely, nonadherence is associated with higher rates of hospital admissions, suboptimal health outcomes, increased morbidity and mortality, and increased health care costs ( 2 ). In the United States, 3.8 billion prescriptions are written annually ( 3 ). Approximately one in five new prescriptions are never filled, and among those filled, approximately 50% are taken incorrectly, particularly with regard to timing, dosage, frequency, and duration ( 4 ). Whereas rates of nonadherence across the United States have remained relatively stable, direct health care costs associated with nonadherence have grown to approximately $100–$300 billion of U.S. health care dollars spent annually ( 5 , 6 ). Improving medication adherence is a public health priority and could reduce the economic and health burdens of many diseases and chronic conditions ( 7 ).

Understanding Medication Nonadherence

Medication adherence is a complex behavior influenced by factors along the continuum of care, relating to the patient, providers, and health systems ( 8 ). Patient-related factors include unintentional factors, which often worsen with increasingly complex medication regimens (e.g., forgetting to take medication or obtain refills, or inadequate understanding of dose or schedules); and intentional factors (e.g., active decision to stop or modify a treatment regimen based on ability to pay, beliefs and attitudes about their disease, medication side effects, and expectations for improvement) ( 9 ) ( Figure ). Additional patient-related barriers include lack of engagement in treatment decisions, impaired cognition (e.g., related to aging or disease), substance abuse, depression, and other mental health conditions. Provider-related factors include barriers to communicating with patients and their caregivers, complex dosing regimens, and limited coordination of care among multiple providers. Health care system and service delivery factors include limited access to an appropriate provider for prescriptions or refills, restricted drug coverage, high costs and copayments, unclear medication labeling and instructions, limited availability of culturally appropriate patient education materials, and inadequate provider time to review benefits, risks, and alternatives to prescribed medications.

Innovative Strategies to Improve Medication Adherence for Chronic Disease Management

Successful efforts to improve rates of adherence often incorporate multiple strategies across the continuum of care. A proven cost-effective strategy to reducing unintentional nonadherence is the use of pillboxes and blister packs to organize medication regimens in clear and simple ways ( 10 ). Combining the ease of packaging with effective behavioral prompts, such as electronic pill monitors that can remind patients to take their medication and provide messages to health care providers when a scheduled drug-dose is missed, supports increased medication adherence ( 11 ).

Interventions that include team-based or coordinated care have been shown to increase adherence rates. In a recent study, patients assigned to team-based care, including pharmacist-led medication reconciliation and tailoring; pharmacist-led patient education; collaborative care between pharmacist and primary care provider or cardiologist; and two types of voice messaging (educational and medication refill reminder calls) were significantly more adherent with their medication regimen 12 months after hospital discharge (89%) compared with patients not receiving team-based care (74%). Patients reported that team-based care improved their comfort in asking clarifying questions, raising concerns about their medication regimen, and collaborating in developing their treatment plan ( 12 , 13 ).

Lowering economic barriers to prescribed medications also improves adherence rates. In 2007, Pitney-Bowes Corporation employees and beneficiaries with diabetes or vascular disease increased their medication adherence rates increased by 3%–4% after the company eliminated or reduced health plan copays for cholesterol-lowering statins and the antiplatelet medication, clopidogrel (used to prevent heart attacks and strokes), compared with beneficiaries insured by another health plan with the same third-party prescription drugs administrator that did not reduce or eliminate copays for the same medications. These improvements, while modest, could result in significant cost savings in the prevention of acute events (e.g., hospitalizations) and progression of major chronic conditions if scaled to larger populations ( 14 ).

System-based strategies that address health disparities can improve clinical goals or reduce disease burden. For example, medication adherence is crucial for persons infected with human immunodeficiency virus (HIV), because treatment lowers the amount of virus circulating in the blood, which improves the patient’s health and reduces the risk of transmitting HIV to others by >90% ( 15 ). Interventions, such as CDC’s Data to Care ( 16 ) strategy, that identify and re-engage nonadherent patients in care by linking them through the health department, their care providers, or both, improve the health of the individual and achieve the public health benefit of reducing HIV transmission ( 17 ).

Advances in health information technology can also improve medication adherence. In a 2011 study, providers using electronic prescribing (e-prescribing) increased first-fill medication adherence by 10% compared with those using paper prescriptions ( 18 ). Some e-prescribing software can monitor prescriptions dispensed or unfilled in near real-time, as well as send patients prompts when a new or refill prescription is available. These data allow providers to review current medication use with patients during office visits, identify gaps or barriers to adherence, and discuss workable solutions.

Health information technology can also be used to show real-time impact of medication use on chronic conditions. Reliant Medical Group, a multispecialty group practice in Massachusetts, provided home blood pressure monitors to 200 of its patients. Patients uploaded blood pressure readings into their electronic health record. At office visits, providers were able to display trends of patients’ blood pressure, discuss barriers if blood pressure was not controlled and patients were not adherent, or add alternative drugs or lifestyle changes if pharmacy data indicated patients were adherent but their blood pressure was still poorly controlled. In addition, health information technology systems enabled providers to view medication coverage by insurer and choose lower cost medications. Reliant also made complex prescribing algorithms easier to follow by establishing and incorporating treatment protocols for hypertension into the electronic health record. Using these and other strategies ( Box ), Reliant improved its hypertension control rate from 68% in 2011 to 79% in 2014 and was recognized as a Million Hearts Hypertension Control Champion in 2015 ( 19 ).

Opportunities in Medication Adherence Outcomes

Although a range of interventions have demonstrated improved medication adherence and health outcomes during the study period, few studies have shown that these benefits were maintained over time ( 20 ). Interventions that can sustain patient medication adherence are needed. One priority for developing sustainable strategies to improve medication adherence includes standardizing research methodology for both clinic and research settings. Currently, studies use a variety of measurement methods. Varying study methodologies prevents comparability across interventions, hinders wide application into clinical practice, and limits efforts that focus on patients with the greatest burden and need. Standardization might also help to understand both the dose-response and effectiveness of interventions over a longer time, increasing sustainability and reducing a waning effect at follow-up time points ( 21 ).

In addition, patient-specific tailored approaches to identifying reasons for nonadherence and aligning intervention efforts to address identified needs are needed. Outcomes might also be improved by recognizing populations at increased risk for nonadherence and addressing the broader reasons for their nonadherence, such as low health literacy. Health literacy is lower among the elderly, racial and ethnic minorities, and persons living in poverty ( 22 ). Interventions to improve medication adherence could be more effective if patient’s health literacy, cultural background, and language preference and proficiency are taken into account when designing communication and patient education materials.

Conclusion and Comments

Medication adherence is critical to improving chronic disease outcomes and reducing health care costs. Successful strategies to improve medication adherence include 1) ensuring access to providers across the continuum of care and implementing team-based care; 2) educating and empowering patients to understand the treatment regimen and its benefits; 3) reducing barriers to obtaining medication, including cost reduction and efforts to retain or re-engage patients in care; and 4) use of health information technology tools to improve decision-making and communication during and after office visits. Understanding root causes of medication nonadherence and cost-effective approaches that are applicable in diverse patient populations is essential to increasing adherence and improving long-term health impact.

Conflict of Interest

Dr. Ho reports grants from Veterans Health Administration during the conduct of the study; personal fees from Janssen, Inc., personal fees from American Heart Association, outside the submitted work. Dr. Garber reports grants from Agency for Healthcare Research and Quality during the conduct of the study.

Corresponding author: Andrea B. Neiman, [email protected] , 770-488-8255.

1 Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, CDC; 2 Rush University, College of Nursing, Chicago, Illinois; 3 Veteran’s Administration Medical Center, Denver, Colorado; 4 University of Colorado Denver; 5 Reliant Medical Group, Worcester, Massachusetts; 6 U.S. Public Health Service Commissioned Corps, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC; 7 Office of the Associate Director for Science, CDC.

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FIGURE . Self-reported reasons* for nonadherence to recommended medication regimens — United States, 2013

Source: Medication Adherence in America: A National Report Card, 2013. Adapted with permission. https://www.ncpanet.org/pdf/reportcard/AdherenceReportCard_Abridged.pdf .

* Participants could provide more than one response, and as such, categories are not mutually exclusive.

BOX. Strategies used by Reliant Medical Group (Massachusetts) to improve adherence to blood pressure medication and increase hypertension control rates

Ensure that patient understands the benefits

• Educate about harms of uncontrolled hypertension and benefits of controlling hypertension
• Make culturally appropriate education materials available
• Automatically print educational information in the After-Visit Summary if patient has diagnosis of hypertension
• Show patients graphs of their blood pressure trends during office visits and online electronic health record (EHR) portal. Use graphs to demonstrate challenges and successes with treatment regimens

Choose lower cost medications

• Use step-therapy protocols that are developed by a multidisciplinary team and are standardized across the organization
• Control access to pharmaceutical marketing
• Make the patient’s payer-specific formulary available in the EHR to inform medication selection
• Use generic medication substitution
• Provide assistance in paying for medications (e.g., RxAssist.org)
• Consult social workers to assist with adherence barriers

Minimize medication complexity

• Choose once-a-day and combination medications
• Engage in dialogue about costs versus convenience (e.g., pill-splitting can reduce cost but increase inconvenience)

Monitor side effects

• Be creative in addressing concerns — e.g., if concerned about swollen feet, use a diuretic, if appropriate — e.g., if concerned about medication causing abnormal potassium level, use a combined angiotensin-converting enzyme (ACE) inhibitor and a diuretic to normalize potassium
• When to monitor side effects — At visits — At prescription renewals, using a standard documentation template — After hospital discharge: automated alerts for new medications
• Consult pharmacists — For complex medication regimens or side effects — After hospital discharge regarding patients who are on high-risk medications

Show effectiveness of the medications in lowering blood pressure

• Empower patient to record blood pressure readings at home
• Provide booklets to record readings
• For patients with financial hardships, provide free home blood pressure monitors
• Offer free blood pressure clinics
• Automatically upload blood pressure readings into the EHR

Monitor medication adherence

• Encourage patients to document their medication-taking behavior
• Use EHR systems that can show medication fill history
• Automate adherence monitoring using payer medication claims
• Review adherence information during visits. Patients’ knowing that a clinician is monitoring adherence is at least as important as a patient seeing the results

Suggested citation for this article: Neiman AB, Ruppar T, Ho M, et al. CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management — Innovations and Opportunities. MMWR Morb Mortal Wkly Rep 2017;66. DOI: http://dx.doi.org/10.15585/mmwr.mm6645a2 .

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• Open access
• Published: 10 May 2019

Medication adherence influencing factors—an (updated) overview of systematic reviews

• Alina Gast 1 &
• Tim Mathes   ORCID: orcid.org/0000-0002-5304-1717 2  

Systematic Reviews volume  8 , Article number:  112 ( 2019 ) Cite this article

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Non-adherence negatively affects the efficacy, safety and costs of therapies. Non-adherence is a multifactorial problem. This systematic review (SR) of SRs (overview) aims to identify factors that can influence the adherence of adult patients with chronic physical diseases.

We performed a systematic literature search in MEDLINE and Embase on June 13, 2018. We included SRs on the factors that can influence adherence in adult patients taking oral medications for treating physical chronic diseases. Two reviewers independently selected studies according to pre-defined inclusion criteria. Two reviewers independently assessed the risk of bias with the ROBIS tool. Data were extracted in standardized tables previously piloted by one reviewer and verified by a second reviewer. We synthesized data in tables in a structured narrative manner.

We included 21 SRs on eight different conditions. We rated eight SRs to be at low risk of bias and 13 to be at high risk of bias. Although higher education, employment, higher financial status and marriage/partnership mostly showed a positive effect on adherence, the impact was unclear because of the high uncertainty of the underlying evidence. The evidence indicates that socioeconomic status and social support might have a positive impact on adherence and that belonging to an ethnic minority might have a negative impact on adherence. Therapy-related factors (e.g., intake regime) and disease-related factors (e.g., duration) mostly showed no impact on adherence. Analysis of gender showed inconsistent results. Age might have a concave relation to adherence, i.e., adherence is lowest in very young and very old people. Depression has a negative impact on adherence. Impacts of other mental and physical comorbidities were uncertain. Co-payments (any or higher) have a negative impact on adherence. In contrast, the impacts of medication costs and insurance status were uncertain.

This overview analyses factors that might impact adherence to oral therapies in adult patients with physical chronic diseases. Our overview suggests that there is a social gradient in adherence. However, for most factors, the evidence was not conclusive due to the risk of bias, inconsistency or imprecision.

Peer Review reports

Medication adherence can be defined as the extent to which a patient’s behaviour corresponds with the prescribed medication dosing regime, including time, dosing and interval of medication intake [ 1 , 2 ]. Non-adherence is a crucial point for the success and safety of many therapies [ 3 , 4 , 5 ]. Medication non-adherence is a widespread problem that causes high costs worldwide [ 5 , 6 , 7 , 8 , 9 , 10 ]. Especially in chronic conditions with long-term therapies, adherence is important to achieve target outcomes but is often low [ 10 ].

Adherence is a multifactorial phenomenon that can be influenced by various factors. These factors can be divided into five different dimensions: social and economic factors, therapy-related factors, disease-related factors, patient-related factors and health care system-related factors [ 10 , 11 ]. Some factors can have an influence on intentional non-adherence (conscious decision not to take the medication; e.g., because of high co-payments), while others can have an influence on non-intentional (forgetting) non-adherence (e.g., forgetfulness because of mental comorbidity).

Insights into the factors that might have a negative influence on adherence are important for several reasons. First, this information can support the identification of patients at high risk for non-adherence. Second, it can support the identification of possible adherence barriers that might be eliminated. Third, it can support the development of individually tailored adherence-enhancing interventions.

The objective of this (updated) overview (systematic review [SR] of systematic reviews) was to identify those factors that influence adherence to oral drugs in patients with physical chronic diseases. Given the considerable amount of literature in this field, this updated overview provides a current and compact overall view on this topic.

There was no published protocol for this overview. Unless otherwise indicated, all described methods were specified before conducting the overview. This overview was not registered.

Information sources

This overview is a focused updated version of an overview published by our research team in 2014 [ 12 ]. This overview is reported according to the Preferred Reporting Items for Overviews of systematic reviews (OoSRs), including the harms checklist [ 13 ].

We performed a systematic literature search in MEDLINE (via PubMed) and Embase (via Embase). The complete search strategy, including the applied search limits, is provided in Additional file  1 . In contrast to our previous search filter, we included unspecific terms for influencing factors (e.g., factors, predictors) as well as specific terms (e.g., gender, age) because we focused only on certain pre-defined influencing factors (for the reasoning, see the “ Study Selection ” section). We anticipated that these parameters would lead to a higher sensitivity compared with the search for the previous overview version. In addition, the search was performed without limiting the publication date. We performed the search of the electronic databases on June 13, 2018. In addition to the electronic searches, we crosschecked the references of all included SRs.

Study selection

We selected SRs according to the following predefined inclusion criteria:

Patients: Adult patients (≥ 16 years) with physical chronic diseases. We considered every physical chronic illness. We excluded SRs that analysed children (if > 20% of the included studies analysed children), and considered only patients with acute conditions or considered only patients with mental illnesses.

Medication: Oral drug intake (at least 50% of patient population)

Exposure: Pre-specified (see the text below) potential influencing factors for adherence. We defined a factor as any exposure that is not controlled by the study investigator

Outcome: Implementation adherence (correct dose, timing and/or frequency of intake) [ 2 ]

Study type: SRs (definition: systematic literature search in at least one electronic database and assessment and documentation of risk of bias of included studies) of quantitative studies

Publication language: English or German

We aimed to summarize the evidence for factors that are widely applicable across different conditions, therapies and regions/settings. Therefore, we limited our overview to unrelated factors of therapy and disease, i.e., we excluded factors that likely strongly vary depending on disease (e.g., symptoms), therapy (e.g., side effects) or health care system (e.g., insurance type). Compared with the previous version, we narrowed the scope by considering only factors for which there were some indices for an influence in the previous broad overview [ 12 ]. We chose the following factors: age, gender, ethnic status, education, employment, financial status/income, marital status/not living alone, social support, measure of intake complexity (e.g., number of tablets, number of medications, frequency of intake), duration of therapy, duration of disease, comorbidity, co-payments, medication costs and insurance status (insured/not insured).

In addition to these pre-defined eligibility criteria, a further criterion was defined post hoc during study selection. Both reviewers agreed to exclude those SRs that reported only the number of statistically significant studies (e.g., 10 studies showed a statistically significant effect of gender) without reporting effect sizes and the total number of studies on a certain comparison (e.g., 12 studies analysed gender). The decision to exclude studies that were reported in this way was made because the results could have been highly biased by selective reporting otherwise.

The study selection (title/abstract screening and full-text screening) was performed by two reviewers independently. Any differences between the reviewers were discussed until consensus.

Data collection

All data were extracted using standardized extraction forms piloted beforehand. Data were extracted by one reviewer, and completeness and accuracy were verified by a second reviewer. Any disagreements were discussed until consensus. For each SR, we extracted the following characteristics: condition/medication, eligibility criteria for primary studies (only other than our applied inclusion criteria), search period and any search limits.

The results were extracted according to the type of evidence synthesis. For all meta-analyses, we extracted pooled effect estimates with 95% confidence intervals, tests and measures for statistical heterogeneity, the number of included studies and the number of patients included in the meta-analyses. In the case that the included SR performed only a narrative synthesis, we used modified vote counting to extract the results. This method has been suggested for presenting results of quantitative synthesis and overcoming problems of simple vote counting [ 14 , 15 ]. We extracted information on the effect direction, total number of included primary studies showing a certain effect direction, statistical significance of primary studies ( p  < 0.05) showing the effect direction and total number of primary studies that analysed a certain factor.

All data in the tables were harmonized so that the influence on adherence (not non-adherence) refers to an increase in the factor regardless of whether the factor is positive (e.g., socioeconomic status) or negative (e.g., co-payments).

Risk of bias assessment of individual studies and across studies

We used the Risk of Bias in Systematic Reviews (ROBIS) tool to assess the included SRs [ 16 ]. The ROBIS tool is based on three phases. Phase 1 aims to assess the relevance of the SR. For this purpose, the relevance of the research question should be assessed. This optional phase was skipped in this overview because the relevance was already completely covered by the eligibility criteria. Phase 2 comprises four different domains (domain 1: study eligibility criteria, domain 2: identification and selection of studies, domain 3: data collection and study appraisal, and domain 4: synthesis and findings) and aims to identify biased areas in the SRs. In the final phase 3, the assessor judges whether the whole SRs is at risk of bias. In addition to the results of phase 2, three additional signalling questions should be considered in phase 3. These three signalling questions refer to the discussion/interpretation of the SRs. We did not extract any data from the discussion/interpretation; therefore, we did not consider these signalling questions in the overall judgement. Thus, the overall judgement of risk of bias is exclusively based on the results of phase 2 [ 17 ]. The ROBIS tool was applied by two independent reviewers (TM, AG). Disagreements were resolved by discussion. TM was also an author of two of the included SRs. To ensure an objective assessment, the risk of bias assessment of these SRs was performed by a reviewer other than TM.

Synthesis of results

For all factors, a summary evaluation of the influence on adherence across SRs was made. The evidence for an impact was rated by considering the following criteria that were inspired by the GRADE [ 18 ] criteria.

Risk of bias of the included SRs and their included primary studies. In primary studies, we considered in particular adjustment for confounding, missing data and adherence measurements

Imprecision (statistical certainty, amount of information on a certain factor [number of primary studies and SRs, effect size)])

Inconsistency (within and between SRs, e.g., due to different adherence measures)

Based on these criteria, the effects were rated as robust evidence for an impact , some evidence for an impact , probably no impact or uncertain impact . The impact rating was performed by two reviewers.

Overlaps (multiple included primary studies) were assessed by creating a cross table of all included SRs and their primary studies. In addition, the corrected covered area (CCA) was calculated. The CCA is a value that indicates the proportion of overlapping primary studies. It is calculated as follows: \( \mathrm{CCA}=\frac{\left(N-r\right)}{\left(r\times c-r\right)} \) ; N  = number of primary studies (includes multiple counting); r  = number of index studies (defined as first-time primary study); and c  = number of included systematic reviews. The CCA can assume a value between 0 and 100%. The smaller the value is, the lower the overlap. Conversely, the higher the value is, the greater the overlap [ 19 ].

The electronic literature research resulted in 4849 hits after removal of duplicates (including hits from the previous search). After title and abstract screening, 4702 articles were excluded, and 147 were judged to be potentially relevant. The full texts of these articles were screened in detail. Fifteen SRs met all eligibility criteria and were included in this overview. Most SRs were excluded because a methodological quality assessment of the included primary studies was not performed or factors other than our pre-specified influencing factors were investigated. In addition to the 15 newly identified relevant SRs, six SR of the previous overview were included. Finally, 21 SRs were included in this overview [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. The process of study selection is illustrated in the PRISMA flowchart [ 41 ] (Fig.  1 ).

Flowchart of the study selection

Characteristics of the included systematic reviews

The following conditions and medications were considered: chronic non-malignant pain [ 35 ], cardiovascular diseases (e.g., coronary artery disease, hypertension, diabetes mellitus) [ 21 , 22 , 23 , 24 , 25 , 26 , 29 , 30 , 33 , 37 ], Parkinson disease [ 36 ], hepatitis C [ 27 ], oral anticancer agents [ 28 , 39 ], inflammatory arthritis [ 38 ], HIV/AIDS [ 31 , 32 , 34 ] and chronic diseases [ 20 ]. Sinnott et al. did not restrict the condition or medication but included all studies on publicly insured patients who were exposed to co-payments for medications [ 40 ]. Of the 21 included SRs, 14 only synthesized the results narratively, and seven performed a meta-analysis. The characteristics of all included SRs are presented in Table  1 . A list of excluded studies is available in Additional file  2 .

The 21 SRs included 313 primary studies, and data from these studies were used in this evidence synthesis. The number of index publications was 285 ( r  = 285), which resulted in a primary study overlap estimated by the CCA of approximately 0.5%. The cross table can be found in Additional file  3 .

Risk of bias of the included systematic reviews

Risk of bias across the SRs was lowest in domain 3 ( data collection and study appraisal ). In this domain, six SRs were judged to be at high risk of bias. Compared with domain 3, the other domains, including 1 (eligibility criteria), 2 (identification and selection of studies) and 4 (synthesis), were at higher risk of bias across studies. In all these domains, more than 50% of the SRs were at high risk of bias. In particular, imprecise eligibility criteria, inadequate restrictions in the eligibility criteria, inappropriate search strategies, simple vote-counting and no protocols available were the most common reasons for the high risk of bias in these domains. Figure  2 shows the results of the phase 2 ROBIS rating according to the four different domains.

Risk of bias in the systematic reviews. orange: high (risk of bias), grey: low (risk of bias), blue-grey: unclear (risk of bias)

A comparison of the individual SRs shows that only three SRs were at low risk of bias in all four domains [ 25 , 27 , 28 ]. In contrast, 2/3 of all included SRs were at high risk of bias in two or three domains [ 20 , 21 , 23 , 24 , 26 , 30 , 33 , 35 , 37 , 38 , 39 ]. Three SRs were rated to be at high risk of bias in all domains [ 22 , 32 , 36 ]. The results for each included SRs are illustrated in Table  2 . We rated the overall risk of bias for eight SRs as low and for 13 SRs as high.

Impact of influencing factors of adherence

The evidence synthesis of the analysed factors (according to the different diseases/therapies) is presented in Table  3 . The results of each individual included SR are presented in the Additional file  4 .

Social and economic factors

The evidence for an impact of education on adherence was uncertain for most diseases/therapies. Some evidence for a positive impact of education on adherence was exclusively noted for cardiovascular conditions [ 23 , 37 ]. The impact of employment was mostly uncertain. Some evidence for a positive impact was exclusively noted in HIV-infected patients [ 32 , 34 ]. The other conditions that were investigated for this influencing factor (hepatitis C, inflammatory arthritis and cardiovascular conditions) showed inconsistent results and thus were judged as uncertain evidence [ 23 , 27 , 38 ]. For the analysis of the influence of ethnic status on adherence, we considered different comparisons because the grouping in primary studies differed widely. Some evidence exist for inflammatory arthritis and robust evidence for cardiovascular conditions (in the USA) that white ethnicity is associated with higher adherence [ 33 , 38 ]. In HIV-infected patients, there was some evidence that white individuals are more adherent than black individuals [ 32 ]. The SRs of cardiovascular conditions showed some evidence that large ethnic groups are more adherent than ethnic minorities [ 37 ]. Among patients with chronic diseases and patients taking oral anticancer agents, there was some evidence that a better financial status has a positive influence on adherence [ 20 , 39 ]. The impact of financial status was uncertain in Parkinson disease, hepatitis C and cardiovascular conditions [ 21 , 23 , 27 , 36 , 37 ]. The influence of the socioeconomic status was uncertain in inflammatory arthritis and patients taking oral anticancer agents [ 28 , 38 ]. In cardiovascular conditions, some evidence exists that a higher socioeconomic status has a positive impact on adherence [ 29 ]. Marital status was investigated in the SRs on Parkinson disease, inflammatory arthritis, chronic diseases, HIV, patients taking oral anticancer agents and cardiovascular conditions. The results were very inconsistent, and consequently, the impact was judged as uncertain overall [ 20 , 23 , 32 , 36 , 38 , 39 ]. In addition, the impact of social support was uncertain in all SRs [ 23 , 28 , 30 , 37 , 38 ].

Therapy-related factors

We found some evidence for a negative influence of intake of different medications in cardiovascular conditions. The impact of all other therapy related factors (duration of therapy, number of tablets, intake frequency, intake at meals) was uncertain in all conditions [ 23 , 28 , 35 , 36 , 37 , 38 , 39 ].

Disease-related factors

Duration of disease was the only disease-related factor considered in this overview. Most of the SRs that analysed this factor showed conflicting effect directions, and the evidence for an impact was thus judged as either uncertain or probably no impact overall [ 23 , 27 , 28 , 35 , 38 , 39 ].

Patient-related factors

In six of eight conditions, positive effect directions for higher age were reported. In two conditions (cardiovascular conditions and Parkinson disease), some evidence of an impact was found, and the impact of the other four conditions/medications was uncertain [ 20 , 23 , 24 , 28 , 35 , 36 , 37 , 38 , 39 ]. In contrast, negative effect directions of higher age in chronic diseases, cardiovascular conditions and oral anticancer agents were reported [ 20 , 21 , 23 , 24 , 28 , 39 ]. However, the evidence for an impact was uncertain. More distinct (no linear) age groups were compared in the SRs on adherence in inflammatory arthritis, chronic diseases, HIV-infected patients, patients taking oral anticancer agents and cardiovascular conditions [ 20 , 21 , 23 , 28 , 31 , 32 , 37 , 38 , 39 ]. In two conditions, there was some evidence for an impact. In HIV-infected patients, persons older than 45 years tend to be more adherent than those under 45 years [ 32 ]. In patients taking oral anticancer agents, there was some evidence that middle-aged people (approximately 45–60) are more adherent than very old (> 75 years) and younger people (< 45 years) [ 28 ]. General comorbidity or physical comorbidity was assessed in inflammatory arthritis [ 38 ], patients taking oral anticancer agents, hepatitis C, chronic diseases and cardiovascular conditions [ 20 , 21 , 27 , 28 , 37 , 39 ]. Overall, positive as well as negative effect directions were reported in all included SRs, and the evidence was therefore judged to be uncertain. General mental comorbidity was considered a potential adherence-influencing factor in the conditions Parkinson disease, hepatitis C, chronic diseases and cardiovascular conditions. Negative effect directions were reported for most conditions, while the results were inconsistent in hepatitis C and cardiovascular conditions [ 20 , 21 , 27 , 30 , 36 , 37 ]. The evidence for an impact was mostly judged as uncertain for this factor. Some evidence for a negative impact of mental comorbidity on medication adherence was exclusively noted in hepatitis C and cardiovascular conditions [ 21 , 27 , 30 , 37 ]. Depression was analysed in patients taking oral anticancer agents, HIV infection or cardiovascular conditions. In patients taking oral anticancer agents and HIV-infected patients, some evidence was observed, and robust evidence for a negative impact was noted in cardiovascular conditions [ 28 , 30 , 32 ]. Gender was analysed in the SRs on chronic pain, hepatitis C, inflammatory arthritis, chronic diseases, oral anticancer agents and cardiovascular conditions [ 20 , 21 , 23 , 27 , 28 , 33 , 35 , 37 , 38 , 39 ]. The impact was judged as uncertain in all SRs because the effect directions were conflicting (within and between SRs). Some evidence for higher adherence in women was noted exclusively in cardiovascular conditions [ 21 , 23 , 33 , 37 ].

Health care system-related factors

For co-payments (any co-payment and higher co-payments), the effect direction was almost always negative. Some evidence for a negative impact of co-payments on adherence in inflammatory arthritis, chronic diseases and cardiovascular conditions exists [ 20 , 22 , 23 , 25 , 26 , 38 ]. The meta-analysis of Sinnott et al. provides robust evidence for a negative impact of co-payments on adherence across different conditions [ 40 ]. The evidence for an impact was uncertain in oral-anticancer agents [ 39 ]. In cardiovascular conditions, there was some evidence that patients not paying any co-payments are more adherent than those patients paying (any) co-payments [ 25 , 26 ]. Medication costs were analysed in patients with inflammatory arthritis and patients taking oral anticancer agents. Only negative effect directions were reported, but the evidence for a negative impact on adherence was uncertain in both conditions [ 38 , 39 ]. It was uncertain whether health insurance status (insured vs. uninsured) influences adherence in patients with chronic or cardiovascular conditions [ 23 , 25 ].

This overview includes 21 SRs on 313 individual primary studies in a broad spectrum of chronic conditions. Compared with the previous version, this focused update increases the certainty of evidence for some factors (e.g., co-payments or ethnic status) and identifies new evidence on other factors (socioeconomic status, depression and insurance status) [ 12 ].

We analysed seven potentially socioeconomic adherence-influencing factors. Although mostly positive effect directions were reported, the overall evidence for an impact is uncertain for employment and education. The evidence synthesis indicates that belonging to an ethnic minority seems to be associated with reduced adherence. In contrast, higher financial status and better socioeconomic position seem to have a positive impact on adherence. None of the therapy-related (but not therapy-specific) factors showed evidence for a strong impact on adherence. The same seems to be true for disease duration. Studies focusing on distinct age groups suggest that age does not have a linear association with adherence but that the association is rather a concave shape with an adherence peak in middle to older ages, i.e., adherence is particularly low in very young and very old persons. Studies that analysed age as a continuous linear variable and studies that dichotomized age showed inconsistent results. The explanation for the inconsistent results of the linear analyses might also be attributed to the fact that the association is indeed non-linear. Gender seems to have no consistent impact on adherence. Considering comorbidities, there was only robust evidence that depression impacts adherence negatively. We also found robust evidence that co-payments reduce adherence. Considering this information together with the socioeconomic factors and age suggests that there is a social gradient in adherence behaviour.

Although the majority of literature on adherence-influencing factors is overwhelming, we could only judge the influence for many factors as uncertain. In addition, from the high risk of bias, the main reason for so many uncertain judgements was imprecision. The main cause for downgrading due to imprecision was insufficient reporting, which prevented us from adequately assessing the results. For example, in many cases, we could not even use modified vote counting satisfactorily. Therefore, unclear impact ratings indicate that the evidence is insufficient to allow a conclusion not that there is the tendency that these factors have no impact.

Moreover, the results for many factors were inconsistent. Overviews of SRs are always at high risk for discordant or heterogeneous results across the included SRs [ 42 ]. We tried to prevent strong heterogeneity by focusing on factors for which we assumed homogeneity across different conditions and considering only implementation adherence to oral drugs. Nevertheless, the results of our overview were also partly heterogeneous. This is particularly true for the influencing factors education, employment, different medications, duration of disease and gender. One might argue that this suggests that the influence of these factors dependents on condition or setting. However, if inconsistency was observed, this was mostly true within as well as between SRs. Thus, we believe that positive findings might be caused by spurious findings in primary studies (confounding bias, type one error rate, selective reporting). A condition-related explanation for heterogeneity might be that many SRs seem to include symptomatic as well as asymptomatic patients. Research has shown that symptomatic patients are mostly more adherent than asymptomatic patients [ 43 , 44 ]. This assumption is supported by the fact that especially therapy- and disease-related influencing factors, which are related to the symptomatic patients, were inconsistent. Moreover, none of the included SRs distinguishes intentional (conscious decision not to take medication) and unintentional adherence (forget to take medication); however, it strongly stands to reason that the influencing factors can depend on the underlying reasons for non-adherence [ 45 ]. Additional sources of inconsistency that we could not control for were different definitions and measurements of influencing factors (e.g., socioeconomic status) and even more adherence measures (e.g., self-reported vs. electronic monitoring, > 90% of pills taken vs. > 80% vs. mean intake).

We included SRs on any physical chronic diseases and analysed only factors we assumed were independent of disease/therapy. Therefore, on the one hand, we believe that our results are widely applicable for implementation adherence to oral drugs in physical chronic diseases. On the other hand, it should be considered in the interpretation of the findings that the influence of a factor might vary between region/setting. In particular, the influence of different ethnic groups probably depends on the country/region since an ethnic minority in one region could be an ethnic majority in another region However, although ethnic minorities are different ethnic groups in different countries, we believe that all ethnic minorities likely face similar adherence challenges independent of the country they live in.

The identified risk factors of non-adherence can indicate patients who are at increased risk for non-adherence. For clinical practice, this information can help identify and select patients who require support for being adherent. In studies on adherence, the information can help with the identification of relevant participants [ 46 ] or the development of adherence risk prediction models [ 47 ]. Moreover, the knowledge of influencing factors of adherence can support the development of tailored health technologies to increase adherence by treating the underlying barriers (e.g., depression treatment, reducing co-payments). In this regard, health policy decision makers should consider that there seems to be a social gradient in adherence.

Our overview has some methodological limitations. First, we limited our literature search to English and German languages because there were no other language skills in our research team and no resources for translating articles. Second, we used modified vote counting; however, we are aware that this type of methodology has strong limitations. Nevertheless, we decided to use modified vote counting because we anticipated that this is the only method to harmonize the results from different types of narrative synthesizes. Third, we only analysed therapy-unrelated factors. Consequently, regarding indications where therapy-related factors play an important role (e.g., adverse events in chemotherapy), our evidence is incomplete per se.

There is sufficient evidence that depression and co-payments have a negative impact on adherence. Evidence suggests that general mental comorbidity and belonging to an ethnic minority might have a negative impact on adherence and that a higher socioeconomic status might have a positive impact on adherence. In addition, the evidence suggests that the influence of age on medication adherence has a concave pattern, i.e., lower adherence in young age groups, increasing adherence with a peak in middle to older age groups and lower adherence in very old age groups. The moderate to high risk of bias in the included SRs and the exclusion of 78 reviews due to missing quality assessment of included primary studies indicate that there is a need for more methodically sound research to provide stronger conclusions. Future primary studies and SRs should use validated adherence measures, adjust the analysis for relevant confounding factors, avoid using arbitrary cut-offs for influencing factors (e.g., age) and report the effect measures with 95% confidence intervals. Furthermore, the studies should analyse intentional and non-intentional adherence distinctly.

Abbreviations

Corrected covered area

Grading of Recommendations, Assessment, Development and Evaluation

Overview of Systematic Reviews

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Risk of Bias in Systematic Reviews

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We thank Stefanie Bühn for her support in the risk of bias assessment.

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AG contributed to the study selection, data extraction, risk of bias assessment, data synthesis, writing manuscript and final approval of the version submitted. TM contributed to the development of study concept, designing and running electronic literature search, study selection, data extraction, risk of bias assessment, data synthesis, revision of the manuscript and final approval of the version submitted. Both authors read and approved the final manuscript.

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Additional file 1:.

Full search strategy. (DOCX 14 kb)

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List of excluded studies. (DOCX 29 kb)

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Results of each individual included SR. (DOCX 19 kb)

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Gast, A., Mathes, T. Medication adherence influencing factors—an (updated) overview of systematic reviews. Syst Rev 8 , 112 (2019). https://doi.org/10.1186/s13643-019-1014-8

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Research Article

Is patient empowerment the key to promote adherence? A systematic review of the relationship between self-efficacy, health locus of control and medication adherence

Contributed equally to this work with: Lilla Náfrádi, Kent Nakamoto, Peter J. Schulz

Roles Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Writing – original draft

* E-mail: [email protected]

Affiliation Institute of Communication and Health, Università della Svizzera italiana, Lugano, Switzerland

Roles Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing

• Lilla Náfrádi, 
• Kent Nakamoto, 
• Peter J. Schulz

• Published: October 17, 2017
• https://doi.org/10.1371/journal.pone.0186458
• Reader Comments

Current health policies emphasize the need for an equitable doctor-patient relationship, and this requires a certain level of patient empowerment. However, a systematic review of the empirical evidence on how empowerment affects medication adherence—the extent to which patients follow the physician’s prescription of medication intake—is still missing. The goal of this systematic review is to sum up current state-of-the-art knowledge concerning the relationship between patient empowerment and medication adherence across medical conditions. As our conceptualization defines health locus of control and self-efficacy as being crucial components of empowerment, we explored the relationship between these two constructs and medication adherence.

Relevant studies were retrieved through a comprehensive search of Medline and PsychINFO databases (1967 to 2017). In total, 4903 publications were identified. After applying inclusion and exclusion criteria and quality assessment, 154 articles were deemed relevant. Peer-reviewed articles, written in English, addressing the relationship between empowerment (predictor) and medication adherence (outcome) were included.

High levels of self-efficacy and Internal Health Locus of Control are consistently found to promote medication adherence. External control dimensions were found to have mainly negative (Chance and God attributed control beliefs) or ambiguous (Powerful others attributed control beliefs) links to adherence, except for Doctor Health Locus of Control which had a positive association with medication adherence. To fully capture how health locus of control dimensions influence medication adherence, the interaction between the sub-dimensions and the attitudinal symmetry between the doctor and patient, regarding the patient’s control over the disease management, can provide promising new alternatives.

The beneficial effect of patients’ high internal and concurrent physician-attributed control beliefs suggests that a so-called “joint empowerment” approach can be suitable in order to foster medication adherence, enabling us to address the question of control as a versatile component in the doctor-patient relationship.

Citation: Náfrádi L, Nakamoto K, Schulz PJ (2017) Is patient empowerment the key to promote adherence? A systematic review of the relationship between self-efficacy, health locus of control and medication adherence. PLoS ONE 12(10): e0186458. https://doi.org/10.1371/journal.pone.0186458

Editor: Monika R. Asnani, University of the West Indies Faculty of Medical Sciences Mona, JAMAICA

Received: September 28, 2016; Accepted: October 2, 2017; Published: October 17, 2017

Copyright: © 2017 Náfrádi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by the Swiss National Science Foundation (FNS 146 980), http://www.snf.ch/en/Pages/default.aspx . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Medication non-adherence—defined as the extent to which patients take medication in ways other than those prescribed by their health care providers—is a serious obstacle to chronic disease care, with a 50% average prevalence across conditions [ 1 , 2 ]. Non-adherence has numerous patient, physician, medication and health care system related factors [ 1 , 2 ]. Several characteristics of the patients, such as health literacy and medication beliefs influence adherence [ 1 – 4 ]. Empowerment [ 5 ]—as an activating force that motivates some people to take their health behavior and management of illnesses into their own hands—is also one of the patient-related factors. Empowerment can be conceived as a personal disposition, referring to the patient’s control and power in the medical context [ 6 ] or as a relational concept, emphasizing the existing equity in the physician-patient relationship [ 7 ]. A collaborative doctor-patient relationship can improve patient empowerment, i.e. the lack of concordance between doctors and patients can lead to paternalism, and negotiated care can bring power balance into the medical relationship [ 8 ]. As a matter of fact, the physicians by facilitating patient engagement in the communication process can foster patient empowerment and better patient outcomes [ 9 ].

Patient empowerment has been associated with positive health and clinical outcomes since the concept made its mark in health care literature [ 5 , 10 , 11 ]. The outcomes considered [ 12 ] include improved disease management [ 13 – 17 ], effective use of health services [ 13 – 15 , 18 ], improved health status [ 19 – 21 ], and medication adherence [ 22 , 23 ]. The association between empowerment and positive health behavior and clinical outcomes generally rests on the assumption that patient autonomous activity is beneficial for their health condition. However, in the case of medication adherence, this assumption might not always hold true. Highly empowered patients might believe that they can make treatment decisions more or less by themselves overruling the physician’s prescription. Indeed, intelligent non-adherence is becoming a common term in the adherence literature, referring to patients´ intentional non-adherence based on rational reasons, such as misdiagnosis or side-effects [ 24 ]. This definition presupposes that non-adherence in case of these patients is the “right” choice which leads to beneficial health outcomes, i.e. the patients are adequately health literate (having necessary knowledge and decision-making skills about the medical treatment [ 25 , 26 ] to judge whether adhere or not to the prescribed medication regimen. Similarly, Bader et al. (2006) defined critical adherence as the patients’ freedom to elect to interrupt or forgo a therapy, based on an autonomous evaluation [ 27 ]. On the one hand, these forms of non-adherence are often viewed as necessary, since adherence is favorable only if the medication is beneficial. On the other hand, if such a high level of patient autonomy is not accompanied by an equally high level of health literacy, the patient might be inclined to non-adherence in a presumptuous manner putting his/her health into jeopardy [ 25 ]. Indeed, a recent review [ 28 ] investigating the consequences of increasing patient empowerment reported that a high level of patient empowerment had a controversial relationship with adherence. Some aspects of patient empowerment (such as information search and knowledge) promote adherence, while others (i.e. decision participation) reduce therapy adherence [ 28 ]. These challenges call for all concerned to review the empirical knowledge available on the relationship between empowerment and adherence.

A multidimensional conceptualization proposed originally in management literature [ 29 , 30 ], and adapted to the health context by Schulz and Nakamoto [ 31 ], perceives empowerment as a motivational construct, holding that patients participate as autonomous actors in health care decisions and consequentially take increased responsibility for such decisions [ 31 ]). This concept has four components: 1. Meaningfulness (refers to the value of activities), 2. Competence (belief in one’s own capabilities), 3. Impact (belief in making a difference), and 4. Self-determination (refers to the extent to which a choice is characterized by autonomous initiation). Based on this conceptualization, in the present review, patient empowerment is operationalized as patients’ perceptions of their own capacity for disease management and their beliefs about how much control they have over their own health outcomes. This definition leads to two main constructs constituting empowerment, which have been widely studied in medication adherence literature: self-efficacy and health locus of control.

Self-efficacy is strongly related to the Competence dimension of the empowerment concept. Self-efficacy draws on social-cognitive theory and can be defined as the individual’s belief in his/her own ability to implement a specific behavior or a set of behaviors [ 32 ]. It can refer to general [ 33 ] or context-specific perceptions of one´s own capacity to mobilize resources and motivation to deal with certain situations and challenges [ 33 ]. General self-efficacy refers to a stable sense of personal competence across situations [ 34 , 35 ]. It has been shown that a high sense of efficacy can be associated with better health outcomes, greater achievement and better social integration [ 32 , 36 ]. Moreover, self-efficacy was found to be the cornerstone of medication adherence in chronic mental illness [ 37 ] and the most prominent factor of adherence across conditions within the socio-cognitive and self-regulation theories [ 38 ].

Health locus of control (HLOC) considers whether an individual’s source of reinforcement for health-related behavior is internal or external. The former relates to a high, the latter to a low level of Impact and Self-determination. The operationalization of the construct has since gone through significant changes. A first approach by Rotter (1966) considered Internal (ILOC) and External locus of control (ELOC) as two endpoints of a one-dimensional continuum [ 39 ]. ILOC means that the individual’s sense of control over their health is directly related to their own actions, while ELOC refers to the perception that one’s health is determined by external factors. A later conceptualization, the Multidimensional Health Locus of Control (MHLOC), kept internality (Internal HLOC), but divided external locus of control (External HLOC) into specified sub-dimensions: Powerful Others, Doctor, Chance and God HLOC [ 40 , 41 ]. HLOC has been widely used as a predictor of health behavior. Generally, it is assumed that people with high Internal HLOC are more likely to behave in healthier ways than those who do not believe that they have control over their health. However, an extremely high level of Internal HLOC has been proposed to be problematic [ 42 ]. By contrast, someone with high scores on the Chance HLOC subscale, believing that it is fate or chance that determines his/her health status, is probably less likely to implement recommended health behavior. Powerful Others HLOC is generally not assumed to encourage health behavior, except if others are supportive of engaging in healthy behavior [ 43 – 45 ]. Wallston (2005) suggested incorporating other variables such as self-efficacy as potential moderators when investigating how HLOC influences health behavior [ 45 ]. This suggestion goes hand in hand with our empowerment concept as it incorporates self-efficacy and health locus of control.

The role of patient empowerment in influencing medication adherence is a cardinal question with major practical implications across all clinical and policy levels. Therefore, the present systematic review seeks to answer the question, whether high level of patient empowerment is associated with greater medication adherence. Thus, the goal is to assess the relevant empirical findings about the relationship between patient empowerment and medication adherence across medical conditions. Medication non-adherence was defined as the extent to which the patients do not agree with/follow the physician’s recommendations regarding taking the prescribed medication, measured by self-report, objective measures or mixed indicators. As empowerment is regarded as consisting of HLOC and self-efficacy, we will address their influence on medication adherence in two separate steps.

Materials and methods

Inclusion and exclusion criteria.

The studies had to meet the following criteria in order to be included in the present systematic review: (1) peer-reviewed articles, (2) written in English, (3) studies having observational or experimental design, (4) addressing the relationship between medication adherence and at least one aspect of empowerment, (5) empowerment should be considered either as an independent variable or as a mediator, (6) medication adherence had to be assessed as an outcome variable and (7) studies including an adult sample. We excluded papers which were not available in English, included a sample of youth, or focused on over the counter medications. Moreover, qualitative studies, commentaries, essays, study protocols, literature reviews, conceptual papers and conference abstracts were also excluded.

Search strategy

In order to select a proper search strategy, a set of keywords was identified based on a prior scoping search identifying the relevant academic jargon. Therefore, we initially searched several databases including PROSPERO, COCHRANE library, Medline and PsychInfo for review articles related to medication adherence and/or empowerment. Subsequently, a Thesaurus and a PubMesh search was conducted in order to complete the list. In the main search, key terms referring to empowerment and its related constructs were combined with either words related to medication adherence or misuse. In order to include as many variants of the key terms as possible, a wildcard search was used where this was deemed necessary. Keywords were connected via the following Boolean operators: ‘Empowerment’ AND ‘Medication’ AND (‘Adherence’ OR ‘Misuse’) (see: Table 1 ).

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https://doi.org/10.1371/journal.pone.0186458.t001

In order to identify relevant articles, two online databases were searched, one with a medical orientation (Medline) and the other with a focus on social sciences (PsychInfo). The search included the literature published since 1966 to May 2017 in Medline and the publications in the time period between 1967 to May 2017 in PsychInfo.

Data analysis and synthesis

The review was prepared in accordance with the PRISMA statement [ 46 ] ( S1 Table ). The original search was carried out by one of the authors (L.N.), and yielded 4903 hits, which were then screened on the basis of the titles and abstracts using three coders for their relevance, applying the above-mentioned inclusion criteria. The interrater agreement was adequate (Cohen’s kappa = 0.95) regarding which publications were deemed relevant and included for full text assessment. A 13-item checklist developed by Wallace et al. (2006) was applied to assess the quality of the included studies. The checklist contains specific questions in order to assess whether the authors provide a clearly defined research question and appropriately describe the theoretical background. Further questions probe the rigor of study design, data collection, data analysis and the solidness of the derived conclusions [ 47 ]. The scores ranged from 0 to 13. The interrater agreement regarding the quality of the papers was 79%. The interrater agreement was calculated based on 10% of the hits, which is the recommended ratio of articles to be coded by independent coders according to rule of thumb [ 48 ]. Relevant data, such as information regarding the sample, methodology, the included measurement tools and outcomes were extracted based on a previously developed coding scheme. In the case of the data extraction, the interrater agreement was 85.6%. The coders of the abstract screening, data extraction and quality assessment included one of the authors (L.N.) and research assistants with a health communication background. Meta-analysis was not considered to be appropriate as the included studies demonstrated large heterogeneity in terms of the conceptualization and operationalization of empowerment as well as medication adherence [ 49 ].

154 articles were deemed to be fit for inclusion based on the full text analysis. None of the studies were judged to have a quality so poor that they had to be excluded. The average quality score was 11.93 out of 13 (SD = 1.6). If the articles reported more than one outcome about the relationship between the empowerment-related constructs and adherence, each result was included separately in the review. Fig 1 provides an overview of the selection process.

https://doi.org/10.1371/journal.pone.0186458.g001

Overview of the results

The vast majority of the studies were conducted in North America (n = 107). Other studies took place in Europe (n = 25), Asia (n = 11), Eurasia (n = 1), Australia) (n = 5), South America (n = 4) and Africa (n = 1).

The studies involved patients diagnosed with various disease groups: HIV/AIDS (n = 52), heart and vascular disorders (n = 18), respiratory diseases (n = 15), renal (n = 12) and of the endocrine system (n = 11). Some studies involved participants suffering from diseases of the brain and nervous system (n = 8), musculoskeletal (n = 6) and digestive system (n = 4), cancer (n = 4) and other conditions (n = 17). A small number of studies concerned patients diagnosed with psychological conditions (n = 7). S2 Table provides an overview of the sample characteristics.

We identified numerous scales measuring a given dimension of empowerment based on our operational definition. As far as locus of control is concerned, most of the studies applied either a one dimensional (RIELCS) [ 39 ] or a multidimensional measurement (MHLOC Scale) [ 40 ] of the concept. Our search revealed studies using several types of self-efficacy beliefs: medication adherence, disease-management, general, coping self-efficacy, etc. Only a minority of the included articles focused on other empowerment-related constructs, such as competence or self-regulation.

Concerning the operationalization of medication adherence, we can distinguish three types: objective measures (using pill count, patients’ medical outcomes or pharmacy records as a proxy of adherence), subjective measures i.e. where patients provided self-reported questionnaires or structured interviews, and lastly mixed measures which apply subjective and objective adherence measures simultaneously. As there is no agreement on a single method which performs well across all criteria [ 50 ], we decided to include all of the studies regardless of the adherence measure applied. See S3 Table for an overview of the included studies and S4 Table for their quality assessment score.

The relationship between self-efficacy and medication adherence

The identified studies addressing the relationship between adherence and self-efficacy focused mainly on medication adherence, disease-management and general self-efficacy (See: Table 2 ).

https://doi.org/10.1371/journal.pone.0186458.t002

Medication adherence self-efficacy refers to a belief in the patient’s capacity to follow a prescribed medical regimen in challenging situations [ 51 ]. Most of the articles (59 out of 66 studies) found a positive link between medication adherence self-efficacy and adherence [ 52 – 100 ], and among these 9 studies also reported that self-efficacy had a mediator role [ 101 – 110 ]. Only three studies considered adherence-self-efficacy solely as a mediator [ 111 – 113 ] and four reported no relationship [ 114 – 117 ].

Disease management self-efficacy refers to the patients’ beliefs in their capacity to manage disease in general [118,119) or condition-specific self-management behavior [ 120 , 121 ]. The studies investigating the relationship between disease management self-efficacy and medication adherence applied specific scales developed to measure efficacy beliefs about implementing tasks related to managing a given condition. The majority of the studies (16 out of 20) reported a positive association [ 118 , 122 – 136 ], while only 3 reported no relationship [ 119 , 137 , 138 ] and 1 suggested mixed results [ 139 ].

General self-efficacy refers to one’s perceived competence across a wide array of life domains (36). General self-efficacy had, in most of the cases (4 studies out of 6), a positive association with adherence [ 140 – 143 ], while 2 studies did not find any relationship [ 144 , 145 ]. Some studies simultaneously applied general as well as disease or drug specific self-efficacy measures and investigated which one was more likely to predict self-reported adherence to medication. Two of the studies reported that disease specific self-efficacy was a more important predictor of adherence than generic self-efficacy [ 142 , 146 ]; the third study reported no relationship [ 145 ].

Studies focusing on other domain-specific self-efficacy measures reported a positive link between adherence and self-efficacy in patient-physician interactions [ 147 , 148 ], coping self-efficacy [ 149 ], bi-cultural self-efficacy [ 150 ], self-efficacy for managing negative mood, adhering to medication, symptoms and fatigue management, communicating with health care providers and getting support from others [ 151 ]. Self-efficacy when disclosing drug use to providers and for safer drug use were not as effective predictors of self-reported adherence as adherence self-efficacy [ 52 ]. Self-efficacy scores for physical function were seen to have a negative link to adherence[ 145 ].

Concerning the different adherence measures , a positive association between self-efficacy and adherence was reported in a greater proportion in studies using subjective (87%) or mixed measures (79%), compared to studies applying objective adherence measures (66.6%).

The relationship between HLOC and medication adherence

HLOC was predominantly measured using two instruments: the one-dimensional RIELCS measure [ 39 ] and the MHLOC [ 41 , 152 , 153 ], which is a multidimensional instrument.

First, we considered the relationship between the RIELCS and medication adherence. Of the 9 studies, in four cases (45%) ILOC was found to be more beneficial for medication adherence than ELOC [ 154 – 157 ]. By contrast, two studies (22%) found that ELOC was related to better medication adherence than ILOC [ 158 , 159 ]. Finally, in three (33%) studies, ILOC and ELOC orientation did not distinguish between compliant and non-compliant patients [ 160 – 162 ].

The results which relate to MHLOC dramatically differ in terms of its sub-dimensions: Internal HLOC and External HLOC. Many studies (10 out of 26 studies) reported a positive association between Internal HLOC and adherence [ 81 , 101 , 163 – 170 ]; only a single study found a negative relationship [ 171 ]. Another study reported that a high level of Internal HLOC promotes critical adherence or non-adherence, i.e. how patients decided to follow or forgo a therapy based on autonomous evaluation [ 27 ]. There was a high number of null findings, i.e. 15 studies reported no relationship between IHLOC and adherence [ 160 , 172 – 185 ].

Examining the MHLOC External sub-dimensions respectively (i.e. Chance, God, Powerful others and Doctor HLOC) allowed us to explore and compare their variable associations with adherence. A large enough proportion of the studies (5 out of 18) found a negative link between Chance HLOC and adherence [ 170 , 183 , 186 – 188 ], while only one study reported a positive relationship (189). Twelve studies reported null findings [ 172 , 174 – 177 , 179 , 180 , 182 , 183 , 185 , 190 , 191 ]. God HLOC had a negative association with medication adherence [ 172 ]. In the case of the Powerful others HLOC , the findings are ambiguous, as the number of studies reporting a negative relationship with adherence [ 169 , 181 , 183 , 192 , 193 ] is only slightly higher (5 studies) than the studies which found a positive link (4 studies) [ 171 , 189 , 194 , 195 ]. In addition, 11 studies reported no relationship [ 172 , 174 – 177 , 180 , 182 – 184 , 191 , 196 ]. Doctor HLOC, by contrast, seems to promote adherence, as studies unequivocally found that people characterized with high Doctor HLOC tend to comply better with their given medical regimen (3 studies) [ 169 , 172 , 194 ]. However, in this case 3 studies also found no association with adherence [ 174 , 183 , 197 ] (see: Table 3 ).

https://doi.org/10.1371/journal.pone.0186458.t003

The studies applying subjective adherence measures reported more association either in a positive or negative direction (58.5%) between the HLOC dimensions and adherence compared to the studies applying mixed (14.3%) or objective (40%) adherence measures.

HLOC can also be conceived as a mediator of the relationship between adherence and various other predictors, such as perceived necessity of the treatment [ 198 ], social support [ 199 ], self-efficacy and outcome expectancy [ 200 ], competence [ 175 , 201 ] and hostility [ 202 ]. Alternatively, MHLOC can also explain to what degree any identified medication non-adherence is deliberate [ 203 ].

Health condition-specific patterns

Regarding the role of self-efficacy in predicting adherence across health conditions, in patients diagnosed with digestive system or musculoskeletal diseases, multiple sclerosis, epilepsy, headache and psychiatric conditions, all studies reported a positive association between adherence and self-efficacy. In HIV, respiratory diseases, cancer, heart and vascular disorders, diabetes and renal diseases, the majority of the studies reported a positive association between adherence and self-efficacy, but there were some null findings, too.

Concerning how HLOC affects medication adherence, the studies involving patients diagnosed with HIV, cancer, diabetes and digestive system diseases reported that Internal HLOC fosters, while External HLOC dimensions appear to hinder adherence. In other conditions, the relationship between adherence and HLOC was more ambigous, i.e. in heart and vascular disorders and mental conditions. Besides Internal HLOC, high levels of Doctor HLOC emerged as a significant predictor of greater adherence in two conditions: respiratory diseases [ 172 , 194 ] and renal disease [ 169 , 201 ].

Other important predictors of adherence were the patients’ autonomy preference regarding respiratory diseases [ 204 ], perceived autonomy among renal transplant patients [ 205 ], self-regulation in heart failure patients [ 206 ] and perceived competence [ 207 ], autonomous motivation [ 180 , 207 ] and treatment-related empowerment [ 208 ] in HIV. In patients diagnosed with diabetes, perceived competence [ 209 ], diabetes empowerment [ 22 ] and Diabetes HLOC [ 210 ] were predictors of adherence.

In the present study, the relationship between patient empowerment and medication adherence was reviewed, with special focus on the two constructs deemed to be the central facets of empowerment: HLOC and self-efficacy.

An overview of the relationship between self-efficacy and adherence

Our results confirm that self-efficacy is a strong predictor of medication adherence. Positive association with adherence holds for of all types of self-efficacy: general, medication adherence, disease management and other domain specific measures. Our findings confirm and expand the findings of McCann et al.’s review [ 37 ], which highlighted the importance of self-efficacy in medication adherence in chronic mental illness, as we found that self-efficacy was an important predictor of adherence both in the case of mental and somatic diseases. On the one hand, the effect of self-efficacy in fostering adherence is so robust that it holds regardless of the type of self-efficacy applied and across all medical conditions. On the other hand, specific measures of both medication adherence self-efficacy and disease management self-efficacy show a positive association with adherence compared to general self-efficacy more consistently. Thus, future research might apply context-specific measures for predicting medication adherence, considering that the most consistent adherence self-efficacy seems to be associated with adherence. However, this strong link might arise from the operational overlap between these constructs, as medication adherence questionnaires sometimes measure barriers to medication adherence, such as certain aspects of adherence self-efficacy [ 50 ].

The relationship between HLOC and adherence

The findings show that Internal HLOC predominantly has a positive link with medication adherence, while External HLOC dimensions have variable associations.

Studies applying the one-dimensional RIELCS [ 39 ] showed a trend suggesting that ILOC is more favorable for adherence than ELOC, but the difference was small. The characteristics of this measure might account for the contradicting findings, as the RIELCS does not distinguish the dimensions of ELOC, and this might lead to individual differences in the interpretation. Alternatively, treating ILOC and ELOC as opposite ends of one continuum may not capture its effect on adherence. Therefore, the MHLOC Scale [ 40 ] seems to be a more appropriate tool when examining the relationship between HLOC and adherence.

As far as MHLOC is concerned, a clear majority of the studies reported a positive relationship between Internal HLOC and adherence, which confirms that patients’ beliefs of being in control of their own health (a facet of high empowerment) is associated with greater adherence. However, the relationship between External HLOC and adherence is variable, as the sub-facets of HLOC show variable relationships with adherence. In accordance with our assumptions, Chance HLOC, which can signal low empowerment, showed a negative association with medication adherence. God HLOC also had a negative link to adherence, but only one study looked into this relationship [ 172 ]. The number of studies reporting a positive and a negative association between Powerful others HLOC and adherence were almost equal. The effect of Powerful others HLOC on adherence might depend on whether these others support or discourage the patients to adhere [ 43 – 45 ]. Indeed, Doctor HLOC seems to be the most beneficial element of External HLOC promoting adherence, especially when it was concurrent with high Internal HLOC [ 169 ]. The variable associations of different External HLOC dimensions with medication adherence indicate that the perceived control dimension of empowerment is far from homogenous. In particular, Doctor HLOC fosters adherence, highlighting how, in a medication management context, not only the belief in one’s own ability and control are beneficial, but also acknowledging the medical expertise and the doctor’s influence on one’s health can be auspicious.

Therefore, to fully understand the relationship between HLOC beliefs and adherence, examining solely the main effects of the sub-dimensions may not be sufficient, but looking into the interaction effects between Internal HLOC and External HLOC as well as External HLOC subdimensions on medical regimen adherence might be more fruitful [ 167 , 211 ]. Some studies recognized the importance of the interactional component of patient empowerment, therefore they addressed how the attitudinal symmetry in the doctor-patient dyads regarding patients’ control over health outcomes influenced medication adherence [ 212 , 213 ]. Indeed, patients who held highly similar beliefs to their physicians regarding a patients’ degree of control over their own health, adhered more to their medication regimen than patients who believed more strongly in their own personal control over their health than their doctor did [ 213 ].

More than half of the studies report no link between HLOC and medication adherence. Wallston suggested that HLOC does not operate alone to determine a behavior [ 44 ], and that other factors such as self-efficacy should be incorporated as a moderator [ 45 ]. This idea is compatible with the empowerment concept, which emphasizes that these constructs can jointly explain health behavior such as adherence. The findings seem robust and applicable across different cultures and countries. However, the North American sample may be considered overly representative in this review (close to 70%); therefore, an international or cultural comparison may not be well-grounded or representative here. Moreover, the majority of the sample being North American may have impacted findings, since the health care system in the United States is characterized by an advanced state of technology, private markets and pluralism [ 214 ]. Patients in the US are expected to decide about purchasing a health insurance plan choosing from various for-profit commercial insurance companies or from non-profit insurers [ 214 ] based on several factors (e.g. premium, deductible and out-of-pocket costs), which might foster patient empowerment compared to countries with a single nationwide system of health insurance.

‘Joint empowerment’ as a facilitator of adherence: Theoretical, operational and policy implications

The review suggests that a shift might be necessary in the conceptual as well as the operational ways of considering patient empowerment. The current literature offers two seemingly opposite approaches: conceiving empowerment as a relational [ 7 ] versus an intrapersonal concept [ 6 ]. Our findings suggest that in the medication adherence context the individual and relational aspects of empowerment should be viewed as the two sides of the same coin. We argue that patients need a high level of self-efficacy and internal health control beliefs, but they also have to be capable of sharing the control over their disease management with the physician. If we conceptualize empowerment in the above described manner, that would require further research to capture the relational empowerment as a dynamic feature of the doctor-patient relationship unfolding during the medical encounter. On the individual level, that would also require a shift from understanding empowerment as patient autonomy to a framework which would consider it as the patients’ perceived capability to cooperate effectively with the physician and sharing control with him/her. More research would be necessary to discover the right amount of control assigned to the patient and to the physician in the different contexts, i.e. in different conditions or stages of the illness, etc.

The theoretical shift suggested above would call for an operational revolution of empowerment, i.e. developing new measures about the patients’ beliefs about being able to collaborate and discuss issues with the physician, and asking for advice when necessary. As this definition of empowerment unavoidably presupposes the need of the patients’ ability to judge when they can act autonomously and when they would be better off asking for guidance from the physician, it raises the question of whether such a high level of empowerment is beneficial without the necessary health literacy skills [ 215 ].

To sum up, patient empowerment can promote medication adherence, but it requires a co-constructed sense of control in the doctor-patient dyad. This has implications for the clinical practice and policy making, i.e.instead of forcing or reinforcing the vision of an overly empowered patient (which can be burdensome for some patients [ 216 , 217 ] and demanding for many health care providers), an equilibrium should be established, in which both parties are interchangeably in control. This requires the health care providers facilitating patient empowerment (internal HLOC and self-efficacy), but also pointing out the importance of relying on the medical expertise of the physicians (Doctor HLOC) while choosing together the best possible treatment. As finding this equilibrium might be challenging, it requires building a strong collaborative doctor-patient relationship and continuous negotiation during the medical encounter. Moreover, patients’ level of health literacy should be taken into account and facilitated, as a recent paper showed that empowerment has a stronger link to better health status among the adequately health literate patients [ 218 ]. Most importantly, this approach has the capacity to reconcile the notion of an empowered patient and the shared decision making framework [ 219 ], without raising the dilemma of power or imbalanced control in the doctor-patient relationship.

Limitations

This systematic review is not without limitations. First, our approach might not have captured other conceptualizations of empowerment existing in relevant literature. Second, no quantitative value can be presented to demonstrate the relationship between empowerment and medication adherence, as neither of the concepts is currently operationalized consistently across studies, which would allow us to conduct a meta-analysis. Thirdly, the medication adherence measures only rarely distinguish between the intentional and unintentional dimensions of non-adherence, possibly leading to a cancelling out of the relationship between empowerment and intentional non-adherence, with the inclusion of unintentional non-adherence. Studies using objective measures more often reported null findings compared to studies applying subjective adherence measures, introducing potential measurement bias to the analysis. Fourthly, the vast majority of the included studies had a cross-sectional correlational design, therefore we cannot draw any causal inference regarding the relationship between empowerment and adherence from them. Moreover, we included observational and interventional studies together in the systematic review, which introduces substantial heterogeneity. However, given the importance of findings emerging from interventional studies for the practical implications and insights gained in causal relationships, including intervention studies might merit particular prominence. Furthermore, we may unavoidably have missed unpublished studies or those that were not captured by the search strategy, potentially leading to publication bias. However, we put a great effort into avoiding publication bias with such preventative measures as searching without limiting by outcome [ 220 ]. The study samples were heterogeneous regarding characteristics such as medical condition, age and education, which may have affected the results. The applied quality assessment checklist did not recommend a cut-off score for low quality, thus all studies with different quality scores were included in the final analysis. Lastly, we included only papers published in the English language, and this might have resulted in missing some relevant work written in other languages.

Conclusions

Our findings indicate that a balanced view would be the most beneficial for facilitating adherence, one alongside which the patients’ beliefs in their own capacity and control over their health is simultaneously present with their acknowledgment of the physician’s role in their disease management. The integration of the relational and individual nature of the construct to a so-called ‘joint empowerment’ approach enables us to address the question of control as a versatile component in a doctor-patient dyad.

Supporting information

S1 table. prisma checklist..

https://doi.org/10.1371/journal.pone.0186458.s001

S2 Table. Sample characteristics.

https://doi.org/10.1371/journal.pone.0186458.s002

S3 Table. Overview of the included studies.

https://doi.org/10.1371/journal.pone.0186458.s003

S4 Table. Quality assessment.

https://doi.org/10.1371/journal.pone.0186458.s004

Acknowledgments

The authors wish to thank colleagues and research assistants for their help with the data extraction and quality assessment of the various papers.

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Factors contributing to medication adherence in patients with a chronic condition: a scoping review of qualitative research.

1. Introduction

2. materials and methods, 2.1. search strategy, 2.2. inclusion and exclusion criteria, 2.3. study selection, 2.4. data extraction, 3.1. barriers to medication adherence, 3.1.1. patient-specific barriers, 3.1.2. illness-specific barriers, 3.1.3. medication-specific barriers, 3.1.4. healthcare and system-specific barriers, 3.1.5. social and culture-specific barriers, 3.1.6. logistical and financial barriers, 3.2. facilitators to medication adherence, 3.2.1. informational, motivational and behavioural factors, 3.2.2. healthcare and system-specific facilitators, 3.2.3. logistical and financial factors, 3.3. summary of findings, 4. discussion, 4.1. main findings, 4.2. strengths and limitations, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Kvarnström, K.; Westerholm, A.; Airaksinen, M.; Liira, H. Factors Contributing to Medication Adherence in Patients with a Chronic Condition: A Scoping Review of Qualitative Research. Pharmaceutics 2021 , 13 , 1100. https://doi.org/10.3390/pharmaceutics13071100

Kvarnström K, Westerholm A, Airaksinen M, Liira H. Factors Contributing to Medication Adherence in Patients with a Chronic Condition: A Scoping Review of Qualitative Research. Pharmaceutics . 2021; 13(7):1100. https://doi.org/10.3390/pharmaceutics13071100

Kvarnström, Kirsi, Aleksi Westerholm, Marja Airaksinen, and Helena Liira. 2021. "Factors Contributing to Medication Adherence in Patients with a Chronic Condition: A Scoping Review of Qualitative Research" Pharmaceutics 13, no. 7: 1100. https://doi.org/10.3390/pharmaceutics13071100

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Food Security to Medication Adherence—Connecting Needs

• 1 Johns Hopkins School of Nursing, Baltimore, Maryland
• 2 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
• 3 College of Health Solutions, Arizona State University, Phoenix
• Original Investigation SNAP and Adherence to Antihypertensive Medications Md. Mohaimenul Islam, PhD; Ximena Oyarzun-Gonzalez, PhD; Seuli Bose-Brill, MD; Macarius M. Donneyong, PhD, MPH JAMA Network Open

Almost 90 years after the first food stamp program in the United States in 1939, there continues to be substantial food and nutrition insecurity, despite important gains and progress. In this age of perceived plenty, basic healthy sustenance eludes too many vulnerable hands. Thus, the increasing recognition of the tight interconnections binding food security, treatment access, and health equity together through threads of stability or precarity has the potential to play a pivotal role in improving cardiovascular outcomes. However, it is critical to ensure that programs that target food insecurity also incorporate interventions to improve nutrition security.

The Supplemental Nutrition Assistance Program (SNAP), signed into law in 1964 as the Food Stamp Act, primarily aims to address food insecurity. After unemployment insurance, SNAP is the most responsive federal program that provides additional assistance during and after economic crises. In 2021, 41 million persons in the US received SNAP. Among them, approximately 69% of SNAP participants have hypertension, and only 43% of SNAP participants are adherent to their antihypertensive medications. 1 Whether SNAP can help improve hypertension medication adherence is an important question. Whether SNAP may be optimized to address adherence is an issue with significant public health implications that researchers and policymakers can prioritize.

Adherence to hypertension medication is an important determinant of cardiovascular health. Poor adherence to cardiovascular medications increases the risk of cardiovascular events by 20% to 35%. 2 Of 119.9 million US adults with hypertension, only half (51%) of the 34 million adults who are recommended to use medications do so consistently. A related public health concern is food insecurity, which disproportionately impacts households with annual income below the poverty line compared with those at or above 185% of the poverty line (36.7% vs 6.8%). 3 As with several determinants of health, there is a critical intersection between food security and medication adherence. For instance, people experiencing social marginalization are more likely to be subject to a “treat or eat” trade-off between prescription medication and household food. 4 Individuals facing food insecurity often struggle to adhere to medical treatments yet shoulder undue blame for circumstances outside their control. Rather than judging individuals, addressing systemic barriers that limit basic health care access and nutrition could alleviate disproportionate disease burdens, especially among underserved populations.

This study by Islam and colleagues 5 contributes to this body of work by highlighting the potential role of SNAP in improving medication adherence among SNAP participants. The study by Islam et al 5 implies that SNAP could potentially mitigate the risk of nonadherence to antihypertensive medications due to food insecurity. Their study reported that persons who received SNAP, compared with nonrecipients, had a lower rate of nonadherence to antihypertensive medications among the food insecure subgroup but not among the food secure subgroup nor the overall population. 5 Insight from the work by Islam et al 5 may inform more extensive implementation and evaluation of interventions that leverage SNAP participation to address food insecurity and medication adherence through clinical-community partnerships. Research that systematically identifies barriers and facilitators of such programs has the potential to provide evidence-based guidelines for stakeholders interested in leveraging SNAP to address nonadherence to hypertension therapy and chronic disease management. Additionally, since sustained SNAP participation appears to be crucial to optimizing the impact of SNAP on health, interventions that seek to ensure SNAP enrollment should also target reducing SNAP churning, defined as disenrollment and enrollment into SNAP within 4 months. 6 Team-based integration of community health workers could allow for continuity of care that will enhance the ability to provide navigation assistance that ensures continuous SNAP participation. There is also a place for advocacy that targets increased adoption of policies that enhance SNAP enrollment and reduce recertification burden, such as reduced recertification frequency and availability of online recertification. 7

Despite these possibilities, there are important obstacles to be considered. Programs that promote food security, like SNAP, are underused, with the most significant barrier to SNAP being noted as the application process. 8 This significantly contributes to the so-called SNAP gap , ie, the gap between individuals who are eligible to enroll and those who are actively enrolled in SNAP. Efforts to improve SNAP participation must be multilevel and move beyond the individual. It is also critical to address other access barriers, such as lack of transportation, through initiatives like mobile food markets . Universal food insecurity screening and streamlining SNAP enrollment within health care and social welfare systems could help boost SNAP participation and decrease food insecurity. Food-is-medicine interventions, which include produce prescriptions, medically tailored groceries, and medically tailored meals, also offer opportunities due to their characteristic multilevel approaches to bridging the divide between health care and nutrition. However, these programs are often centered within the health care system and systematically exclude individuals with limited health care access. This limitation could be addressed by improving the health care navigation system. Community health workers may be vital to improving navigation by connecting underserved populations to food-is-medicine programs while targeting medication adherence through community outreach and health promotion efforts. Integration of this workforce is feasible, since health system navigation can also be extended toward efforts to address food insecurity screening through SNAP application assistance, in addition to connecting to community members who are less likely to engage with health care through traditional methods. Nutrition security programs and interventions that respect individual food preferences and are culturally tailored are needed. The proliferation of digital health tools as a result of the COVID-19 pandemic also offers a unique opportunity for innovative strategies such as virtual food markets with deliveries. Extending efforts to promote access to programs to improve food insecurity will expand public health efforts to improve overall health.

Islam et al 5 present interesting results; however, several questions remain unanswered. Estimates could have been strengthened if comparisons were made between SNAP participants and SNAP-eligible nonparticipants, using the available data sets. The analyses could have been further strengthened if SNAP disbursement was explored monthly rather than quarterly. 8 Health care access is an intractable problem and could be a major confounder in this study, as health care access may impact both SNAP access and hypertension medication adherence. Health care facilities, as early as 2010, have been assisting patients in obtaining resources to meet their food insecurity needs, like assisting with federal benefits applications, including SNAP applications. 9 Assessing health care access as a confounder may contribute to our understanding of the association of SNAP participation with hypertension medication adherence. Given that the Medical Expenditure Panel Survey data analyzed in this study contain measures for health care access, there may have been a missed opportunity to explore the role of limited care access in the study findings in how receipt of SNAP could improve hypertension adherence. More rigorous research is also needed to understand the pathways through which SNAP participation influences medication adherence and any variation across subpopulations. Research in this area should seek to reduce bias by accounting for the issue of self-selection bias, whereby SNAP participants differ on observable characteristics and potentially unobservable characteristics. 6

Access to food, nutrition security, and medication adherence are interdependent factors integral to a healthy population and to achieving equitable health outcomes. Without reliable nourishment, related pillars of well-being, like medication adherence, quality medical care, and better health outcomes, all wobble under the strain of food insecurity. As highlighted by the research of Islam et al, 5 to improve cardiovascular outcomes and overall health outcomes and truly advance health equity, prioritizing universal food and nutrition security is critical. With compassion and unified voices, public health policies that leave no child, family, or community without adequate resources for realizing their human potential can be championed. Although the road stretches long ahead, each small growth in community nourishment and care pulls us step-by-step toward a society defined not by deprivation, but rather one where all can thrive with dignity.

Published: February 23, 2024. doi:10.1001/jamanetworkopen.2023.56570

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Ogungbe O et al. JAMA Network Open .

Corresponding Author: Oluwabunmi Ogungbe, PhD, MPH, RN, Johns Hopkins University Bloomberg School of Public Health, 525 N Wolfe St, Baltimore, MD 21205 ( [email protected] ).

Conflict of Interest Disclosures: None reported.

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Ogungbe O , Ellis A , Ojinnaka CO. Food Security to Medication Adherence—Connecting Needs. JAMA Netw Open. 2024;7(2):e2356570. doi:10.1001/jamanetworkopen.2023.56570

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Medication adherence for people with acquired communication disorders: A systematic review

Affiliations.

• 1 Department of Speech and Hearing Sciences, University College Cork, Cork, Ireland.
• 2 School of Pharmacy, University College Cork, Cork, Ireland.
• 3 School of Pharmacy and Biomolecular Science, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
• PMID: 39252187
• DOI: 10.1111/bcp.16226

Conditions such as stroke, dementia and neurodegeneration are major contributors to the incidence of acquired communication disorders in Europe. Pharmacological interventions play a central role in the management and treatment of these conditions, though many patients with an acquired communication disorder may be at a higher risk of medication non-adherence than their peers. The objectives of the current review were to identify, in the context of people with acquired communication disorders: factors that influence medication adherence; current interventions targeting medication adherence; and current measures of medication adherence. This study was conducted and reported in accordance with both PRISMA and SWiM guidelines. Two authors independently screened the results of a literature search, assessed risk of bias and extracted relevant data. Eight studies were identified for inclusion. The results of this review indicate that patient-related factors are most indicative of medication non-adherence in a population with acquired communication disorders, followed by socioeconomic factors and medication-related factors. Despite the recognized importance of medication adherence, no gold standard of assessment or intervention currently exists for this population. Half of the included studies replaced patients with communication difficulties with caregiver proxies, thus reducing opportunities for patients to have agency over their own healthcare. The term "acquired communication disorders" encompasses a range of conditions with diverse aetiologies, presentations and needs, and future research should be tailored to specific patient groups most at risk of medication non-adherence, namely those with aphasia and cognitive-communication impairments. Patients should be empowered to participate in future research to ensure the literature accurately represents their lived experience.

Keywords: acquired communication disorders; clinical pharmacy; medication adherence; speech and language therapy; systematic review.

© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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• Aldridge D, Cahill L, Theodoros D. Assessment of communication competence in acquired communication disorders: a systematic scoping review. Int J Speech‐Lang Pathol. 2022;25(2):1‐11. doi:10.1080/17549507.2022.2055142
• Papathanasiou I, Coppens P. Aphasia and related neurogenic communication disorders. 2nd ed. Jones & Bartlett Learning; 2017.
• Brookshire RH, Mcneil MR. Introduction to neurogenic communication disorders. 8th ed. Elsevier; 2015.
• Mitchell C, Gittins M, Tyson S, et al. Prevalence of aphasia and dysarthria among inpatient stroke survivors: describing the population, therapy provision and outcomes on discharge. Aphasiology. 2020;35(7):1‐11. doi:10.1080/02687038.2020.1759772
• Pedersen PM, Jørgensen HS, Kammersgaard LP, Nakayama H, Raaschou HO, Olsen TS. Manual and oral apraxia in acute stroke, frequency and influence on functional outcome. Am J Phys Med Rehab. 2001;80(9):685‐692. doi:10.1097/00002060‐200109000‐00008

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Association of adherence to the EAT-Lancet diet with risk of dementia according to social economic status: a prospective cohort in UK Biobank

• ORIGINAL ARTICLE
• Published: 12 September 2024

Cite this article

• Wanying Zhao 1   na1 ,
• Qian Chen 2   na1 ,
• Qi Zhang 1 ,
• Siqi Li 1 ,
• Jiaqi Zhao 1 ,
• Wanlan Chen 1 ,
• Jialu Yang 1 ,
• Min Xia 1 &
• Yan Liu 1  

The EAT-Lancet Commission has proposed a reference diet aiming to promote human health and environmental sustainability. Socioeconomic disadvantage and poor diet are well-known risk factors for dementia; however, whether the effect of this reference diet on dementia varies by socioeconomic status has not been investigated. The dietary habits of 190,893 participants from UK-Biobank were assessed; the association of EAT-Lancet diet with incident dementia across socioeconomic status was determined by Cox models. One thousand seven hundred twenty-eight dementia cases were identified during a median of 12.24 years follow-up. An inverse association between adherence to EAT-Lancet diet and all-cause dementia (high vs. low; hazard ratio [HR], 95% confidence interval [CI]: 0.82, 0.72–0.94) or late-onset dementia (high vs. low; HR, 95% CI: 0.78, 0.68–0.91) was observed only in individuals with high socioeconomic status. On the contrary, no protective effects of EAT-Lancet diet on early-onset dementia were observed, regardless of the socioeconomic status. Our findings indicated that adherence to an environment-friendly diet helps attenuate risk of dementia only in individuals with high socioeconomic level.

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Data Availability

The data supporting this study were obtained from the UK Biobank ( https://www.ukbiobank.ac.uk/ ) under a data access agreement.

Abbreviations

World Health Organization

Mediterranean-DASH diet intervention for neurodegenerative delay

• Socioeconomic status

Body mass index

Total cholesterol

High-density lipoprotein-cholesterol

Low-density lipoprotein-cholesterol

International Classification of Diseases

Standard deviations

Multiple Imputation by Chained Equation

Hazard ratio

Confidence interval

Restricted cubic spline curve

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This study was supported by the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22hytd03), and the Guangzhou Science and Technology Plan Project (No. 202201011146).

Fundamental Research Funds for the Central Universities,22hytd03,Yan Liu ,Guangzhou Science and Technology Plan Project,No. 202201011146,Qian Chen

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Wanying Zhao and Qian Chen contributed equally as first authors.

Authors and Affiliations

Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China

Wanying Zhao, Qi Zhang, Siqi Li, Jiaqi Zhao, Wanlan Chen, Jialu Yang, Min Xia & Yan Liu

Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China

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W.Z. and Q.C. designed the research; Q.C., Y.L., and J.Y. acquired the data; W.Z., Q.C., Q.Z., and S.L. performed the statistical analysis; W.Z., Q.C., J.Z., W.C., and J.Y. drafted the manuscript; Y.L. and M.X. made critical revision of the manuscript for key intellectual content. All authors read and approved the final manuscript.

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Correspondence to Yan Liu .

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Zhao, W., Chen, Q., Zhang, Q. et al. Association of adherence to the EAT-Lancet diet with risk of dementia according to social economic status: a prospective cohort in UK Biobank. GeroScience (2024). https://doi.org/10.1007/s11357-024-01333-7

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DOI : https://doi.org/10.1007/s11357-024-01333-7

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Medication Adherence: WHO Cares?

Associated data.

The treatment of chronic illnesses commonly includes the long-term use of pharmacotherapy. Although these medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. Factors contributing to poor medication adherence are myriad and include those that are related to patients (eg, suboptimal health literacy and lack of involvement in the treatment decision–making process), those that are related to physicians (eg, prescription of complex drug regimens, communication barriers, ineffective communication of information about adverse effects, and provision of care by multiple physicians), and those that are related to health care systems (eg, office visit time limitations, limited access to care, and lack of health information technology). Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifactorial. To assess general aspects of medication adherence using cardiovascular disease as an example, a MEDLINE-based literature search (January 1, 1990, through March 31, 2010) was conducted using the following search terms: cardiovascular disease, health literacy, medication adherence, and pharmacotherapy . Manual sorting of the 405 retrieved articles to exclude those that did not address cardiovascular disease, medication adherence, or health literacy in the abstract yielded 127 articles for review. Additional references were obtained from citations within the retrieved articles. This review surveys the findings of the identified articles and presents various strategies and resources for improving medication adherence.

BP = blood pressure; CVD = cardiovascular disease; MI = myocardial infarction; MTMS = medication therapy management services; WHO = World Health Organization

Keep a watch…on the faults of the patients, which often make them lie about the taking of things prescribed. For through not taking disagreeable drinks, purgative or other, they sometimes die. Hippocrates, Decorum

In its 2003 report on medication adherence, 1 the World Health Organization (WHO) quoted the statement by Haynes et al that “increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.” Among patients with chronic illness, approximately 50% do not take medications as prescribed. 1 , 2 This poor adherence to medication leads to increased morbidity and death and is estimated to incur costs of approximately $100 billion per year. 3 Thus, Hippocrates' exhortation to the physician to “not only be prepared to do what is right himself, but also to make the patient…cooperate” 4 has consistently failed for more than 2000 years. Today's ever more complicated medical regimens make it even less likely that physicians will be able to compel compliance and more important that they partner with patients in doing what is right together.

This review will discuss general aspects of medication adherence, using cardiovascular disease (CVD) as an example, and provide the physician with various practical strategies and resources for improving medication adherence among their patients.

We conducted a MEDLINE database literature search limited to English- and non–English-language articles published between January 1, 1990, and March 31, 2010, using the following search terms: cardiovascular disease, health literacy, medication adherence , and pharmacotherapy . Of the 405 articles retrieved, those that did not address CVD, medication adherence, or health literacy in the abstract were excluded, leaving 127 for inclusion in the review. Additional references were obtained from citations within the retrieved articles.

For editorial comment, see page 268

GENERAL ASPECTS OF MEDICATION ADHERENCE

Medication-taking behavior is extremely complex and individual, requiring numerous multifactorial strategies to improve adherence. An enormous amount of research has resulted in the development of medications with proven efficacy and positive benefit-to-risk profiles. This millennium has seen a new and greater focus on outcomes. However, we seem to have forgotten that between the former and the latter lies medication adherence:

The WHO defines adherence to long-term therapy as “the extent to which a person's behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds

Article Highlights

• Approximately 50% of patients do not take medications as prescribed
• Medication adherence is not exclusively the responsibility of the patient
• Increasing adherence may have a greater effect on health than improvements in specific medical therapy
• Medication-taking behavior is complex and involves patient, physician, and process components
• Identification of nonadherence is challenging and requires specific interviewing skills
• Solutions include encouraging a “blame-free” environment, opting for less frequent dosing, improving patient education, assessing health literacy, and paying attention to rational nonadherence
• Many helpful Web-based resources are available

with agreed recommendations from a health care provider.” 1 Often, the terms adherence and compliance are used interchangeably. However, their connotations are somewhat different: adherence presumes the patient's agreement with the recommendations, whereas compliance implies patient passivity. As described by Steiner and Earnest, 5 both terms are problematic in describing medication-taking behavior because they “exaggerate the physician's control over the process of taking medications.” The complex issues surrounding the taking of medication for chronic disease cannot easily be distilled into one word. Recognition of this complexity will help avoid assigning blame exclusively to the patient and assist in identifying effective solutions.

Measurement of medication adherence is challenging because adherence is an individual patient behavior. The following are some of the approaches that have been used: (1) subjective measurements obtained by asking patients, family members, caregivers, and physicians about the patient's medication use; (2) objective measurements obtained by counting pills, examining pharmacy refill records, or using electronic medication event monitoring systems; and (3) biochemical measurements obtained by adding a nontoxic marker to the medication and detecting its presence in blood or urine or measurement of serum drug levels. Currently, a combination of these measures is used to assess adherence behavior. Along with the monitoring of outcome, these tools assist investigators in studying medication adherence.

Patients are generally considered adherent to their medication if their medication adherence percentage, defined as the number of pills absent in a given time period (“X”) divided by the number of pills prescribed by the physician in that same time period, is greater than 80% 3 , 6 :

One limitation to calculating adherence using this method is that it assumes that the number of pills absent were actually taken by the patients. In addition, this method may not be representative of long-term adherence patterns because patients may exhibit white-coat adherence , or improved medication-taking behavior in the 5 days before and 5 days after a health care encounter. 3

INCIDENCE OF NONADHERENCE

According to a 2003 report published by the WHO, adherence rates in developed countries average only about 50%. 1 Adherence is a key factor associated with the effectiveness of all pharmacological therapies but is particularly critical for medications prescribed for chronic conditions. Of all medication-related hospitalizations that occur in the United States, between one-third and two-thirds are the result of poor medication adherence. 3 A fair amount of data is available regarding medication adherence in CVD because, for many of the risk factors, adherence can be roughly approximated via the measurement of surrogate markers. For example, adherence to antihypertensive therapy can be approximated by measuring blood pressure (BP) control, and adherence to lipid-lowering therapy can be approximated by measuring lipid levels. Because most research is disease-specific and not focused on medication adherence alone, this review will focus on medication adherence as it relates to CVD. Examining adherence in patients with CVD is a useful model for helping physicians understand medication adherence in other chronic conditions.

Cardiovascular complications resulting from hypertension, hyperlipidemia, and diabetes lead to substantial disability, morbidity, and mortality. For example, for every increase of 20 mm Hg in systolic BP and every increase of 10 mm Hg in diastolic BP, the risk of stroke and ischemic heart disease doubles. 7 Because of this increased risk, comprehensive treatment plans for patients with established CVD include antidiabetes, antihypertensive, and lipid-lowering (typically statin-based) therapies for patients who present with diabetes, hypertension, and dyslipidemia, respectively. 8

Although it is well known that antidiabetes, antihypertensive, and lipid-lowering therapies significantly reduce the risk of ischemic events, 9 - 11 long-term adherence to these medications is poor even among patients who have already experienced a cardiovascular event ( Figure 1 ). 12 For example, despite the fact that pharmacological antihypertensive therapy has a positive safety and tolerability profile and reduces the risk of stroke by approximately 30% and myocardial infarction (MI) by approximately 15%, 11 evidence from a number of studies suggests that as many as 50% to 80% of patients treated for hypertension are nonadherent to their treatment regimen. 13 - 15 According to the WHO, this lack of adherence is the most important cause of failure to achieve BP control. 1 Failure to achieve BP control significantly increases the risk of MI, stroke, and hospitalization. 16 , 17 As expected, adherence to antihypertensive therapy reduces the risk of these events. 18

Persistence with secondary prevention medication in the 24 months after ischemic stroke in Sweden. Persistent use of secondary preventive drugs declines rapidly during the first 2 years after stroke.

From Stroke , 12 with permission.

Comprehensive treatment plans for patients with CVD also include indefinite use of antiplatelet therapy. 8 For patients with heart disease, ischemic cerebrovascular disease, or peripheral artery disease, aspirin or clopidogrel monotherapy has a favorable benefit-to-risk profile; for patients who experience an ischemic cerebrovascular event, therapy with aspirin plus extended-release dipyridamole is an additional treatment option. 19 For patients who experience acute coronary syndrome or undergo percutaneous coronary intervention with stent implantation, dual antiplatelet therapy with aspirin and either clopidogrel or prasugrel is recommended for at least 12 months for those not at a high risk of bleeding. 20

Like adherence to antihypertensive therapy, adherence to statins and antiplatelet agents is poor, as are the outcomes associated with nonadherence. Within 6 months to 1 year after having been prescribed statins, approximately 25% to 50% of patients discontinue them 21 - 24 ; at the end of 2 years, nonadherence is as high as 75%. 25 , 26 Achievement of the treatment goals recommended by the National Cholesterol Education Program is also poor. 27 , 28 With regard to antiplatelet therapy, studies that assessed long-term aspirin use found that rates of adherence beyond 1 year ranged from 71% to 84%. 29 - 32 For dual antiplatelet therapy recipients, premature discontinuation of clopidogrel rates has been reported to occur in 12% to 14% of patients within 1 to 3 months of initiation 33 , 34 and in up to 20% of patients beyond 6 months. 35 , 36

Nonadherence to lipid-lowering and antiplatelet therapies is associated with an increased risk of adverse cardiovascular outcomes. 16 , 32 , 34 , 36 - 41 Aside from the increased risk of MI, stroke, and death, stent recipients who prematurely discontinue clopidogrel also have an increased rate of stent thrombosis. 34 , 36 , 42 - 45 For example, in an analysis of 3021 drug-eluting stent recipients, discontinuation of clopidogrel within 6 months of stent implantation was the strongest predictor of 6-month stent thrombosis (hazard ratio, 13.74; 95% confidence interval, 4.04-46.68; P <.001). 43 In a study of 500 drug-eluting stent recipients, 13.6% of patients discontinued thienopyridine therapy within 30 days. 34 These patients had a 10-fold greater mortality rate at 1 year than those who continued thienopyridine therapy (7.5% vs 0.7%). 34

CAUSES OF POOR MEDICATION ADHERENCE

Poor adherence to medical treatment severely compromises patient outcomes and increases patient mortality. According to the WHO, improving adherence to medical therapy for conditions of hypertension, hyperlipidemia, and diabetes would yield very substantial health and economic benefits. 1 To improve medication adherence, the multifactorial causes of decreased adherence must be understood. The WHO classifies these factors into 5 categories: socioeconomic factors, factors associated with the health care team and system in place, disease-related factors, therapy-related factors, and patient-related factors. 1 In broader terms, these factors fall into the categories of patient-related factors, physician-related factors, and health system/team building–related factors.

Patient-Related Factors

Several patient-related factors, including lack of understanding of their disease, 46 lack of involvement in the treatment decision–making process, 47 and suboptimal medical literacy, 48 contribute to medication nonadherence. In the United States alone, an estimated 90 million adults have inadequate health literacy, 49 placing them at risk for increased rates of hospitalization and poorer clinical outcomes. 50 , 51 The patient's health beliefs and attitudes concerning the effectiveness of the treatment, their previous experiences with pharmacological therapies, and lack of motivation also affect the degree of medication adherence. 3 , 52 , 53 Medication adherence continues to decline even after a catastrophic event such as a stroke ( Figure 1 ) 12 ; thus, it is not surprising that treating asymptomatic conditions to prevent the possible occurrence of adverse events years later presents an even greater challenge. Specific factors identified as barriers to medication adherence among inner city patients with low socioeconomic status were high medication costs, lack of transportation, poor understanding of medication instructions, and long wait times at the pharmacy. 55 A lack of family or social support is also predictive of nonadherence, 52 , 56 , 57 as is poor mental health. 3 , 53 , 58 These findings are clinically relevant for patients with CVD because studies have shown that depression and anxiety are common in patients with coronary artery disease or stroke. 59 - 61 Indeed, the poorer outcomes experienced by patients with depression and CVD may be due, at least in part, to poorer medication adherence by depressed patients. 62 , 63

Physician-Related Factors

Not only do physicians often fail to recognize medication nonadherence in their patients, they may also contribute to it by prescribing complex drug regimens, failing to explain the benefits and adverse effects of a medication effectively, and inadequately considering the financial burden to the patient. 3 , 55 Ineffective communication between the primary care physician and the patient with a chronic disease such as CVD further compromises the patient's understanding of his or her disease, its potential complications, and the importance of medication adherence. 5 Failing to elicit a history of alternative, herbal, or supplemental therapies from patients is another source of ineffective communication.

Communication among physicians is often insufficient and may contribute to medication nonadherence. Direct communication between hospitalists and primary care physicians occurs in less than 20% of hospitalizations, and discharge summaries are available at less than 34% of first postdischarge visits. 64 Inadequate communication between physicians, hospitalists, primary care physicians, and consultants also contributes to medication errors and potentially avoidable hospital readmissions. 64 , 65

Health System/Team Building–Related Factors

Fragmented health care systems create barriers to medication adherence by limiting the health care coordination and the patient's access to care. 66 Prohibitive drug costs or copayments also contribute to poor medication adherence. 35 , 67 Health information technology is not widely available, preventing physicians from easily accessing information from different patient care–related venues, which in turn compromises patient care, timely medication refills, and patient-physician communication. In an overtaxed health care system in which clinicians see a large volume of patients without resources to meet individual patient needs, the amount of time a clinician spends with patients may be insufficient to properly assess and understand their medication-taking behaviors. This lack of time may preclude engaging the patient in a discussion on the importance of medication adherence and strategies to achieve success.

STRATEGIES TO IMPROVE MEDICATION ADHERENCE

Between 2000 and 2002, the typical Medicare beneficiary saw a median of 7 physicians per year: 2 primary care physicians and 5 specialists. 68 This finding highlights the need for coordinated, multifactorial strategies to improve medication adherence. However, given the enormous complexities involved in medication adherence, research on improving adherence has been challenging and generally focused on single disease states. A recent Cochrane review of 78 randomized trials found no one simple intervention and relatively few complex ones to be effective at improving long-term medication adherence and health outcomes, 69 underscoring the difficulty of improving medication adherence.

Although improving medication adherence is challenging, clinicians can take several steps to assist patients' medication-taking behavior, and subsequently, outcomes. The ensuing discussion will focus on strategies to improve medication adherence related to the areas of patient-, physician-, and health system/team building–related factors. A summary of available resources that can be used to implement these strategies is found in Table 1 .

Strategies and No-Cost Resources Aimed at Overcoming Barriers to Medication Adherence

Medication adherence is primarily in the domain of the patient. 1 Because patients recall as little as 50% of what is discussed during the typical medical encounter, 70 effective patient education must be multifactorial, individualized, and delivered in a variety of methods and settings outside of the examining room. A key component of any adherence-improving plan is patient education. In one recent prospective study of 1341 patients with hypertension, education of both the patient and physician was associated with improved BP control vs education of the physician alone. 71 Formal health education programs, such as diabetes self-management education, have been shown to be effective 72 ; however, access to similar non–disease-specific programs is limited. In the absence of a formal program, physicians would do well to emphasize the availability of other educational resources, including but not limited to pharmacists, community health programs, and interactive Web-based materials such as those found at www.medlineplus.gov ( Table 1 ). It might also be beneficial to recommend to patients that they engage local librarians to help them access the Internet.

The more empowered patients feel, the more likely they are to be motivated to manage their disease and adhere to their medications. Thus, another key factor that can improve patient-related medication adherence is actively involving patients in treatment decisions when possible. One simple way to involve patients is to ask what time of day they would prefer to take their medications. One patient may be more likely to adhere to his or her medications if they were taken in the evening, whereas for another, the morning may be preferred. Only the patient can make this decision. Ascertaining how quickly patients would like to achieve the desired medical outcome also engages the patients in their care. For patients with CVD, this would include how quickly they would like to achieve controlled BP and lipid levels. Patients' answer to this question can help the physician determine how quickly medication may need to be titrated and how often patients will need to be seen in the office or undergo laboratory testing. If a number of alternative treatment options are recommended, offering patients choices encourages active participation in their treatment. For example, once adherence to one medication or treatment is realized and a sense of accomplishment attained, moving to the next recommendation and treatment goal is more achievable. Similarly, the physician should avoid prescribing numerous medications and behavioral modifications at any one visit because this may overwhelm the patient and induce a sense of futility. If it is necessary to prescribe more than one drug or intervention during a given visit, a rationale should be provided for which are most important because it will help ensure that, if patients decide to stop taking their medications for any reason, they will discontinue the most important medications last. It is also hoped that providing a rationale would encourage patients to inform their physicians of any plans to change medications, allowing for discussion.

Inadequate health literacy is often underrecognized and therefore not addressed by physicians. 73 According to data from the first National Assessment of Adult Literacy, conducted in 2003, 77 million US adults (35%) have basic or below basic health literacy, whereas only 26.4 million (12%) have proficient health literacy. 74 Many patients with basic or below basic health literacy may be unable to read a medicine bottle or poison warning. 75 In another study, almost half of patients with low literacy admitted shame, which prevented them from seeking needed help. 76 Of patients who admitted having reading problems and being ashamed, more than 85% hid their limited literacy from co-workers or supervisors, and approximately 50% hid it from their children. 76 The economic consequences of low health literacy skills are exemplified in a 1992 study conducted by the University of Arizona that showed that total annual health care costs for patients enrolled in Medicare with low health literacy were 4 times greater than costs for patients with high health literacy. 75 Comments such as “I'll read this when I get home” or “I forgot my glasses, can you read this to me?” are clues that the patient may have poor literacy. Simple tools to help the clinician are presented in Table 1 .

To help combat poor health literacy and its negative effect on medication adherence, a “shame-free” environment must be created. Possible solutions to poor patient literacy include providing the patient with pictorial and audiovisual educational material instead of written instructions. Given that less than 60% of the US population has English as their first language, 75 providing information in the patient's native language may also lessen the burden of poor health literacy. For example, the Web site www.medlineplus.gov provides simple audiovisual education in more than 40 languages and 250 topics. The topics available in multiple languages include several related to CVD, such as cholesterol, coronary artery disease, diabetes, heart attack, hypertension, peripheral artery disease, and stroke.

Recognizing and treating mental illness must be a priority when treating patients for other chronic conditions such as CVD. Often, successful treatment of patients' coexisting illnesses depends on first treating any underlying mental illness.

Consideration of patients' economic status is of paramount importance. Recognizing that patients' economic constraints will limit their ability to adhere to their medication, the physician may direct patients to programs that provide financial assistance. Such programs include pharmaceutical company–based assistance plans, state-based assistance plans, and pharmacies that provide 30-day supplies of widely prescribed medications, including many of those often prescribed for patients with CVD, for less than $5 ( Table 1 ). A hospital social worker, practice champion, or community center volunteer may offer the time and resources necessary to assist individual patients.

The substantially improved adherence of patients who report a good relationship with their physician highlights the important role of physicians in the medication adherence equation. 3 Similar to any relationship, one key to a good physician-patient relationship is effective communication. Thus, perhaps the foremost strategy physicians can use to increase medication adherence is to follow a patient-centered approach to care that promotes active patient involvement in the medical decision–making process. As part of such a patient-centered approach, the physician should consider patients' cultural beliefs and attitudes. For instance, a common cultural attitude held by many patients is a preference for herbal remedies. Reassuring such a patient with diabetes that metformin is derived from the French lilac might improve his or her acceptance of the therapy.

A recent article by Reach 54 addressed the behavior of people who have a “taste for the present rather than the future” and proposed that these “impatient patients” are unlikely to adhere to medications that require long-term use. In it, he proposes that, if an “impatience genotype” exists, assessing these patients' view of the future while stressing immediate advantages of adherence may improve adherence rates more than emphasizing potentially distant complications. Reach 54 suggests that rather than attempt to change the character of those who are “impatient,” it may be wise to ascertain the patient's individual priorities, particularly as they relate to immediate vs long-term gains. For example, while advising an “impatient” patient with diabetes, stressing improvement in visual acuity rather than avoidance of retinopathy may result in greater medication adherence rates. Additionally, linking the cost of frequently changing prescription lenses because visual acuity fluctuates with glycemic levels may provide insight to the patient and an immediate financial motivation for improving adherence.

Overall, by acknowledging the presence of cultural beliefs and attitudes, physicians can build trust with their patients and proactively address any culture- or belief-related adherence barriers. 77 An essential component of effective physician-patient relationships is the creation of an encouraging, “blame-free” environment, in which patients are praised for achieving treatment goals and are given “permission” to honestly answer any questions related to their treatment.

By asking the appropriate questions, physicians can accurately assess which medications patients are taking and how they are taking them. At a routine visit, patients may be asked twice to list their medications (eg, on a form while waiting to be seen and again when the nurse escorts them to the examination room). However, simply listing medications does not address whether they are actually being taken. Thus, if the physician assumes that the medications listed are being taken, the scene for miscommunication is set. Assessment of medication-taking patterns may be more efficiently obtained by asking a number of direct questions in a nonjudgmental way ( Table 2 ).

Questions a Clinician Can Ask to Assess a Patient's Medication Adherence

Inquiring whether patients plan on “rationing” or “sharing” their medication for financial or other reasons is essential because this is a common practice often kept from physicians. If physicians are aware that patients plan to ration their medication, they will be able to discuss the importance of taking the medication as directed or to prescribe a different medication that is more “forgiving.” Forgiving drugs are defined as those for which a missed dose is less detrimental to long-term outcomes. 78 Alternatively, physicians might prescribe a drug taken on a monthly basis or administered by depot or transdermally.

Physicians have several opportunities to improve medication adherence when prescribing drugs. Prescribing the maximum number of doses possible at one time, thereby limiting the frequency of pharmacy visits, and acknowledging the patient's economic status by adhering to their formulary improve adherence by minimizing economic barriers. An increased number of pills ingested per day may also decrease adherence. 29 , 79 - 81 A recent study by Benner et al 81 of approximately 6000 patients enrolled in a managed care setting focused on the effect of previous prescription burden on future adherence rates when antihypertensive or lipid-lowering therapy were added. Adherence rates decreased to 41%, 35%, and 30% in patients who received 0, 1, and 2 previous medications, respectively; among patients with 10 or more previous medications, adherence was 20% ( Figure 2 ). It is interesting to note that adherence rates were increased by initiating antihypertensive and lipid-lowering therapies concurrently. To help combat the decreased adherence associated with polypharmacy, physicians should consider prescribing fixed-dose combination pills when possible. Indeed, data suggest that adherence to multidrug antihypertensive and lipid-lowering therapy regimens is improved when single- vs multiple-pill regimens are used. 82 - 84 For example, a meta-analysis of fixed-dose vs free-drug regimens in more than 20,000 patients identified a 26% decrease in the risk of nonadherence associated with a fixed-dose combination. 82

Percentage of patients adherent (proportion of days covered ≥80%) to antihypertensive (AH) and lipid-lowering (LL) therapy, by prescription burden.

From Am J Health Syst Pharm , 81 with permission. ©2009, American Society of Health System Pharmacists, Inc. All rights reserved.

Medications with once-daily dosing may be preferable to medications with multiple doses per day because minimizing the frequency of dosing has been shown to improve adherence. 85 In a meta-analysis, adherence ± SD to once-daily dosing was found to be 79%±14%; to twice-daily dosing, 69%±15%; to dosing 3 times per day, 65%±16% ( P =.008 vs once-daily); and to dosing 4 times per day, 51%±20% ( P <.001 vs once-daily; P =.001 vs twice-daily dosing) ( Figure 3 ). 3 , 86 These data suggest that a 10% decrease in adherence will occur with each additional daily dose. Because complex treatment regimens are associated with decreased adherence, 79 physicians would be wise to prescribe drugs that can be taken at the same time of day. If complex treatment regimens cannot be avoided, open acknowledgement of this by the physician may improve the physician-patient relationship, thus increasing adherence.

Adherence to medication according to frequency of doses. Vertical lines represent 1 SD on either side of the mean rate of adherence (horizontal bars).

From N Engl J Med , 3 with permission from the Massachusetts Medical Society. All rights reserved.

When prescribing a new medication, the physician should provide the patient with all necessary and important information, including the name of the medication; its purpose (eg, to lower BP); the rationale for choosing it (eg, other drugs are available to lower your BP, but this one is equally effective and is available on your insurance plan's formulary list); the frequency of dosing (eg, once daily); when it should be taken (eg, in the morning with your other medications); how long it should be taken (eg, for 1 year or lifelong); and any potential adverse effects, their likelihood of occurring, whether they will resolve without intervention, and how the treatment plan may change if they do not resolve. Unfortunately, physicians frequently fail to communicate all of this information to their patients. In one study, Tarn et al 87 found that in more than 65% of audiotaped cases they analyzed, physicians had omitted at least one piece of critical information when discussing a new medication with a patient. 87 Education regarding the duration of medication use was lowest (17%) for cardiovascular medications. 87

Patients' perceptions of adverse effects contribute significantly to decisions regarding medication adherence. In a study of patients with hypertension, adverse effects were listed as the most common concern among patients who were not adherent to their antihypertensive medication. 88 Nonadherence to medications secondary to adverse effects is termed rational nonadherence , which Garner 89 defines as “the cessation of a prescribed therapy because of concern for, or the presence of, medication side effects.” Garner further states that rational nonadherence “is nearly impossible to circumvent if a patient's specific side-effect concerns are not substantially addressed.” Therefore, it is critical that adverse effect profiles are considered when prescribing a medication and discussed with the patient before the initial prescription and at every visit thereafter.

Using the teach-back approach (ie, asking patients to repeat the important points) and asking patients to read and interpret the medication label are ways in which the physician can confirm that patients understand all aspects of their new medication, which in turn increases adherence. Patient medication lists with pictograms are helpful and are available at sites listed in Table 1 . Use of motivational interviewing is another effective communication tool. Motivational interviewing, a counseling technique originally developed to help treat addiction, is designed to help patients identify and overcome reasons they may be reluctant to change their behavior. 90 A meta-analysis of 72 randomized controlled trials showed significant benefit for motivational interviewing in achieving cholesterol and BP control, with psychologists and physicians able to achieve an effect in 80% of the studies. 91 A randomized trial conducted in 190 African Americans with hypertension showed that the addition of motivational interviewing led to steady maintenance of adherence during a 1-year period, in contrast to the control group, in which adherence rates declined significantly. 92

The health system in which a physician practices is integral to achieving the ultimate goal of improved patient health. Because medication adherence is an important contributor to improved patient health, health care systems must evolve in a way that emphasizes its importance. Health system changes are necessary to ensure that sufficient time is allotted to discussing aspects of medication adherence. 93 Time constraints may be addressed by developing a team-based approach to health care ( Table 1 ). The team-based approach includes training nonphysician staff to perform duties traditionally completed by physicians, thus allowing the physician more time to discuss the patient's medication adherence patterns. For example, during a telephone reminder for an upcoming appointment, clerical staff might remind patients to bring in all their medications and pill boxes for review at the office appointment. Other aspects of a team-based approach to health care include assessment of nonadherence by office staff and pharmacists, pharmacist-based patient education, phone call reminders, Web-based tools, and assignment of a case manager. Because these activities occur outside of the physician-patient encounter, they will not lengthen the visit and may increase efficiency. The importance of a team-based approach to managing medication use is highlighted by the medication therapy management services (MTMS) mandated by the 2003 Medicare Prescription Drug Improvement and Modernization Act. 94 Medication therapy management services, which are provided by insurers mainly through community-based pharmacists, are designed to provide education and counseling to improve patient understanding of their medications, improve medication adherence, and detect adverse drug reactions. Preliminary studies suggest that patient participation in MTMS programs improves medication adherence and patient outcomes 95 - 97 ; thus, physicians should encourage eligible patients to participate in MTMS programs.

Increased implementation of electronic medical records and electronic prescribing has the potential to increase adherence by identifying patients at risk of nonadherence and targeting them for intervention. A large US study showed that a greater than 30-day delay in filling an initial prescription for a statin independently predicted medication nonadherence. 98 However, increased use of electronic records would allow for the implementation of systems that could identify delayed filling on an initial prescription, thus allowing the physician to intervene and perhaps prevent poor adherence. Some pharmacies already use automated reminders to alert patients that their prescriptions should be refilled and remind physicians to contact their patients who do not refill their prescriptions.

Initiating long-term medications during hospitalization for an acute event, rather than beginning therapy after discharge, may improve adherence. In a post hoc analysis of the EPILOG (Evaluation of PTCA to Improve Long-term Outcome) trial of patients undergoing percutaneous coronary intervention, those prescribed lipid-lowering therapy while hospitalized were 3 times more likely than those prescribed therapy after hospital release to be adherent at 6 months. 99 Initiating therapy while patients are hospitalized is thought to improve adherence because patients and their caregivers are focused on cardiovascular risk and how it can be reduced during this “teachable moment.” 100 Many patients perceive that medications initiated while they are in the hospital are essential for their health. 100

A critically important health system–related factor that improves medication adherence, as well as patient safety, is appropriate medication reconciliation. Medication reconciliation is the process of creating the most accurate list possible of all medications a patient is taking, including drug name, dosage, frequency, and route, and comparing that list against admission, transfer, and/or discharge orders. The goal of medication reconciliation, a national priority of the Joint Commission on Accreditation of Healthcare Organizations, is to ensure provision of correct medications to patients at all transition points and avoid medication duplication and errors. 101 On the basis of the observation that primary care physicians do not receive the hospital discharge summary before the patient's next contact or treatment 66% of the time, 68 much greater emphasis on medication reconciliation is needed if medication adherence and patient safety are to improve. An important component of the reconciliation process is the use of a personalized, upto-date medication list for patients to keep with them at all times (for sources of downloadable medication lists, see Table 1 ). These personalized medication lists are particularly important for patients with chronic conditions such as CVD, which typically necessitate the use of multiple medications. By reviewing medication lists at every visit, physicians can ensure that other physicians have not prescribed new medications without their knowledge. For example, if a patient is seeing his or her primary care physician for the first time after an MI, an updated medication list will help ensure that the primary care physician is aware of any new medications. Furthermore, the list can serve as a basis to discuss actual medication usage patterns with the patient.

Strong evidence shows that many patients with chronic illnesses have difficulty adhering to their recommended medication regimen. Believing that medication nonadherence is the “fault” of the patient is an uninformed and destructive model that is best abandoned. As the former Surgeon General C. Everett Koop reminded us, “Drugs don't work in patients who don't take them.” 3 Thus, physicians must recognize that poor medication adherence contributes to suboptimal clinical benefits, particularly in light of the WHO's statement that increasing adherence may have a greater effect on health than any improvement in specific medical treatments. 1 The multifactorial nature of poor medication adherence implies that only a sustained, coordinated effort will ensure optimal medication adherence and realization of the full benefits of current therapies. Current recognition of the importance of medication adherence has resulted in the development of many useful Web-based resources.

Supplementary Material

Acknowledgments.

Editorial assistance with searching the literature, coordinating revisions, and creating figures and tables in preparation of this manuscript was provided by Melanie Leiby, PhD, and additional assistance with correspondence and permissions was provided by Barbara A. Murphy, both of inScience Communications, a Wolters Kluwer business, and funded by the Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership. The authors would like to thank Joyce Pallinger, MS, MLIS, Manager, and Karly Vesely, MLIS, Medical Librarian, of the MacNeal Hospital Library for additional support in obtaining references.

An earlier version of this article appeared Online First.