LAW: Can Anything Be Done To Make A Century-Old Drug More Affordable?

After completing this application-based continuing education activity, pharmacists will be able to

· Discuss the effect of high insulin costs on public health

· Describe the development of insulin as a treatment for diabetes and how its cost has evolved

· Characterize the factors contributing to the high costs of insulin

· Review the regulatory and legal issues which have had or will have an effect on the cost of insulin

After completing this application-based continuing education activity, pharmacy technicians will be able to

· Discuss the effect of high insulin costs on public health

· Describe the development of insulin as a treatment for diabetes and how its cost has evolved

· Characterize the factors contributing to the high costs of insulin

· Review the regulatory and legal issues which have had or will have an effect on the cost of insulin

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

More than 100 years ago, insulin was found to be an effective treatment for diabetes, yet the disease continues to be a major public health concern. Many patients with diabetes undertreat the disease despite insulin’s ready accessibility, due, in part, to the rapidly increasing cost of the medication. Significantly, the cost of insulin is subject to a complex, opaque price setting process with many stakeholders that encourages high list prices. There is also little competition in the insulin market, manufacturers aggressively protect their markets, and there are few alternatives to brand name products. Meanwhile, Congress is grappling with measures to lower out-of-pocket insulin costs, including capping co-pays on insulin products. This continuing education activity will review many of the factors that influence the cost of insulin and the consequences of high prices. It will also discuss regulatory and public health efforts to control costs and the role of the pharmacy team.

INTRODUCTION

“The skyrocketing cost of insulin has become a crisis in the US. Some people are dying because they can't afford the life-saving drug.” Columnist Rachel Gillett.¹

Diabetes is a rapidly growing global health problem with enormous health, social, and economic consequences.^1-3 This chronic metabolic disorder is characterized by prolonged hyperglycemia due to inadequate pancreatic production or utilization of the hormone insulin.³ Approximately 6.5% of the global population (almost 300 million people) suffer from diabetes.² In the U.S., the Centers for Disease Control and Prevention (CDC) estimates that 10.5% of the population (34 million people) have diabetes and that the prevalence rises to 26.8% among those aged 65 years or older.⁴ Direct medical costs and lost productivity attributable to diabetes was estimated to be $327 billion in 2017, making it the most expensive chronic disease in the nation.^5,6

Complications from diabetes are a serious public health concern. Diabetes is a principal cause of retinopathy, kidney failure, heart attacks and stroke, lower limb amputation, and ketoacidosis which can be fatal.³ Individuals with diabetes are twice as likely to have heart disease or stroke than those without diabetes.⁵ A total of 16 million emergency department (ED) visits were reported with diabetes as a listed diagnosis among adults aged 18 years or older in 2016.⁴

Management of diabetes is critical to preventing complications and high health care costs from the disease. However, many patients do not adequately manage their diabetes, in part due to high treatment costs. This continuing education activity will discuss some of the reasons behind the high costs of treating the disease and the impact that high prices have on patients. It will also review regulatory and public health efforts to reign in the rising costs of insulin.

INSULIN

Diabetes can be managed, and its consequences avoided or delayed with diet, physical activity, tobacco avoidance, and regular screening and treatment for complications.^3,5 Medication, of course, is also a key to management. Prescribers use many different classes of oral medications to manage diabetes,⁷ but the emphasis in this activity will be on insulin. Insulin is the mainstay of therapy for individuals with type 1 diabetes, and many patients with type 2 diabetes also benefit from insulin therapy.⁸ Prior to the discovery of insulin in 1921, diabetes was difficult to manage. The primary treatment consisted of highly restrictive diets, which compromised the immune system and stunted growth, and often led to death by starvation.⁹

In 1921, Frederick Banting, a Toronto surgeon without laboratory training, medical student Charles Best, physiologist John Macleod, and biochemist James Collip successfully isolated and purified insulin from a dog’s pancreas and showed that it would normalize blood glucose levels when administered to diabetic animals.¹⁰ Later, insulin was extracted in larger amounts from cattle and was first given to a 14-year-old dying diabetic patient who developed an allergic reaction. After the Canadian researchers purified it further, they gave a second dose to the patient 12 days later; the patient showed dramatic improvement as his blood glucose dropped to near normal levels with no obvious adverse effects.¹⁰ This observation spurred widespread use of insulin in patients with diabetes. Banting and Macleod were jointly awarded the 1923 Nobel Prize in Physiology or Medicine in recognition of their life-saving discovery (The committee did not recognize Best, the lowly med student, for his contribution).¹⁰ Banting, Collip, and Best were also awarded patents on insulin and the method used to make it in 1923. They all sold their patents to the University of Toronto for $1 each.¹⁰ Banting famously said, “Insulin does not belong to me, it belongs to the world,” proclaiming his desire that everyone who needed it should have access to it.¹⁰

Researchers at the university tried to manufacture insulin for distribution but realized they could not meet the demands of the North American market.¹¹ The university licensed the technology to Eli Lilly which possessed the expertise to produce large batches of insulin. Under the arrangement, Lilly was allowed to apply for U.S. patents on any improvements to the manufacturing process.¹¹ The university also established licensing agreements to produce insulin with other companies, including Nordisk and Novo which laid the foundation for the future domination of the insulin market by a few companies.¹¹ When the animal-based insulin patents began to expire, researchers developed new technologies. They bioengineered human insulin in 1982 and then analog insulin (insulin which has been genetically modified to improve its pharmacokinetic profile) and created new therapies and continued patent protection.¹¹ Today, approximately 7.4 million Americans use insulin, including roughly 1.4 million people who use it to treat type 1 diabetes.⁹

Pharmacists and technicians are aware that patients with type 1 and type 2 diabetes use a combination of short-acting, rapid-acting, intermediate-acting, and long-acting insulins to control their glucose levels. Today, the insulin analogs are widely prescribed and are the standard of care for people with type 1 diabetes and also a component of care for people with type 2 diabetes; the analogs are generally more expensive than other, older types of insulin.⁹

Even though diabetes is treatable and has been for more than a century, it remains the 7^th leading cause of death in the U.S., accounting for 87,647 fatalities in 2019.^5,9 Despite the availability of this century-old treatment, many patients undertreat their diabetes, contributing to complications and high mortality from the disease. Results from an international survey of patients with type 1 diabetes found that approximately 25% of patients in the U.S. had rationed insulin in the previous year.¹² Why would patients show such low adherence to a proven, lifesaving medication?

One reason is cost. High-list prices, health plan structures, and high out-of-pocket costs make it difficult for many diabetic patients to adhere to their medications, especially insulin. Some patients maintain that they spend an estimated 50% of their monthly income on insulin and diabetes products.¹¹ Studies have found that approximately one of every four survey respondents in the U.S. report underuse of their insulin at least once within the previous year due to high cost.^12,13 This is the highest rate of insulin rationing of any high-income country in the world.¹⁴ An international survey found that only 6.5% of respondents from high income countries excluding the U.S. reported rationing in the previous year, compared with roughly 25% in the U.S.¹⁴ In addition to rationing insulin, 33.5% of individuals from the U.S. reported rationing of blood glucose testing supplies.¹⁴

The financial burden is, not unexpectedly, especially acute for economically disadvantaged individuals who have a higher rate of diabetes. Rates of diabetes are higher among people living in impoverished regions of the U.S., such as Appalachia and the Mississippi Delta, and also among those who are eligible for Medicare and Medicaid.⁹ Adults with less than a high school education are also more likely to be diagnosed with diabetes than those with at least a high school diploma.⁹ Similarly, minority communities are also disproportionally affected by this disease, with Native Americans, Hispanics, Black Americans, and Asian Americans representing more than 45% of those diagnosed with the disease, despite these groups making up 39% of the U.S. population.⁹ Cost-related rationing of insulin was the leading cause of hospital admissions for diabetic ketoacidosis among inner-city minority patients.¹⁴ Approximately 24% of adults with diabetes earning below the poverty level use insulin, either alone or in combination with oral medications.¹⁵

An online survey performed by the American Diabetes Association in 2018 also found that a quarter of respondents reported that the cost of insulin had affected their purchase or use of insulin during the previous year. The percentage was even higher for dependent child insulin users (34%).¹⁶ More than 20% of users admitted missing doses monthly or even weekly. They also had to choose between buying insulin or other health-related purchases such as physician visits (32%), health insurance (26%), or other medications (36%). Many also had to choose between purchasing insulin or other essential items such as utilities (30%), housing (27%), transportation (32%), as well as non-essential purchases like vacations (41%) and entertainment (43%).¹⁶ Patients have also made employment decisions based on the availability of adequate health insurance to cover the cost of their insulin.¹¹ Patients also claim that they have been forced to make unhealthy food choices that can worsen the disease, purchasing cheaper alternatives due to spending on insulin.¹¹ The excessive costs also caused 23% of individuals to change to a less expensive insulin type or brand, while many skipped filling at least one insulin prescription.¹⁶

Moreover, surveys have found that insulin users for whom cost affected their purchase or use of insulin experience adverse health effects at higher rates than those for whom cost was not an issue. When cost was a factor, 72% of individuals experienced episodes of poor blood glucose control during the previous three months (compared with 42% in users who were not affected by the cost), and 80% had their most recent A1C level measured at 7.5 or higher (59% when cost was not a factor).¹⁶ Patients have also claimed that they have intentionally allowed themselves to reach a state of diabetic ketoacidosis so that they would receive insulin in an ED instead of purchasing it.¹¹

Not unexpectedly, 73% of individuals dealing with price increases also experience negative emotions (e.g., stress or anxiety), more than twice the rate of those not facing a price increase (31%).¹⁶ There have even been reports of deaths in patients with type 1 diabetes due to a lack of affordable insulin.^14,17 The underutilization of insulin due to concerns over cost not only produces serious avoidable short- and long-term health consequences, but also raises overall costs for the U.S. health care system.^9,15 It is remarkable that this has occurred with a medication whose discoverers refused to profit from it.

PAUSE AND PONDER: How would you start a conversation about economic stress with a patient who appears to be underusing insulin?

ARE COSTS REALLY THAT HIGH?

There is a public perception that the cost of prescription drugs is out of control; indeed, Americans pay an average of three times as much as patients in the U.K. for the world’s top 20 medications.¹⁸ But is insulin, in the words of Representative Tom Reed (R., N.Y.), “the poster child of this broken marketplace”?¹⁸

Insulin in the U.S. is more expensive than anywhere else in the world. The average manufacturer price of insulin is more than four times higher in the U.S. than it is in the next most expensive country (Chile) and more than 10 times the average cost in the 32 developed countries surveyed.¹⁹ In 2018, spending on insulin in the U.S. was $28 billion, compared with $484 million in Canada.²⁰ The average American insulin user spends almost five times as much annually than their Canadian counterparts. The average cost per unit of insulin in the United States increased by 10.3% between 2016 and 2019 compared with an increase of only 0.01% in Canada during the same time period.²⁰ By comparison, in 1923, two years after the introduction of insulin therapy, the U.S. had the lowest global price of insulin.²¹ As recently as the 1960s, vials of insulin were available in the U.S. for 84¢, equivalent to $7.36 in today’s dollars.¹⁸

The list price of insulin per milliliter in the United States increased, on average, 2.9% annually between 1991-2001, 9.5% per year from 2002 and 2012, 20.7% annually between 2012 and 2016, with a smaller increase from 2016 to 2018.⁶ Analog insulins have seen the largest price increase, rising more than 1000% since the 1990s.^14,17 The average annual per capita cost of insulin now approaches $6,000.⁶ (Note that the average yearly social security benefit in the U.S. is $18,458.)

The cost of insulin contributes an estimated $48 billion to the direct costs of treating diabetes (before accounting for any rebates or discounts) which represents 20% of the total spending.⁶ If current trends continue, the cost of insulin could reach $121.2 billion by 2024, or $12,446 annually for each patient receiving insulin.⁶

WHY?

The reasons for the enormous increase in the retail price of insulin are complex and varied. It has been argued that one of the common justifications for the high price tag on prescription drugs, research and development costs, is not applicable to insulin.¹⁷ Insulin is not a new drug and even the most commonly used modern analogs are 20 years old or more.¹⁷ In addition, over the past 60 years, the increase in the cost of insulin exceeds the rate of inflation by nearly 43-fold.¹⁸ If research and development costs are not driving the price increase, what is?

Notably, there is little competition in the insulin market. Only three companies, Eli Lilly, Novo Nordisk, and Sanofi, manufacture over 90% of the world’s insulin and investigations have found that they generally raise their prices at the same time.^17,21-23 It should be pointed out, however, that the manufacturing of biologics, compared with small molecules, involves a higher level of engineering and facility requirements. Additional steps are needed to ensure compliance with good manufacturing practices, regulatory requirements and to minimize batch-to-batch variability, all of which would affect production costs.²¹ The scale and optimization of production processes are also important to reduce the overall cost of the finished product which hinders smaller pharmaceutical manufacturers from entering the market.²¹

Other factors also contribute to rising insulin prices. An important trend over the past decade is a shift in insulin prescribing from less expensive human insulins to more expensive human insulin analogs.¹⁵ More than 90% of privately insured patients with type 2 diabetes in the U.S. who receive insulin are currently prescribed the more expensive analog version.^17,21

Price Setting

Another significant factor affecting the price of insulin is the large number of stakeholders (e.g., manufacturers, wholesalers, pharmacy benefit management services [PBMs], pharmacies, health plans, employers, and the Federal government) involved in the insulin supply chain and price setting, all of whom use varying degrees of negotiating power.^9,15 Multiple transactions occur among these stakeholders during distribution and payment and there is no one agreed-upon price for any insulin formulation.¹⁵

Although pharmacy staff are generally aware of the pricing dynamics, a brief review will place the insulin costs into context. Prices, rebates, and fees are negotiated among the stakeholders affecting the ultimate price paid by the patient with diabetes at the point of sale. The true cost of insulin can be difficult to pinpoint because of the complex nature and lack of transparency in the financial agreements among the stakeholders.^11,24

Manufacturers set a list price for their product, but the list price is usually not what payers pay nor what the manufacturers receive.^15,24 The manufacturers, generally, receive the net price which is the list price minus fees paid to wholesalers, discounts paid to pharmacies, and rebates paid to PBMs or health plans.¹⁵ While manufacturers control the list price of insulin, a substantial portion of the negotiating power has shifted from manufacturers to PBMs.¹⁵

PBMs attempt to lower costs by leveraging formulary coverage. PBMs administer the prescription medication benefit for more than 266 million Americans and 70% of all prescription claims are managed by the top three PBMs.¹⁵ PBMs have the power to provide exclusive formulary coverage and use this discretion to give them substantial clout in negotiations with manufacturers.¹⁵ Insulin manufacturers compete fiercely, attempting to gain favorable formulary placement and maximize market share and revenue for their products.^9,15 They use rebates as one bargaining chip.^9,15

These interactions give PBMs little incentive to discourage manufacturers from increasing their list prices since rebates, discounts, and fees PBMs negotiate are typically based on a percentage of a drug’s list price.⁹ There is an advantage for manufacturers to raise the list prices to provide bigger incentives (discounts) for the participants in the supply chain.¹¹ In other words, PBMs benefit when there is a larger “spread” between the list price and the real price paid by the health plan, so both the PBMs and manufacturer gain from higher list prices.^9,11,15 Since payers ultimately pay the “real” (discounted) price and not the list price, inflating the benchmark price does not increase the cost to the PBMs.¹¹

A Senate investigation found instances in which insulin manufacturers were apparently discouraged from setting lower list prices for their products, which would likely lower out-of-pocket costs for patients, due to concerns that PBMs and health plans would react negatively.⁹ Although it might be expected that rebates would reduce patient costs at the point-of-sale, they may be used instead by the employer or the health plan to reduce insurance premiums.¹¹ Significantly, insulin list prices have tended to rise more rapidly than the net price due to increasing rebates and discounts negotiated between stakeholders. In some cases, rebates and discounts may approach half of the insulin list price.^15,25 This suggests that participants in the distribution system are largely responsible for the increase in insulin costs.²⁵ It has been estimated that proceeds from insulin sales flowing to insulin manufacturers and insurers have decreased over time, while PBMs, pharmacies, and wholesalers have substantially increased their share of the funds.²⁵

Many participants in the pricing system benefit from the arrangement, but one essential participant who does not is the patient who needs insulin and is paying the artificially inflated list price. In particular, patients with high deductible insurances, Medicare recipients in the “donut hole,” patients subject to co-insurance, and especially patients without health insurance are in jeopardy.^11,24 Over the past decade there has been a shift away from traditional health plans, which provided broad coverage, to high-deductible health plans, and the deductibles themselves have risen; even plans available under the Affordable Care Act can have high deductibles depending on the “tier.” ¹¹ Thus, it would seem that decisions made from negotiations between stakeholders that affect formulary choice may not be based on the patient’s best financial or medical interest.¹⁵

Recently, the Federal Trade Commission (FTC) voted unanimously to conduct an in-depth probe of PBMs since, according to one commission member, “(f)or most Americans, pharmacy middlemen control what medicine you get, how you get it, when you get it, and how much you pay for it. Yet PBM practices are cloaked in secrecy, opacity, and almost impenetrable complexity.”²⁶

Patent Issues

Not only do a few companies dominate the market, they also maintain significant patent protection that limits incursion of competitive alternatives into the market. Currently, there are no patents on human insulin and most patents on first generation insulin analogs have also expired.²¹ Manufacturers have made improvements with new formulations providing more reliable control of diabetes and more convenience for users. However, the newer formulations prolong the patent life and provide up to 37 years of market protection.¹⁷ Companies also engage in what is known as “patent evergreening,” where they continually apply for renewed patents for their drugs after making incremental (in some cases, insignificant) changes to their medications.^17,18,23,27

For example, the long-acting insulin product insulin glargine (Lantus) was first patented in 1994 and was due to expire in 2015. Sanofi filed 74 patents for newer versions of the drug that can provide protection until 2031.^11,17,18 Sanofi maintains that the newer patents “are related to new and unique inventions” although there is evidence suggesting that the improvements are mostly minimal.¹⁸ Sanofi also points out that while the list price for its insulin has increased, the actual price paid by consumers is lower than it was in 2006, due to the nature of the market.¹⁸ In addition to modifying the insulin product, manufacturers have also filed and received patents for insulin delivery devices which effectively extends the patent life of the delivered insulin.^18,21

Patent disputes can influence cost in many ways. The threat of a lawsuit alleging patent infringement would discourage other manufacturers from developing competing products even if the suit is without merit.¹⁷ Even if the suit is litigated and found to be without merit, large litigation costs and marketing delays would occur.²² In 2014, Sanofi filed a suit against Lilly alleging a violation of its patent on insulin glargine. The companies reached a deal under which Lilly agreed to delay the launch of its product until 2016 and pay royalties to Sanofi.²⁸

Even more disturbing is the strategy of “pay-for-delay” patent dispute in which a competing manufacturer acknowledges the original patent and agrees to defer marketing its product for a specified period of time.^17,22 In return, the competing manufacturer receives a payment from the patent holder, a legal means for a manufacturer to pay a competitor not to enter the market.²² When Merck filed a new drug application for its rival to insulin glargine, Sanofi filed a suit claiming that Merck violated 10 of its patents, including ones for the drug and its insulin delivery device.²⁸ After the suit was filed, Merck announced it would no longer pursue its interest in the drug, possibly reaching a deal to receive payments from the suing company.²²

Biosimilars

Patents are not the only barrier to the introduction of alternatives to brand-name insulin. Insulin is a therapeutic biologic (not a chemically synthesized small molecule/drug) and the FDA treats alternative biologic products as biosimilars and not as generics; this leads to a more cumbersome and expensive regulatory approval process.^17,23 The FDA defines biosimilars as “a biological product that is highly similar to, and has no clinically meaningful differences from, a biological product already approved by the FDA.” ²⁹ Production and approval of biosimilars costs nearly as much as a new drug and requires similar testing and regulatory approval.^22,23 The development of a biosimilar takes five to nine years and costs at least $100 million,³⁰ leaving little financial incentive to develop cheaper options. The first insulin biosimilar, Basaglar, was introduced in the U.S. in December 2016, almost two years after the first biosimilar was approved in Europe, and requires that a prescriber supplies a new prescription.¹⁷ A second biosimilar (Admelog) was approved in 2018.¹⁷

In 2021, the FDA approved Semglee (insulin glargine-yfgn) as the first interchangeable insulin biosimilar.²⁹ The “interchangeable” designation means that it can be substituted for Lantus (insulin glargine, approved in 2000) without the intervention of a prescriber, similar to pharmacist-initiated generic drug substitution for small molecules.^27,29

PAUSE AND PONDER: What factors would you consider before substituting an interchangeable insulin? Would cost be one?

CAN ANYTHING BE DONE TO CONTAIN INSULIN COSTS?

The soaring cost of insulin has caught the attention of legislators, healthcare advocates, and the public.

Rising drug prices are a concern to the public at large. More than half of respondents in a March 2022 poll by the Kaiser Family Foundation agreed that limiting how much drug companies can increase the price of prescription drugs each year to the rate of inflation should be a “top priority” for Congress.³¹ A majority of respondents also say placing a limit on out-of-pocket costs for seniors (52%) and, specifically, capping out-of-pocket costs for insulin at $35 a month (53%) should be top priorities for Congress in the coming months.³¹ Several different approaches to reigning in costs involving multiple stakeholders have been proposed.

Congressional Actions

The most far-reaching proposal is the Build Back Better Act (BBBA) which was passed by the U.S. House of Representatives on November 19, 2021, but stalled in the Senate. This is a broad and complex 2,135-page bill with many provisions that would commit $2.2 trillion to a long list of health, social, and environmental proposals.³² The BBBA includes several provisions that would lower prescription drug costs for people with Medicare and private insurance and reduce drug spending by the federal government and private payers.^32,33

The key proposals dealing with drug costs, if eventually passed, would include³³

Allowing the Federal Government to negotiate prices for some high-cost drugs covered under Medicare Part B and Part D
Requiring rebates to limit annual increases in drug prices in Medicare and private insurance for drugs whose prices rise faster than the inflation rate
Cap out-of-pocket spending for Medicare Part D enrollees by instituting a hard cap of $2,000 in 2024
Eliminate cost sharing for adult vaccines covered under Medicare Part D
Limit cost sharing for insulin for individuals with Medicare and private insurance. Currently, Part D and private insurance plans vary in terms of the insulin products they cover and what enrollees pay for insulin products. Under the BBBA, participating plans would cover insulin products at a monthly copayment of $35. Participating plans would not have to cover all insulin products at the $35 monthly copayment but would include one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting).

Since the large BBBA endeavor has not progressed in Congress, the House of Representatives passed a scaled back version (Affordable Insulin Now Act) in March of 2022 that specifically addressed insulin costs.³⁴ The bill would cap cost-sharing under the Medicare prescription drug benefit for a month's supply of covered insulin products at $35 and cap private health insurance cost sharing for selected insulin products at $35 or 25% of a plan's negotiated price (after any price concessions). The cap would become effective in 2023. At the time this activity was prepared, the effort was awaiting Senate action. A modified bipartisan Senate bill with a $35 co-pay cap has been introduced.

The industry trade group, the Pharmaceutical Research and Manufacturers of America (PhRMA), does not favor the act, calling the proposed law heavy-handed and flawed. PhRMA’s position is that it would make the “broken insurance system worse and throw sand in the gears of medical progress” and “doesn’t address perverse incentives in the system that are leading to higher costs for patients.”³⁵

Biosimilars

The previously discussed biosimilars also aim to encourage more affordable insulin substitutes.²³ Before 2010, the U.S. lacked a regulatory pathway for the development of biosimilar medications.^15,36 In 2010, the Biologics Price Competition and Innovation Act (BPCIA) was signed into law as part of the Affordable Care Act. This new law created an FDA approval pathway for biosimilar and interchangeable biologic products while preserving incentives for the development of new medications.^36,37 Typically, biosimilars marketed in the U.S. have launched with initial list prices 15% to 35% lower than comparable list prices of the original reference products.²⁹ The BPCIA provides two separate pathways for a biological product to compete with a reference product: either as a biosimilar or as an interchangeable. Interchangeable products are subject to more stringent requirements.^23,36

To be considered a biosimilar, the route of administration, dosage form, and strength must be the same as the reference product.^36,38 The sponsor must show that it is “highly similar” to the reference product and that no clinically meaningful differences between the biosimilar and the reference product exist in terms of safety, purity, and potency of the product.³⁸ Only minor differences in clinically inactive components are permitted in biosimilar products.³⁰

The biosimilar must also possess the same mechanism of action as the reference product for the condition it is intended to treat, and the manufacturing conditions and facilities must meet standards to ensure safety, purity, and potency.^36,38 To be interchangeable, the manufacturer must demonstrate two things^36,38:

That the product produces the same clinical result as the reference product in patients.
If it is to be used more than once in a given individual, any safety risks or diminished efficacy from switching between the reference substance and the biosimilar is no greater than the risks from using the reference product alone.

Pharmacists should take note of an important difference between biosimilars and generics. Generics (small molecules) only need to demonstrate bioequivalence, while biosimilars need to demonstrate therapeutic equivalence.³⁶ The equivalence must be based on data derived from animal studies, clinical studies, and analytics that show a similarity to the reference product.³⁶ As noted above, meeting the biosimilar criteria requires much more time and expense than substantiating generic equivalency. Pharmacists also need to appreciate that even if a product is defined as “interchangeable,” it is not possible to create identical versions of reference biologic medicines due to their complexity.³⁰

The BPCIA also has market exclusivity provisions that address manufacturers’ concerns.³⁶ Applicants for biosimilar products cannot submit an application until four years after the date on which the reference product was first licensed. Further, the FDA cannot approve the biosimilar or interchangeable until 12 years after the date on which the reference product was first licensed. In addition, the applicant must provide the manufacturer of the reference product with notice of intent 180 days before marketing the product. The first interchangeable product also has market exclusivity for at least a year.³⁶

FDA approval of biosimilars, however, is not the only obstacle to marketing insulin substitutes. As noted above, biosimilars must contend with patent evergreening.^17,27 Biosimilars will also not necessarily grab a large market share.²⁷ Lilly, Novo Nordisk and Sanofi have launched their own “authorized generics,” essentially their own drugs repackaged and marketed at discounted prices.²⁷ Lilly and Sanofi produced the first two (Basaglar and Admelog), which provides little in the way of competition; they are priced only about 15% to 20% less than their respective original forms.^17,39

More significantly, the complex price setting maneuvering that affects the cost of insulin could also impede cheaper biosimilar acceptance. Since PBMs can make more money from discounts on brand name products, they have more to gain from prioritizing the dominant brands and little incentive to include biosimilars in formularies.^17,27,39 In addition, since pharmacists can substitute interchangeable products, pharmacists have the discretion whether or not to dispense the less expensive formulation.

Over the Counter

Pharmacy personnel should recall that when Congress established federal prescription drug regulations in 1951, the types of insulin available at that time, unlike the more recent analogs, did not require a prescription.⁴⁰ Human insulin injection is available over the counter in 49 U.S. states and the District of Columbia and about 15% percent of U.S. patients who buy insulin purchase it over the counter without a prescription.^40,41 This presents a dilemma for patients and clinicians.^40,41 On one hand, this provides an opportunity for patients to obtain insulin without delay, especially in an urgent situation,⁴¹ at a more affordable price (average price of $54.09, compared with $114.40 for prescription short-acting insulins.¹⁹). On the other hand, it could be dangerous for a patient to adequately assess the appropriate dosage and timing for optimal glucose control without training or guidance from a health care provider especially if they are switching between different versions of insulin.⁴⁰ Physicians may not be aware that insulin can still be purchased OTC and may be puzzled by a patient’s sudden change in blood glucose.⁴¹ The FDA maintains that the older insulins were approved for OTC sale because they are less concentrated and did not require medical supervision for safe use.⁴¹

State Activities

States have also taken measures to influence insulin cost and use while waiting for federal actions.

In 2019, Colorado became the first state to limit co-pays for patients who use insulin, capping individual prescription at $100 for a 30-day supply ($200 if patients use two types of insulin), although payers have exploited some loopholes.⁴² The law applies to private insurers but not to patients on Medicare. Since then, seven other states (Illinois, Maine, New Mexico, New York, Utah, Washington, West Virginia) have enacted similar measures and five others (Connecticut, Florida, Kentucky, Tennessee, Virginia) are contemplating similar legislation.⁴² In New Mexico, the cap is set at $25.

Pharmacy staff are also reminded that, generally, individual state laws govern generic substitution.⁴² Some states have become concerned that biosimilars are not “identical” to the reference product, consequently pharmacy staff should become familiar with their state’s regulations regarding biosimilar substitution.⁴³ At least one U.S. state (Indiana) does not permit OTC sales of insulin due to the safety concerns noted above.^19,41

Individuals

Insulin prices have risen to such an extent that patients have taken matters into their own hands. The disparity in price has motivated many Americans to travel to Canada to purchase their insulin where the price may be as little as 1/10 the cost in the U.S.^1,9,44 Governmental policy controls insulin prices in Canada, including price caps and negotiations with manufacturers and often insulin does not require a prescription.⁴⁴

PAUSE AND PONDER: How would you advise a patient who is contemplating purchasing insulin from Canada as a cost-saving measure?

In another approach to reducing the cost of insulin, biohackers have been attempting to make insulin by converting proinsulin obtained from yeast to insulin with the hope of providing a method for do-it-yourself production that could be shared online.^18,45 If they are successful, anyone, hypothetically, could construct a lab and manufacture open-source insulin in a garage at a lower cost.¹⁸ However, they could still run afoul of FDA regulations and need to conform to Good Manufacturing Practices.^18,45

PAUSE AND PONDER: How would you respond to a patient who asks you about OTC or “homemade” insulin?

Patients are also filing lawsuits challenging manufacturer’s “schemes” to unlawfully inflate the benchmark prices of rapid- and long-acting insulins.¹¹

SUMMARY AND CONCLUDING REMARKS

Insulin maintains a critical place in the treatment of diabetes more than 100 years after the discovery of its beneficial effects, yet the disease is poorly managed in many patients, in part due to the escalating cost of newer forms of the drug. Insulin prices in the U.S. are far higher than in the rest of the world, fueled by a pricing system riddled with disincentives to keep prices low. Patients with no or low-quality health insurance are particularly impacted. Congress and states are examining possible solutions to the problem, notably by placing caps on out-of-pocket spending on insulin.

Pharmacy staff, as the point of contact with patients receiving insulin, are ideally situated to help patients who are struggling with adherence to their medication. Patients would benefit from pharmacists who can advise them about the different forms of insulin and delivery devices.⁴⁶ The Endocrine Society recommends that pharmacists learn about lower cost options offered by manufacturers and share their findings with patients and prescribers.²⁴ Pharmacists should also be ready to discuss the pros and cons of OTC insulin products. Pharmacists have also gained an opportunity (and responsibility) to manage costs with the approval of the first interchangeable insulin product.

Another helpful role would be to educate patients about available patient assistance programs especially since many patients may be unfamiliar with them or unsure about whether they qualify and how to apply.⁴⁶ This is a function that pharmacy technicians can fulfill. It is also vital that pharmacy staff remain familiar with Congressional and State efforts to lower out-of-pocket costs of insulin described above and some may choose to serve as patient advocates. Finally, if open-source methods of manufacturing insulin prove to be successful, it could potentially introduce opportunities for compounding pharmacies to make insulin at a lower cost.¹⁸ Insulin may never be as affordable as Frederick Banting hoped, but at least encouraging signs suggest that fewer patients will find it necessary to forego their life-saving treatment because of the expense.

As this activity was being prepared for posting, the Senate passed the long-debated Inflation Reduction Act which dealt with climate, taxes, and health care. The relevant features will allow the government to negotiate costs for certain drugs paid for by Medicare (10 in 2026 and 20 in 2029) and will cap out-of-pocket expenses for insulin at $35 per month for Medicare patients but not for private insurers.

LAW: CAN ANYTHING BE DONE TO MAKE A CENTURY-OLD DRUG MORE AFFORDABLE?

Post-test-Pharmacists and Technicians

Learning Objectives
After completing this activity, participants should be able to  

1. Discuss the effect of high insulin costs on public health
2. Describe the development of insulin as a treatment for diabetes and how its cost has evolved
3. Characterize the factors contributing to the high costs of insulin
4. Review the regulatory and legal issues which have had or will have an effect on the cost of insulin

1. Where does diabetes rank among the leading causes of death in the U.S.?
A. Third
B. Seventh
C. Fifteenth

2. Approximately how many patients report that they have rationed their insulin (during the previous year)?
A. 5%
B. 10%
C. 25%

3. Banting, Best, and Macleod received patents for developing methods to produce injectable insulin in 1923. What did they do with their patents?
A. They started a pharmaceutical company that is still making insulin.
B. They sold their patents to the University of Toronto for $1 each.
C. They licensed the technology to a major pharmaceutical company

4. The average manufacturer price of insulin in the U.S. is approximately how much higher than the average price in the rest of the world?
A. Double
B. Six-fold
C. Ten-fold

5. The price of insulin changes frequently. Which of the following statements is correct?
A. The net price (after discounts have been applied) has been increasing more rapidly than the manufacturer’s list price
B. The uninsured patient pays the net price at the pharmacy
C. Manufacturers compete to gain preferred formulary coverage for their insulin by offering PBMs the largest differential between list and net price

6. Which of the following applies to the commercial development of a biosimilar?
A. It is less expensive to develop a biosimilar than a generic drug because the technology is more straightforward
B. The manufacturer of the original product has a period of market exclusivity before an application for a biosimilar can be approved
C. Biosimilars, like generic drugs, only need to demonstrate bioequivalence to obtain approval from the FDA.

7. What does it mean if an insulin product is “interchangeable”?
A. It is identical to a product made by another manufacturer, basically a generic version
B. It can be substituted for a brand name product if the prescriber issues a new prescription
C. It can be substituted for a brand name product at the discretion of the pharmacist

8. Which of the following is correct regarding patents on insulin?
A. All but one insulin analog is currently protected by its original patent, and the one for which the patent expired is rarely used
B. Most commercially available insulin analogs still have patent protection from their original patent.
C. Manufacturers file numerous modifications to their insulin formulations to extend patent protection by as much as 37 years.

9. What effect would a proposed act recently passed by the U.S. House of Representatives have on the price of insulin?
A. It would mandate that CMS negotiates prices for some high-cost drugs covered under Medicare
B. It would cap cost-sharing under the Medicare prescription drug benefit for a month's supply of covered insulin products at $35
C. It would make most current insulin analogs OTC

10. Colorado became the first state to cap insulin prescriptions prices. The Colorado law does which of the following?
A. It caps out-of-pocket costs for insulin prescriptions at $100 for a 30-day supply for all patients
B. A patient pays one capped monthly price regardless of how many different types of insulin they use
C. The cap applies to anyone who uses insulin regardless of insurance coverage (self-pay, Medicare, and private insurance)

11. What is the percentage increase in the cost of analog insulins over the past three decades?
A. 100%
B. 500%
C. 1000%

LAW: CAN ANYTHING BE DONE TO MAKE A CENTURY-OLD DRUG MORE AFFORDABLE?

Post-test-Pharmacists and Technicians

Learning Objectives
After completing this activity, participants should be able to  

1. Where does diabetes rank among the leading causes of death in the U.S.?
A. Third
B. Seventh
C. Fifteenth

2. Approximately how many patients report that they have rationed their insulin (during the previous year)?
A. 5%
B. 10%
C. 25%

4. The average manufacturer price of insulin in the U.S. is approximately how much higher than the average price in the rest of the world?
A. Double
B. Six-fold
C. Ten-fold

11. What is the percentage increase in the cost of analog insulins over the past three decades?
A. 100%
B. 500%
C. 1000%

References

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https://www.businessinsider.com/insulin-price-increased-last-decade-chart-2019-9
2. Kaul K, Tarr JM, Ahmad SI, Kohner EM, Chibber R. Introduction to diabetes mellitus. Adv Exp Med Biol. 2012;771:1-11.
3. World Health Organization. Diabetes. November 10, 2021. Accessed September 15, 2022. https://www.who.int/en/news-room/fact-sheets/detail/diabetes
4. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Accessed September 15, 2022.
https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf
5. America’s Health Rankings – Diabetes. United Health Foundation 2021 Annual Report.
AmericasHealthRankings.org. Accessed September 15, 2022.
https://www.americashealthrankings.org/explore/annual/measure/Diabetes
6. Hayes TO, Farmer J. Insulin Cost and Pricing Trends. American Action Forum. April 7, 2020. Accessed September 15, 2022. https://www.americanactionforum.org/research/insulin-cost-and-pricing-trends/
7. Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol. 2021;9(8):525-544.
8. American Diabetes Association Position Statement. Approaches to Glycemic Treatment. Diabetes Care. 2016;39(Suppl 1):S52-S59.
9. Insulin: Examining the Factors Driving the Rising Cost of a Century Old Drug. United States Senate Finance Committee Staff Report. January 14, 2021. Accessed September 15, 2022.
https://www.finance.senate.gov/imo/media/doc/Grassley-Wyden%20Insulin%20Report%20(FINAL).pdf
10. Diabetes UK. 100 Years of Insulin. Accessed September 15, 2022.
https://www.diabetes.org.uk/research/research-impact/insulin
11. Class Action Complaint. Chaires v Sanofi. United States District Court District of Massachusetts. Filed January 30, 2017. Accessed September 15, 2022.
https://static01.nyt.com/science/01-30-17_Insulin_Class_Action_Complaint_Hagens_Berman.PDF
12. Pfiester E, Braune K, Thieffry A, et al. Costs and underuse of insulin and diabetes supplies: Findings from the 2020 T1International cross-sectional web-based survey. Diabetes Res Clin Pract. 2021;179.
https://doi.org/10.1016/j.diabres.2021.108996 Accessed September 15, 2022. https://www.sciencedirect.com/science/article/pii/S0168822721003557
13. Herkert D, Vijayakumar P, Luo J, et al. Cost-Related Insulin Underuse Among Patients with Diabetes. JAMA Intern Med. 2019;179(1):112–114.
14. Costs and Rationing of Insulin and Diabetes Supplies: Findings from the 2018 T1international Patient Survey. T1International. Accessed September 15, 2022.
https://www.t1international.com/media/assets/file/T1International_Report_-_Costs_and_Rationing_of_Insulin__Diabetes_Supplies_2.pdf
15. Cefalu WT, Dawes DE, Gavlak G, et al. Insulin Access and Affordability Working Group: Conclusions and Recommendations. Diabetes Care. 2018;41(6):1299–1311.
16. American Diabetes Association. Insulin Affordability Survey, 2018. Accessed September 15, 2022. http://main.diabetes.org/dorg/PDFs/2018-insulin-affordability-survey.pdf
17. Rajkumar SV. The High Cost of Insulin in the United States: An Urgent Call to Action. Mayo Clin Proc. 2020;95(1):22-28.
https://www.mayoclinicproceedings.org/article/S0025-6196(19)31008-0/fulltext
18. Burningham G. The Price of Insulin Has Soared. These Biohackers Have a Plan to Fix It. Time. October 24, 2019. Accessed September 15, 2022. https://time.com/5709241/open-insulin-project/
19. Mulcahy AW, Schwam D, Edenfield N. Comparing Insulin Prices in the United States to Other Countries: Results from a Price Index Analysis. Santa Monica, CA: RAND Corporation, 2020. Accessed September 15, 2022. https://www.rand.org/pubs/research_reports/RRA788-1.html
20. Schneider T, Gomes T, Hayes KN, et al. Comparisons of Insulin Spending and Price Between Canada and the United States. Mayo Clin Proc. 2022;97(3):573-578.
21. Keeping the 100-year-old Promise: Making Insulin Access Universal. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO Accessed September 15, 2022.
https://www.who.int/publications/i/item/9789240039100 Link to download.
22. 8 Reasons Why Insulin is so Outrageously Expensive. T1 International. January 20, 2019. Accessed September 15, 2022.
https://www.t1international.com/blog/2019/01/20/why-insulin-so-expensive/
23. Zelitt J. Pay or Die: Evaluating the United States Insulin Pricing Crisis and Realistic Solutions to End It. Stetson Law Rev. 2021;50:453-489. Accessed September 15, 2022.
https://www2.stetson.edu/law-review/wp-content/uploads/2021/04/Zelitt.PayorDie.pdf
24. The Endocrine Society, Addressing Insulin Access and Affordability: An Endocrine Society Position Statement. J Clin Endocrin Metab. 2021;106(4):935–941.
25. Van Nuys K, Ribero R, Ryan M, Sood N. Estimation of the Share of Net Expenditures on Insulin Captured by US Manufacturers, Wholesalers, Pharmacy Benefit Managers, Pharmacies, and Health Plans From 2014 to 2018. JAMA Health Forum. 2021;2(11):e213409. doi:10.1001/jamahealthforum.2021.3409 Accessed September 15, 2022. https://jamanetwork.com/journals/jama-health-forum/fullarticle/2785932
26. Rowland D. FTC Agrees to 'Shine A Light' on How Drug Middlemen Impact Your Prescription Prices. Columbus Dispatch. June 9, 2022. Accessed September 15, 2022.
https://www.dispatch.com/story/news/2022/06/08/drug-prices-heart-new-ftc-investigation-pharmacy-benefit-managers-pbms/10002565002/
27. Insulin — the New Battleground for Drug Pricing. Nat Biotechnol. 2022;40:1. https://doi.org/10.1038/s41587-021-01203-z Accessed September 15, 2022.
https://www.nature.com/articles/s41587-021-01203-z
28. Bisserbe N, Landouro I. Sanofi Files Suit Against Merck, Claiming Patent Infringements. WSJ. September 19, 2016. Accessed September 15, 2022.
https://www.wsj.com/articles/sanofi-files-suit-against-merck-on-patent-infringements-1474285467
29. U.S. Food and Drug Administration. FDA Approves First Interchangeable Biosimilar Insulin Product for Treatment of Diabetes. July 28, 2021. Accessed September 15, 2022.
https://www.fda.gov/news-events/press-announcements/fda-approves-first-interchangeable-biosimilar-insulin-product-treatment-diabetes
30. Pfizer. Let’s Take a Closer Look at the Characteristics of Biosimilars. Accessed September 15, 2022.
https://www.pfizerbiosimilars.com/characteristics-of-biosimilars
31. Kirzinger A, Kearney A, Quasem M, et al. KFF Health Tracking Poll – March 2022: Economic Concerns and Health Policy, The ACA, and Views of Long-term Care Facilities. Kaiser Family Foundation. March 31, 2022. Accessed September 15, 2022.

KFF Health Tracking Poll – March 2022: Economic Concerns and Health Policy, The ACA, and Views of Long-term Care Facilities

32. H.R.5376 - Build Back Better Act. 117th Congress (2021-2022). Accessed September 15, 2022.
https://www.congress.gov/bill/117th-congress/house-bill/5376
33. Cubanski J, Neuman T, Freed M. Explaining the Prescription Drug Provisions in the Build Back Better Act. Kaiser Family Foundation. November 23, 2021. Accessed September 15, 2022.

Explaining the Prescription Drug Provisions in the Build Back Better Act

34. H.R.6833 — 117th Congress (2021-2022). Affordable Insulin Now Act. Accessed September 15, 2022.
https://www.congress.gov/bill/117th-congress/house-bill/6833
35. Pharmaceutical Research and Manufacturers of America. House Drug Pricing Plan Will “Throw Sand in the Gears of Medical Progress.” November 19,2021. Accessed September 15, 2022.
https://phrma.org/resource-center/Topics/Cost-and-Value/House-Drug-Pricing-Plan-Will-Throw-Sand-in-the-Gears-of-Medical-Progress
36. Koballa KE. The Biologics Price Competition and Innovation Act: Is a Generic Market for Biologics Attainable? Wm & Mary Bus Law Rev. 2018;9(2):479-520. Accessed September 15, 2022.
https://scholarship.law.wm.edu/cgi/viewcontent.cgi?referer=https://www.google.com/&httpsredir=1&article=1150&context=wmblr
37. Biologics Price Competition and Innovation Act. Accessed September 15, 2022. https://www.dpc.senate.gov/healthreformbill/healthbill70.pdf
38. Regulation of Biological Products 42 U.S. Code § 262. Accessed September 15, 2022.
https://www.law.cornell.edu/uscode/text/42/262
39. Bagley D. Devil in the Details: The Impact of the First Interchangeable Biosimilar Insulin. Endocrine News. August 2021. Accessed September 15, 2022.

Devil in the Details: The Impact of the First Interchangeable Biosimilar Insulin

40. Goldstein JN, McCrary M, Lipska KJ. Is the Over-the-Counter Availability of Human Insulin in the United States Good or Bad? JAMA Intern Med. 2018;178(9):1157–1158.
41. Tribble SJ. You Can Buy Insulin Without a Prescription, But Should You? Kaiser Health Network. December 14, 2015. Accessed September 15, 2022.
https://khn.org/news/you-can-buy-insulin-without-a-prescription-but-should-you/
42. Yan K. Eight States Pass Legislation to Place Caps on Insulin Price; Five More Await Ruling. diaLogue.
diaTribe Foundation. Accessed September 15, 2022.
https://diatribe.org/foundation/about-us/dialogue/eight-states-pass-legislation-place-caps-insulin-price-five-more-await-ruling
43. National Conference of State Legislatures. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. May 3, 2019. Accessed September 15, 2022.
https://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx
44. Rauhala E. As Price of Insulin Soars, Americans Caravan to Canada for Lifesaving Medicine. Wash Post. July 31, 2019. Accessed September 15, 2022.
https://www.washingtonpost.com/world/the_americas/as-price-of-insulin-soars-americans-caravan-to-canada-for-lifesaving-medicine/2019/06/14/0a272fb6-8217-11e9-9a67-a687ca99fb3d_story.html
45. Osterath B. Do-It-Yourself Insulin: Biohackers Aim to Counteract Skyrocketing Prices. DW. May 24, 2019. Accessed September 15, 2022.
https://www.dw.com/en/do-it-yourself-insulin-biohackers-aim-to-counteract-skyrocketing-prices/a-48861257
46. Gogineni HP, Gogineni RV. Increasing Insulin Prices - Role of Pharmacists in Assisting Patients with Diabetes to Enhance Access. Biomed. J. Sci. & Tech. Res. 2018;8(2) :1-4.
DOI: 10.26717/ BJSTR.2018.08.001633. Accessed September 15, 2022. https://biomedres.us/pdfs/BJSTR.MS.ID.001633.pdf

Inhalers: A Demonstration is Worth One Thousand Words

After completing this application-based continuing education activity, pharmacists will be able to

· DESCRIBE the different types of inhalers currently available in the United States

· OUTLINE the relationship between the inhaler type and patient characteristics

· DESCRIBE how to order demonstration devices

· IDENTIFY the ideal time and place to employ a demonstration device with patients

After completing this application-based continuing education activity, pharmacy technicians will be able to

· DESCRIBE the different types of inhalers currently available in the United States

· OUTLINE the relationship between the inhaler type and patient characteristics

· DESCRIBE how to order demonstration devices

· IDENTIFY the ideal time and place to employ a demonstration device with patients

Asthma and chronic obstructive pulmonary disease (COPD) are chronic conditions affecting millions of people worldwide. Patients frequently have suboptimal inhaler technique, leading to less effective treatment, inadequate disease control, and reduced quality of life. Patient education and ongoing assessment and support are vital to improving outcomes, but healthcare professionals are often unable to provide this level of care effectively. This continuing education activity reviews the various types of inhaler devices along with important counseling points for each. It offers guidance on choosing appropriate devices based on patient characteristics. It also provides some guidance for how pharmacy personnel can teach, assess, and reinforce proper inhaler technique. Finally, it gives suggestions for ordering and using demonstration devices.

The Accreditation Counsel for Pharmacy Education prefers the use of generic names in continuing education activities to eliminate bias. In this activity, we made the decision to use brand names because of the large number of drugs, combination products, and device combinations currently available.

INTRODUCTION

Asthma and chronic obstructive pulmonary disease (COPD) are common conditions that affect many individuals’ daily functioning. Worldwide, roughly 340 million people have asthma, and 390 million people have COPD.^1,2 It’s well-known that patients often have suboptimal inhaler technique, and numerous professional organizations have advocated for more counseling at every point in the healthcare system.^3,4 Although several new and improved pulmonary inhalation devices are available, inhaler use skills have lagged.⁵

Two systematic reviews analyzed studies of inhaler technique among patientsand healthcare professionals from 1975 to 2014.^5,6 Each review divided the studies into an earlier (1975 to 1994) and a later (1995 to 2014) period to assess changes over time. The review of 54,354 patients over 144 studies found that approximately 30%, 40%, and 30% percent of patients had correct, acceptable, and poor technique, respectively. There was no significant difference in inhaler use skill between the earlier and later time periods.⁵ The review of 6,304 healthcare professionals over 55 studies found that correct inhaler technique among healthcare professionals declined from around 20.5% in the earlier time period to just 10.8% in the later time period.⁶

Using inhalers correctly is essential to disease control. A systematic literature review found an association between inhaler use errors and worsened disease outcomes for patients with asthma and COPD in almost all included studies.⁷ Longitudinal studies found that reductions in inhaler use errors improved disease outcomes.

Ultimately, most patients receive their inhalers from a pharmacy. Research shows that community pharmacists can positively impact inhaler technique, asthma control, quality of life, and medication adherence with educational interventions.⁸ Pharmacy personnel are strategically positioned to improve outcomes for people with asthma and COPD by

Being familiar with the various inhalers available, understanding how to use them, and knowing the counseling points for each
Recognizing patient-specific factors that could impact inhaler administration
Understanding the importance of educating and evaluating patients on inhaler technique, and planning how to best deliver this care

Medication Classes Found in Inhalers

Several pharmacologic classes of medications (and combinations of these classes) are available in inhaler products:

Short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) relax airway smooth muscles by stimulating beta_2-adrenergic receptors.⁴ Patients with asthma and/or COPD can use beta agonist medications as needed for relief of acute symptoms, and on a regular schedule for symptom prevention.^3,4
Short-acting muscarinic antagonists (SAMA) and long-acting muscarinic antagonists (LAMA) cause bronchodilation by inhibiting muscarinic receptors in the airway smooth muscles.⁴ Patients with COPD can use SAMA and LAMA medications as maintenance therapy.^4,9 Patients with asthma who are already using a LABA and an inhaled corticosteroid (ICS) can add on a LAMA maintenance medication if needed.³
ICS reduce airway inflammation and are used as daily maintenance medications to prevent asthma exacerbations.³ Patients with COPD may also use ICS in combination with LABA or LABA plus LAMA as a daily maintenance medication. Prescribing information for corticosteroid inhalers advises patients to rinse their mouths with water after inhalation and to spit the water out afterward to reduce the risk of fungal infection in the mouth and pharynx.^10-12

TYPES OF INHALER DEVICES

Pressurized Metered Dose Inhalers

A pressurized metered dose inhaler (pMDI) has two components: a plastic actuator with mouthpiece, and a pressurized canister which may contain^13,14

the active medication
a spray-generating propellant to move the medication out of the inhaler
co-solvents to allow the inhaler ingredients to mix well
surfactants to stabilize the mixture and prevent drug particles from clumping together or sticking to the canister

The propellant is typically hydrofluoroalkane (HFA), a replacement for the chlorofluorocarbon (CFC) propellants used in many early inhalers.¹³ The Montreal Protocol of 1987 called for phasing out CFCs due to their ozone-depleting properties. The liquid inside a pMDI canister may be formulated as a solution or as a suspended micronized powder. Each time a patient actuates the inhaler (i.e., presses the button to release a spray), a metering chamber in the canister measures the correct liquid volume for that dose. The device releases large particles (about 45 micrometers) from the mouthpiece in a cloud of vapor, and particle size decreases to between 0.5 and 5.5 micrometers as the aerosol evaporates.

Pause and ponder: How do you think the ban on chlorofluorocarbons impacted the inhaler market?

To maximize lung deposition of medication from a pMDI, patients should take a slow, deep breath lasting about four to six seconds and actuate the inhaler at the start of (or immediately after starting) this breath.¹³ If patients mistime the actuation or inhale too quickly, medication is more likely to deposit on the tongue or the back of the throat and patients will swallow it instead. This phenomenon—also known as oropharyngeal deposition—can reduce the effective medication dose and increase adverse effects (e.g., oral thrush and hoarseness with inhaled corticosteroids).¹³ Table 1 lists the medications available as pressurized metered dose inhalers.

Table 1. Pressurized Metered Dose Inhalers^9,10,15-24

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol HFA (Ventolin HFA, ProAir HFA, Proventil HFA, generic)	90 mcg
SABA	levalbuterol HFA (Xopenex HFA, generic)	45 mcg
SAMA	ipratropium HFA (Atrovent)	17 mcg
ICS	ciclesonide HFA (Alvesco)	80 mcg 160 mcg
	fluticasone HFA (Flovent HFA, generic)	44 mcg 110 mcg 220 mcg
	mometasone HFA (Asmanex HFA)	100 mcg 200 mcg
ICS/LABA	fluticasone/salmeterol HFA (Advair HFA)	45 mcg/21 mcg 115 mcg/21 mcg 230 mcg/21 mcg
	budesonide/formoterol HFA (Symbicort, generic)	80 mcg/4.5 mcg 160 mcg/4.5 mcg
	mometasone/formoterol HFA (Dulera)	50 mcg/5 mcg 100 mcg/5 mcg 200 mcg/5 mcg
LAMA/LABA	glycopyrrolate/formoterol HFA (Bevespi Aerosphere)	9 mcg/4.8 mcg
ICS/LAMA/LABA	budesonide/glycopyrrolate/formoterol HFA (Breztri Aerosphere)	160 mcg/9 mcg/4.8 mcg

HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

Spacers and Valved Holding Chambers

A spacer is a tube or bag, often made of plastic, that a patient connects to a pMDI before use.²⁵ Medication particles traveling through these devices slow down before reaching the mouth. This also allows the aerosol propellant more time to evaporate, leaving smaller particles to be inhaled. Lower velocity and smaller particle sizes reduce oropharyngeal deposition, so more medication reaches the lungs. However, patients still need to time inhalation with actuation, and they should avoid exhaling into the spacer to prevent dilution (weakening) of the dose.

Valved holding chambers (VHC) are like spacers, but they have a one-way valve between the chamber and the mouthpiece.²⁵ VHCs trap the aerosols in the chamber, allowing time for patients with poor hand-breath coordination to inhale their medication. The one-way valve blocks exhalations from reaching the aerosols in the chamber, allowing patients to use multiple inhalations or tidal (restful) breathing if needed. For doses requiring multiple medication puffs, healthcare providers should counsel patients to prepare, actuate, and inhale each puff separately rather than spraying multiple puffs into the spacer or VHC at once.¹³

Due to gravity, impaction, and electrostatic charge, some medication is lost in a spacer or VHC before reaching the patient.²⁵ Washing a spacer or VHC with detergent (a water-soluble cleansing agent) and letting it air dry before first use can reduce the electrostatic charge and limit drug particle loss to the device walls. Some spacers and VHCs are made with anti-static material, but often come at a higher cost to the patient.

The Global Asthma Network (which aims to improve asthma care, particularly in low- and middle-income countries) advises that people can make effective spacers from 500 ml plastic bottles if commercial spacers are unavailable or too expensive.¹ A cost-effectiveness analysis determined home-made spacers (most of which were made from plastic water bottles) to be more cost-effective than commercial spacers in Columbia (a middle-income country).²⁶ The study found lower overall treatment costs and no difference in hospital admission rates.

Breath-Actuated pMDIs

A breath-actuated pMDI of beclomethasone dipropionate HFA (Qvar Redihaler) is available to overcome the problem of hand-breath coordination.²⁷ This inhaler is available in 40 mcg/actuation and 80 mcg/actuation. As the name implies, it actuates when the patient takes a breath, but it does not rely on a high inspiratory flow rate to deliver the medication. An inspiratory flow rate of just 20 L/min activates the inhaler, which then uses the HFA propellant to assist with dose delivery. Other breath-activated inhalers (discussed below) require up to 88 L/min for activation, which may be difficult for individuals with asthma or COPD who are already having trouble breathing. Young children and adults have tidal breathing inspiratory flow rates of 8 to 16 L/min and 13 to 18 L/min respectively.²⁷ Therefore, a breath-activated pMDI may require only a bit more inspiratory effort than the patients’ usual breathing.

Soft Mist Inhalers

Soft mist inhalers (SMIs) do not contain a propellant.²⁵ Instead, these inhalers use a spring to create pressure and spray the drug solution through a nozzle, forming two jets of liquid that collide to create a slow-moving mist. The mist’s low velocity increases drug deposition in the lungs rather than the oropharynx. An SMI’s aerosol cloud lasts about six times longer than a pMDI’s, increasing the window for effective inhalation in patients who have trouble coordinating actuation and inhalation. Table 2 shows the medications available as soft mist inhalers.

Table 2. Soft Mist Inhalers^28-31

Class	Medication (Trade name)	Dose/actuation
Class	Medication (Trade name)	Dose/actuation
SAMA/SABA	ipratropium bromide/albuterol sulfate (Combivent Respimat)	20 mcg/100 mcg
LAMA	tiotropium (Spiriva Respimat)	1.25 mcg 2.5 mcg
LABA	olodaterol (Striverdi Respimat)	2.5 mcg
LAMA/LABA	tiotropium/olodaterol (Stiolto Respimat)	2.5 mcg/2.5 mcg

LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

Dry Powder Inhalers

Dry powder inhalers (DPI) are breath-actuated and breath-powered inhaler devices. To improve powder flow and accurate dose metering, manufacturers combine the active medication with a carrier powder or formulate it into spherical agglomerates (small sphere-shaped particles).³² Patients’ inspiratory flow and the resistance inside the inhaler generate turbulent energy that disaggregates (separates) the medication. Quick inhalation optimizes this process. The resulting tiny drug particles (less than 5 micrometers) can reach the lungs, while the larger carrier particles land in oropharynx and are swallowed.

DPIs typically require an inspiratory flow rate of at least 30 to 60 L/min, which some patients may have difficulty achieving.²⁵ There is also a possibility of decreased medication delivery from a DPI during disease exacerbations (periods of worsening), when patients’ ability to generate a forceful inspiration may be impaired.³²Table 3 lists available dry powder inhalers.

Table 3. Dry Powder Inhalers^15,33-46

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol (ProAir RespiClick, ProAir Digihaler)	117 mcg
LABA	salmeterol (Serevent Diskus)	50 mcg
ICS	budesonide (Pulmicort Flexhaler)	90 mcg 180 mcg
	fluticasone propionate (Flovent Diskus)	50 mcg 100 mcg 250 mcg
	fluticasone furoate (ArmonAir Digihaler)	55 mcg 113 mcg 232 mcg
	fluticasone furoate (Arnuity Ellipta)	50 mcg 100 mcg 200 mcg
	mometasone (Asmanex Twisthaler)	110 mcg 220 mcg
ICS/LABA	fluticasone/salmeterol (Advair Diskus, Wixela Inhub, generic)	100 mcg/50 mcg 250 mcg/50 mcg 500 mcg/50 mcg
	fluticasone/salmeterol (AirDuo RespiClick, AirDuo Digihaler, generic)	55 mcg/14 mcg 113 mcg/14 mcg 232 mcg/14 mcg
	fluticasone/vilanterol (Breo Ellipta, generic)	100 mcg/25 mcg 200 mcg/25 mcg
LAMA	aclidinium bromide (Tudorza Pressair)	400 mcg
	tiotropium bromide (Spiriva Handihaler)	18 mcg (per capsule)
	umeclidinium (Incruse Ellipta)	62.5 mcg
LAMA/LABA	umeclidinium/vilanterol (Anoro Ellipta)	62.5 mcg/25 mcg
ICS/LAMA/LABA	fluticasone/umeclidinium/vilanterol (Trelegy Ellipta)	100 mcg/62.5 mcg/25 mcg 200 mcg/62.5 mcg/25 mcg

ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist

INHALER TECHNIQUE EDUCATION

Consider that participants in most randomized controlled trials receive thorough education on inhaler use, must demonstrate competence to be included, and receive ongoing evaluations of their technique.⁴ This is the context in which inhaler efficacy is established. Ideally, all patients would have access to similar standards of care to ensure maximum benefit of inhaled medications. Inhaler technique support can also improve adherence. If patients are using inhalers incorrectly and not seeing clinical improvement, they may discontinue them due to perceived lack of efficacy.⁴⁷ A survey of patients with COPD found significantly greater adherence and confidence in treatment among patients whose inhaler technique had been checked by a healthcare professional within the past two years.⁴⁸

Healthcare providers must consider patient preferences, health literacy, and language barriers when choosing appropriate education methods.⁴⁷ A survey of inhaler-using adults seen at a pulmonary clinic or outpatient pharmacy compared education preferences between English and non-English speakers.⁴⁹ Both groups shared a preference for in-person, active learning methods but had low interest in participating in education sessions outside of regular clinic visits. The aforementioned survey of patients with COPD found that 83% thought a demonstration was “very helpful” for learning inhaler technique.⁴⁸ Only 58% and 34% thought the same about a video or leaflet, respectively.

Pharmacists Can Improve Inhaler Use

Pharmacists are best placed to provide in-person, active demonstrations to patients where they already come to pick up their medications. Research shows that pharmacists can provide effective inhaler use education (if and when their workflow allows for it). A 2017 systematic review of critical inhaler errors in asthma and COPD found that pharmacist-led inhaler education interventions produced statistically significant improvements in patients’ inhaler technique in seven out of eight studies.⁵⁰

Published studies of pharmacist-led interventions provide examples of counseling methods that have proven effective. A pre- and post-intervention study of 211 patients with COPD in Vietnam examined the efficacy of face-to-face inhaler training with a pharmacist. Training followed this format⁵¹:

Patients demonstrated technique on a placebo inhaler device
Pharmacists corrected each mistake and explained why the correction was important
Pharmacists demonstrated every step verbally and physically with a placebo inhaler
Patients performed the technique again
Patients and pharmacists repeated this process until patients could complete all steps correctly

This procedure took about six minutes for initial training and three minutes for follow-up trainings.⁵¹ Pharmacists provided training monthly for three months, once at six months, and once at 12 months. They also included label stickers on inhalers with a summary of the steps for use. The percentage of patients using correct inhaler technique increased by over 40% from baseline to six months but declined somewhat between six and 12 months. Researchers concluded that patients benefit from an initial intensive period of repeated training sessions, followed by long-term follow-up at least every three months.⁵¹

Another study of 72 subjects examined the efficacy of different inhaler training methods by assigning patients to do one of the following⁵²:

Read an MDI package insert pamphlet
Watch a Centers for Disease Control and Prevention video demonstrating technique
Watch a YouTube video demonstrating technique
Receive direct instruction from a pharmacist

Only two minutes were allotted for the interventions (to mimic what might be feasible in a community pharmacy setting).⁵² The pharmacist-led counseling sessions were loosely scripted based on a checklist of proper inhaler technique. After a pharmacist explained and demonstrated inhaler use, subjects could ask questions if time permitted. Study investigators (including the pharmacists performing the direct instruction sessions) used a standardized checklist to assess all participants immediately following the training. There was a statistically significant difference between pharmacist-led instruction and each of the other interventions but not between any of the three other intervention groups. More than 70% of patients in the pharmacist-led intervention group demonstrated correct inhaler use after training compared with less than 20% of patients in the other intervention groups.⁵²

Pause and Ponder: Why might a live demonstration provide better training than a video demonstration of the same time duration?

The 2022 GINA report emphasizes the importance of providing patients with ongoing inhaler technique training and assessment. The report recommends that pharmacists, nurses, and other healthcare workers³

physically demonstrate using placebo inhalers (and spacers or VHCs, if applicable)
check against a device-specific checklist as patients demonstrate technique
supply a take-home handout with steps for inhaler use (ideally including pictures)
check and re-train patients at every opportunity, as errors frequently recur four to six weeks after training

Pause and ponder: In your workplace, would it be feasible to provide two minutes of counseling with every inhaler refill? How might you identify patients who most need inhaler use training?

Of note, devices exist to evaluate patients’ inspiratory flow and inhalation technique when prescribing, training, or assessing.⁴⁷ Although these may not be feasible to use in most community pharmacy settings (and are outside the scope of this continuing education module), they may be very useful in other settings (e.g., a pulmonary clinic). Devices include the AIM (Aerosol Inhalation Monitor), the In-Check DIAL, and the 2-Tone trainer.⁴⁷

Inhaler Administration Counseling

pMDIs

Most pMDIs require users to prime (release sprays into the air) before first use (see Table 4).^17-20When priming a pMDI, users should spray it in the air away from the face. If the inhaler requires shaking, they should also be sure to shake well before each priming spray. Most pMDIs require shaking prior to actuation but some, including Atrovent HFA and Alvesco, do not.^9,10 Patients should always avoid spraying pMDIs into their eyes; the package insert for Atrovent HFA instructs users to close their eyes during inhaler actuation.⁹

Table 4. Priming Requirements for pMDIs^10,15-24

Product(s)	Prime before first use and if not used for more than:	Number of Sprays
Advair HFA^a	28 days	4 sprays
Proventil HFA Ventolin HFA^b	14 days
Bevespi Aerosphere^b Breztri Aerosphere^b Flovent HFA^a	7 days
Asmanex HFA Dulera	5 days
Xopenex HFA	3 days
ProAir HFA^b	14 days	3 sprays
Alvesco	10 days	3 sprays
Symbicort^a	7 days	2 sprays
Atrovent HFA	3 days	2 sprays

^aAlso need to be primed if dropped; ^bAlso need to be primed after cleaning; HFA = hydrofluoroalkane

The following are general administration instructions for pMDIs^17-20:

Check for a firm fit of the canister in the actuator
Remove cap from mouthpiece and check mouthpiece for any foreign objects
If product requires shaking, shake well (typically for 5 seconds)
Facing away from the inhaler, exhale completely
Holding inhaler upright with mouthpiece down, place mouthpiece in mouth
Form a tight seal with lips, keep tongue below mouthpiece, and tilt head back slightly
While breathing in deeply and slowly through the mouth, press down on the canister until it stops moving and has released a puff and remove finger from the canister
Continue to breathe in as long as possible, then remove the mouthpiece
Hold breath as long as is comfortable (up to 10 seconds)
Breathe out gently, away from the inhaler
Replace cap right away

Patients should never use the canister of one inhaler with the actuator of another inhaler.^9,23,24 Patients should clean pMDIs at least once a week. Cleaning instructions for pMDIs vary by product (see Table 5).

Table 5. pMDI Cleaning Requirements^10,15-24

Product	Cleaning instructions
Proventil HFA	Remove the canister from the actuator; DO NOT let the canister get wet. Remove the cap from the mouthpiece. Run warm water through the top and bottom of actuator for 30 seconds in each direction. Thoroughly shake dry. Check the mouthpiece for remaining medication buildup. Let air-dry completely (overnight if possible). If not fully air-dried before next dose, shake the plastic actuator as dry as possible, insert the canister, shake the inhaler, and actuate it twice. Repeat the original cleaning procedure after taking the necessary dose(s).
Ventolin HFA
Xopenex HFA
ProAir HFA
Atrovent HFA
Bevespi Aerosphere
Breztri Aerosphere
Flovent HFA	Clean after evening dose. DO NOT remove the canister from the actuator. Use a water-dampened cotton swab to clean the small circular opening where medicine sprays out of the canister, twisting in a circular motion. Repeat with a new damp swab. Wipe the inside of the mouthpiece with a clean, damp tissue. Let air dry overnight.
Advair HFA
Asmanex HFA	DO NOT remove the canister from the actuator. Wipe inside and outside surfaces of the actuator with a dry, lint-free tissue or cloth. DO NOT wash or put any parts in water. Use a dry folded tissue to wipe over the front of the small hole where the medicine comes out of the Alvesco inhaler.
Alvesco
Symbicort
Dulera

HFA = hydrofluoroalkane

All available MDI inhalers have dose counters built into either the canister or the actuator. For most products, the dose counter’s numbers or background will change to red when the inhaler is running low, reminding patients to refill their medication. Healthcare providers should counsel patients not to use inhalers after the dose counter reads zero, even if the canister does not feel empty and still operates. People should not put canisters in water to see if they float as a means of gauging whether medication remains (an old trick that is no longer recommended) or try to alter dose counters. They should also never use a sharp object to unblock an actuator or throw a pMDI into a fire or incinerator. All pMDI inhalers require storage at room temperature, and most should be stored with the mouthpiece down so that the tip of the canister valve is facing down. This keeps the gasket inside of the canister wet so that it does not become brittle and allow outside moisture to enter the canister.⁵³

In addition to general counseling for pMDIs, specific counseling points for breath-actuated pMDIs include four points⁵⁴:

There is no button to press; opening the cap prepares the dose. If patients leave the cap open for more than two minutes, they will need to close and reopen the cap before inhaling their dose.
Do not shake (especially not with the cap open, as this may actuate the inhaler). Do not prime or use with a spacer or VHC.
Clean weekly with a clean, dry tissue or cloth
Do not take the inhaler apart

SMIs

To set up an SMI (Respimat inhaler), remove the clear base, label the cartridge with the discard date (three months from first use), and insert the narrow end of the cartridge into the inhaler.^28-31 With the inhaler on a firm surface, push down until the cartridge clicks into place (this often takes more force than patients expect). Replace the clear base so that it clicks into place. Do not take the inhaler apart after assembly. To actuate the inhaler, patients should remember the acronym TOP:

Turn the clear base half a turn in the direction of the arrows until it clicks
Open the cap fully
Press the dose-release button and close the cap.

Before first use, repeat the actuation steps until a mist is visible.^28-31 Then repeat three more times. To take an inhalation

Turn the base and open the top
Fully exhale away from the inhaler
Put mouthpiece in mouth and form a tight seal with lips, keeping mouthpiece above the tongue and pointing towards the back of the throat; be sure not to block air vents with lips or fingers
While taking a slow, deep breath through the mouth, press the dose-release button and breathe in as long as possible
Remove inhaler from mouth and hold breath as long as is comfortable (up to 10 seconds)
Breathe out slowly away from the inhaler
Close cap

Pharmacists should counsel patients to prime the device with one puff if not used for more than three days or four visible puffs if not used for more than 21 days.^28-31 Patients should clean the SMI’s mouthpiece (including the metal part inside) once a week with a damp cloth or tissue. These inhalers have dose indicators and automatically lock when empty. Patients should not spray the device into their eyes or use the SMI with a spacer or VHC. SMIs require room temperature storage.

DPIs

To administer DPIs^33-36

Open cover or remove cap and check mouthpiece for foreign objects

Prepare dose (see Table 6)
Fully exhale away from the inhaler
Put mouthpiece in mouth and form a tight seal with lips, keeping tongue below mouthpiece; be sure not to block air vents with lips or fingers
Breathe in quickly and deeply, generating a forceful breath right from the start of inhalation
After breathing in all the way, remove inhaler from mouth and hold breath for as long as is comfortable (up to 10 seconds)
Breathe out slowly away from the inhaler
Cover mouthpiece

Table 6. Preparing and Administering DPI Doses^{15,33-37,39-46}

DPI Type	Dose Preparation and Related Notes
Digihaler	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Built in sensors track adherence and inspiratory flow rates. The inhaler sends information to an application using Bluetooth technology. The inhalers work even if they are not wirelessly connected to the mobile application.
Diskus	Hold inhaler in left hand with thumb of right hand in thumb grip. Push thumb grip away to snap mouthpiece into place. Hold in a level, flat, horizontal position. Slide lever away from mouthpiece until it clicks. Keep holding Diskus level during inhalation. To close after inhalation, patients put their thumb in the thumb grip and pull back towards themselves until the inhaler clicks shut over the mouthpiece. Do not close before inhaling, tilt, play with the lever, or move the lever more than once; doses may be lost.
Ellipta	Open the cover until it clicks. If patients open and close the cover without inhaling the medicine, the dose will be lost inside the inhaler, but patients will not receive a double dose.
Flexhaler	Hold brown grip in one hand and use the other to twist off white cover. Hold inhaler upright with one hand still on brown grip and the other in the middle of the inhaler. Twist brown grip as far as possible in one direction, and then back all the way in the other direction. Priming is required before first use (follow instructions for preparing a dose twice). The inhaler will click in the process of preparing a dose. Do not click the brown grip multiple times without inhaling. The dose indicator will count down with each click. However, it is not possible to receive more than one dose at a time. Do not shake the inhaler after preparing a dose.
Handihaler	Press green button and pull cap away to uncover mouthpiece. Then pull mouthpiece away to uncover center chamber. Remove a capsule from blister packaging (without using sharp instruments) and place it in the center chamber. (Discard unused capsules accidentally exposed to air. Close mouthpiece until it clicks. With mouthpiece pointing up, press green piercing button until flat against base only once, then release. Do not shake. When the capsule is pierced, small pieces of gelatin may be created. These may end up in the mouth or throat and are not harmful. Hold inhaler horizontally when inhaling and inhale twice from the same capsule. The capsule should rattle during inhalation. Do not swallow or manually open capsules.
Pressair	Hold inhaler horizontally with green button on top. Press and release the green button to prepare dose. Do not tilt inhaler. Check that control window changes to green. Do not hold green button down when inhaling. Correct inhalation causes an audible click and control window changes from green to red. Pushing green button multiple times before inhaling does nothing; patients will not lose a dose or get a double dose.
RespiClick	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Always close the cap after each inhalation. Patients will waste the medication if they open and close the cap without inhaling.

Patients may or may not taste or feel the powder from a DPI upon inhalation. It is fine if they do, and they should not take an extra dose if they don’t. Patients cannot use spacers, VHCs, or masks with DPIs. Manufacturers formulate most DPIs with lactose powder as an ingredient, so patients with severe milk protein allergies should not use them.

Individuals should not wash DPIs. If cleaning is necessary, using a dry tissue or cloth is appropriate. Patients should store DPIs at room temperature and protect them from heat and humidity; they are more sensitive to humidity than are other inhalers. They should not store the Tudorza Pressair inhaler on a vibrating surface.

DEVICE SELECTION TO MATCH PATIENT NEEDS

Individualizing delivery device selection is crucial for optimizing outcomes of aerosol drug therapy. Healthcare professionals must consider patient-, drug-, device-, and environmental-related factors. A good starting point may be to observe a patient’s natural inhalation.⁵⁵ For example, if the patient instinctively takes slow, deep breaths, a pMDI or SMI might be a good fit. If the patient tends to inhale quickly and deeply, a DPI may be ideal. Table 7 discusses other important factors to consider.

Table 7. Inhaler Suggestions Based on Patient-Specific Factors^25,27,56-58

For people with…	…Consider
Inability to achieve a good lip seal around an inhaler’s mouthpiece (e.g., pediatric, facial weakness, cognitive impairment)	pMDI with spacer/VHC and facemask
Inability to learn and perform specific breathing techniques	pMDI with VHC
Difficulty generating an inspiratory flow rate of at least 30 to 60 L/min (e.g., older age, female gender, airflow limitation, respiratory muscle weakness, lung hyperinflation, history of COPD exacerbations requiring hospitalization)	pMDI; breath-actuated pMDI; SMI
Poor manual dexterity or limited hand strength	Breath-actuated pMDI; SMI (may need help with initial cartridge installation); DPI (one that does not require complicated manipulations for dose preparation)
Difficulty with hand-breath coordination	Breath-actuated pMDI; pMDI with VHC; DPI; SMI
Inability to store inhaler away from heat and humidity	Non-DPI inhaler (particularly sensitive to heat and humidity)

COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; pMDI = pressurized metered dose inhaler; SMI = soft mist inhaler; VHC = valved holding chamber

Patients often use multiple inhaled medications for asthma and COPD. Prescribing the same inhaler type for all a patient’s inhaled medications eliminates confusion over varying administration techniques.⁵⁹ Clinicians can also prescribe combination products where appropriate to simplify treatment regimens.

Consider the Cost

Affordability is another vital consideration and will depend on the patient’s insurance status. While most inhalers are brand-name only, a few generic inhalers are available (see examples in Tables 1-3). Prioritizing patient preference when selecting inhalers can improve adherence.⁶⁰ Central to patient satisfaction are issues such as simplicity of use, treatment time, comfort, portability, cleaning requirements, taste, and effect on the throat. If a patient remains unable to use a device effectively after several training visits, consider switching to another inhaler type.

INHALER USE MISTAKES

A literature review and meta-analysis of inhaler use errors in patients with asthma and COPD found that 50% to 100% of patients made at least one error when using their inhaler. Error rates were higher for patients⁶¹

using MDIs compared to those using DPIs
with COPD compared to those with asthma
with a longer history of device use compared to patients new to inhaler treatment
using multiple inhalers compared to those using only one inhaler

Errors are also common in patients using SMIs. A systematic literature review and meta-analysis of patients with COPD, bronchitis, or emphysema found that nearly 60% made at least one error when using a SMI.⁶² Other factors associated with higher error rates include^50,61

older age
lower education level
female gender
lower socioeconomic status
having two or more comorbidities

Pause and ponder: In your workplace, would it be feasible to provide training and technique assessment with every inhaler refill? If not, how might you identify and prioritize patients who most need inhaler use training?

While perfect inhaler use is ideal, patients often have complex medication regimens and healthcare professionals often have heavy workloads. It’s vital to prioritize the most essential steps in the inhaler use process, including those that have a proven impact on patient outcomes. The CRITIKAL study used data from the iHARP asthma review service (a multicenter cross-sectional study of adults with asthma) to identify inhaler use errors associated with worsening asthma control.⁶³ Investigators used data from 3660 patients to pinpoint these critical errors which included⁶³

not opening the cover or removing cap from mouthpiece
insufficient inspiratory effort
incorrect position of head
not breathing out before inhalation
not holding breath after inhaling medication, or holding for less than three seconds
not sealing lips around mouthpiece
incorrectly priming, timing, or inhaling the second dose (if needed)

Demonstration Devices

Demonstration devices are placebo inhalers, meaning they contain no active medication. They may be available free of charge from device manufacturers. These are ideal for training since the lack of active drug allows for repeated cycles of education and patient demonstration (“teach-back”). Many demonstration inhalers are specifically marked as “only for use by a single patient” to prevent the possible spread of disease.⁶⁴ Keep demonstration inhalers in a separate area of the pharmacy, and do not send them home with patients to avoid any confusion.⁶⁵

We collected the following information by calling inhaler manufacturers directly. Typically, anyone in a healthcare provider’s office or pharmacy is allowed to order demonstration devices on behalf of a prescriber or pharmacy. To order demonstration devices

Determine the patient population and disease state you will be addressing
Generate a list of common devices your patients use
Identify the manufacturer of each device and visit the manufacturer’s website or the website for the specific product
Obtain the email and phone number for customer service representatives and note days and times available (keep in mind the time zone)
Reach out to the company’s local representative or customer care representative to request demonstration devices
Provide all information required (generally your full name, title, state license number, phone number, address of the pharmacy or office you plan to have the devices delivered to and the facility’s secondary contact information [e.g., fax, email])

When making a demonstration device request, pharmacy staff should allow several weeks for processing and device delivery. The number of devices available also varies. For example, one inhaler manufacturer provides 15 or 20 demonstration devices in response to requests, while another requires a manager review of any request for more than three devices.

Appendix 1 provides contact information for the manufacturers of several inhaler devices. Demonstration device availability can change over time; some companies have demonstration devices in stock only periodically and will advise calling back another time. Companies may also stop carrying demonstration devices for their older products. The GOLD report identifies a lack of placebo inhalers as a common barrier to educating patients.⁴ However, if efforts to obtain demonstration devices are unsuccessful, pharmacists can teach patients using their own devices instead.

Manufacturers may also provide patient assistance programs and co-pay assistance to help with affordability. Patients with commercial or private health insurance are often eligible to participate in co-pay assistance programs and receive a savings card to help lower the cost of the prescription. Healthcare providers can also request additional educational materials and pamphlets to hand out. Referring patients who may be struggling with affording their medications to the manufacturer for assistance and to investigate the patients’ benefits to determine discounts available is highly recommended.

CONCLUSION

Pharmacy personnel are well positioned to help patients maximize the benefit of their inhaled medications. An awareness of available inhalers and the requirements and techniques for their use can help healthcare professionals identify whether patients and their devices are a good match. Recognizing the importance of ongoing training and assessment, pharmacy staff can encourage brief yet frequent counseling sessions with patients as they refill their inhaled medications. Pharmacy personnel should proactively order inhaler demonstration devices from manufacturers (if available) to facilitate patient education.

Good

Better

Best

1. Be familiar with different inhaler devices, including counseling points and potential barriers to use for each

2. Encourage any patient picking up an inhaler to speak with the pharmacist about technique

3. Provide pictorial instructions for use with every inhaler

1. Obtain inhaler demonstration devices and use them with patients

2. Based on refill patterns, recognize patients who may be over- or under- using inhalers and assess for suboptimal technique

3. Check against a device-specific checklist when assessing patient technique

1. Check and re-train on inhaler technique at every opportunity

2. Explain the reason behind any corrections

3. Repeat the teach-back/correction cycle until patients are confident and competent

Appendix I. Inhaler Manufacturer Contact List (Current as of July 1, 2022)

Company	Products (demo device unavailable)	Business Contact
AstraZeneca	Symbicort HFA Pulmicort Flexhaler Bevespi Aerosphere Breztri Aerosphere	1-800-236-9933 Monday-Friday, 8am-6pm ET https://www.astrazeneca-us.com/az-in-us/Contact-us.html Discount card eligibility: https://www.azandmeapp.com/home.html
Boehringer Ingelheim Pharmaceuticals, Inc.	Spiriva Respimat Striverdi Respimat Combivent Respimat Stiolto Respimat Atrovent HFA Spiriva Handihaler	Direct Representative Line: 1-800-243-0127 https://www.boehringer-ingelheim.us/contact-form Patient assistance program: 1-800-556-8317 or www.bipatientassistance.com
GlaxoSmithKline (GSK)	Breo Ellipta Ventolin HFA Trelegy Ellipta Flovent HFA Anoro Ellipta Advair HFA Incruse Ellipta Flovent Diskus Arnuity Ellipta Serevent Diskus Advair Diskus	GSK Response Team: 1-888-825-5249 Monday-Friday, 8:30am-5:30pm ET https://www.contactus.gsk.com/callback/hcp.html Discount card eligibility: www.gskforyou.com
Organon & Co.	Asmanex HFA Dulera HFA Asmanex Twisthaler	Service Center: 1-844-674-3200 Coupons for patients with private insurance: www.asmanex.com ; www.dulera.com
Mylan	Wixela Inhub	Customer Relations Team: 1-800-796-9526 Discount card eligibility: www.wixela.com
Sunovion	Xopenex HFA	Customer Service (Respiratory): 1-844-276-8262
Teva	albuterol sulfate HFA (generic) ProAir RespiClick levalbuterol tartrate HFA (generic) fluticasone propionate/salmeterol inhalation powder, USP QVAR Redihaler	Clinician Support Line: 1-877-867-3034 Patient assistance program: 1-800-896-5855

HFA = hydrofluoroalkane

All information was obtained by calling companies directly and was up to date as of July 1, 2022.

Pharmacist Post-test

Learning Objectives
After completing this continuing education activity, pharmacists will be able to
• DESCRIBE the different types of inhalers currently available in the United States
• OUTLINE the relationship between the inhaler type and patient characteristics
• DESCRIBE how to order demonstration devices
• IDENTIFY the ideal time and place to employ a demonstration device with patients

Questions 1-3 pertain to the following case:
MG, a 76-year-old male, is picking up a refill of his Advair HFA. He mentions that this medication has worked well for him for a couple years now, but he’s having difficulty actuating his inhaler lately due to worsening arthritis in his hands. He isn’t always able to time the spray well with his breathing.

1. Which of the following changes do you recommend that MG discuss with his doctor?
A. Using a VHC with the Advair HFA
B. Switching to Wixela Inhub
C. Switching to Anoro Ellipta

2. MG discusses your suggestion with his doctor, and obtains a prescription for Wixela Inhub. However, he wants to try a demonstration device before filling the prescription to ensure it is easy for him to use. If you don’t have any on hand, which of the following is TRUE?
A. MG should come back in a few days, since you can quickly order the demonstration device through your wholesaler
B. It will likely take a few weeks to order and receive the demonstration device from the manufacturer, if it is available
C. You will need to get a prior authorization before you can order him a demonstration device, so you can teach him with his own inhaler

3. Actually, you do have a demonstration device on hand, and you instruct MG on its use. He demonstrates good technique and decides to fill his prescription. To ensure that MG maintains good technique, which of the following should you do?
A. Send the demonstration device home with MG for ongoing practice; ask him to bring the demonstration device back when he comes to refill his inhaler so you can recheck his technique, ideally in 4 to 6 weeks
B. Send the demonstration device home with MG for ongoing practice; ask him to bring the demonstration device back so you can recheck his technique, ideally in 2 to 3 weeks
C. Do not send the demonstration device home; when MG comes to refill his inhaler, use a new demonstration device or his own prescribed device to recheck his technique, ideally in 4 to 6 weeks

4. JM is a 20-year-old male who admits he doesn’t follow the cleaning instructions for his Flovent HFA inhaler and says it’s just not going to happen. He will wipe it with a tissue if it looks dirty, but that’s about it. Given JM’s cleaning preferences, which of the following inhalers would be the best alternative to his Flovent HFA?
A. Arnuity Ellipta
B. Stiolto Respimat
C. Alvesco

5. Which of the following inhalers requires a slow, deep breath?
A. Tudorza Pressair
B. Spiriva Handihaler
C. Striverdi Respimat

6. A patient is using Anoro Ellipta and Flovent Diskus daily. Which of the following would be the best option to simplify her treatment regimen and improve adherence?
A. Trelegy Ellipta (flutica/umec/vilan)
B. Breztri Aerosphere (budes/glycol/formo)
C. Incruse Ellipta (umec) + Breo Ellipta (flu/vil)

7. Which of the following patient attributes is appropriately matched with an inhaler type?
A. Limited hand strength; pMDI
B. Poor hand-breath coordination; DPI
C. Maximum inspiratory flow of 20 L/min; DPI

8. Which of the following is TRUE about soft mist inhalers?
A. They contain a stronger propellant than pMDIs
B. They do not require a high inspiratory flow rate
C. They require good manual dexterity for actuation

9. Which of the following is correct technique for Spiriva Handihaler administration?
A. Using scissors to carefully open only one blister at a time
B. Taking only one inhalation from each capsule to avoid overdose
C. Listening for the capsule to rattle during inhalation

10. Which of the following is an appropriate counseling point for Alvesco?
A. Clean the actuator with running water weekly
B. Prime before first use and if not used for more than 3 days
C. Rinse with water and spit out after each use

Pharmacy Technician Post-test

Learning Objectives
After completing this continuing education activity, pharmacy technicians will be able to
• DESCRIBE the different types of inhalers currently available in the United States
• OUTLINE the relationship between the inhaler type and patient characteristics
• DESCRIBE how to order demonstration devices
• IDENTIFY the ideal time and place to employ a demonstration device with patients

1. Which of the following inhalers can be used with a spacer or VHC?
A. Advair HFA
B. Wixela Inhub
C. Anoro Ellipta

2. Which of the following is TRUE about ordering an inhaler demonstration device?
A. You can always order them through your wholesaler for next day delivery
B. It will likely take a few weeks to order and receive one from the manufacturer, if it is available
C. You will likely need to get a prior authorization before you can order one

3. Which of the following is TRUE regarding inhaler demonstration devices?
A. Pharmacies should send them home with patients to allow for continued practice
B. Pharmacies should store them next to their medication-containing counterparts
C. Many are labeled for single-patient use to prevent the risk of disease transmission

4. A patient mentions to you that he uses running water to wash the mouthpiece of his inhaler each week. For which inhaler would this be a problem?
A. Breztri Aerosphere
B. ProAir HFA
C. Asmanex HFA

5. Which of the following inhalers requires a slow, deep breath?
A. Tudorza Pressair
B. Spiriva Handihaler
C. Striverdi Respimat

6. A patient tells you he has trouble remembering whether he has taken his inhalers in a given day and he wishes there was an inhaler that could track his use and send the information right to his cell phone. What type of inhaler has this feature?
A. Respimat inhalers
B. Digihaler inhalers
C. Ellipta inhalers

7. You work in a very humid part of Florida. A patient picking up his inhaler confides in you that he is currently living out of his car and that he stores his medications in his glove compartment. Which inhaler type would prompt you to refer this patient to the pharmacist?
A. Pressurized metered dose inhaler
B. Dry powder inhaler
C. Soft mist inhaler

8. Which of the following would prevent a patient from using a dry powder inhaler?
A. The patient can’t get a good seal around a mouthpiece
B. The patient is unwilling to perform routine inhaler cleaning
C. The patient has poor hand-breath coordination

10. Which patients should you advise to review their inhaler technique with the pharmacist?
A. Only patients with questions about inhaler technique
B. Only patients who are starting on a new inhaler or switching devices
C. All patients using inhalers, ideally every four to six weeks

References

1. Global Asthma Network. The Global Asthma Report 2018. 2018. Accessed July 6, 2022. http://globalasthmareport.org/resources/Global_Asthma_Report_2018.pdf
2. Adeloye D, Song P, Zhu Y, et al. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med. 2022;10(5):447-458. doi:10.1016/S2213-2600(21)00511-7
3. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2022. Accessed July 6, 2022. https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf
4. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report. 2021. Accessed July 6, 2022. https://goldcopd.org/2022-gold-reports-2/
5. Sanchis J, Gich I, Pedersen S; Aerosol Drug Management Improvement Team (ADMIT). Systematic review of errors in inhaler use: has patient technique improved over time?. Chest. 2016;150(2):394-406. doi:10.1016/j.chest.2016.03.041
6. Plaza V, Giner J, Rodrigo GJ, et al. Errors in the use of inhalers by health care professionals: a systematic review. J Allergy Clin Immunol Pract. 2018;6(3):987-995. doi:10.1016/j.jaip.2017.12.032
7. Kocks JWH, Chrystyn H, van der Palen J, et al. Systematic review of association between critical errors in inhalation and health outcomes in asthma and COPD. NPJ Prim Care Respir Med. 2018;28(1):43. Published 2018 Nov 16. doi:10.1038/s41533-018-0110-x
8. Mahdavi H, Esmaily H. Impact of educational intervention by community pharmacists on asthma clinical outcomes, quality of life and medication adherence: A systematic review and meta-analysis. J Clin Pharm Ther. 2021;46(5):1254-1262. doi:10.1111/jcpt.13419
9. Atrovent HFA [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.;2020
10. Alvesco [package insert]. Zug, Switzerland: Covis Pharma; 2020.
11. Flovent Diskus [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2022.
12. Asmanex Twisthaler [package insert]. Jersey City, NJ: Organon & Co.; 2021.
13. Blake K, Lang J. Chapter 43:Asthma. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw Hill; 2020:32-38. Accessed July 6, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=228901475
14. Myrdal PB, Sheth P, Stein S. Advances in metered dose inhaler technology: formulation development. AAPS PharmSciTech. 2014;15(2):434-455
15. Albuterol. Lexi-Drugs. Lexicomp Online. Lexicomp; 2020. Updated August 6, 2022. Accessed August 16, 2022. https://online.lexi.com.
16. Levalbuterol. Lexi-Drugs. Lexicomp Online. Lexicomp; 2020. Updated July 6, 2022. Accessed August 16, 2022. https://online.lexi.com.
17. Flovent HFA [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2021.
18. Asmanex HFA [package insert]. Jersey City, NJ: Organon & Co.; 2021
19. Advair HFA [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2021.
20. Symbicort [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017
21. Budesonide and Formoterol. Lexi-Drugs. Lexicomp Online. Lexicomp; 2020. Updated August 6, 2022. Accessed August 16, 2022. https://online.lexi.com.
22. Dulera [package insert]. Jersey City, NJ: Organon & Co.; 2021.
23. Bevespi Aerophere [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
24. Breztri Aerophere [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021.
25. Hess D, Dhand R. The use of inhaler devices in adults. In: Post TW, ed. UpToDate. UpToDate; 2022. Last Updated September 29, 2020. Accessed July 6, 2022. https://www.uptodate.com/contents/the-use-of-inhaler-devices-in-adults
26.Rodríguez-Martínez CE, Sossa-Briceño MP, Sinha IP. Commercial valved spacers versus home-made spacers for delivering bronchodilator therapy in pediatric acute asthma: a cost-effectiveness analysis. J Asthma. 2021;58(10):1340-1347. doi:10.1080/02770903.2020.1784195
27. Teva Respiratory LLC. About QVAR RediHaler® (beclomethasone dipropionate HFA Maintenance Inhaler). Updated February 2022. Accessed July 6, 2022. https://hcp.qvar.com/about-qvar-redihaler/
28. Combivent Respimat [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2021.
29. Spiriva Respimat [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2021.
30. Striverdi Respimat [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2021.
31. Stiolto Respimat [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2021.
32. Azouz W, Chrystyn H. Clarifying the dilemmas about inhalation techniques for dry powder inhalers: integrating science with clinical practice. Prim Care Respir J. 2012;21(2):208-213. doi:10.4104/pcrj.2012.00010
33. Serevent Diskus [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2022.
34. Pulmicort Flexhaler [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
35. ArmonAir Digihaler [package insert]. Parsippany, NJ: Teva Pharmaceuticals USA; 2020.
36. Arnuity Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2018.
37. Advair Diskus [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020.
38. Wixela Inhub [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2021.
39. AirDuo RespiClick [package insert]. Parsippany, NJ: Teva Pharmaceuticals USA, Inc.; 2021.
40. AirDuo Digihaler [package insert]. Parsippany, NJ: Teva Pharmaceutical USA, Inc.; 2021.
41. Breo Ellipta [package insert]. Research Triangle Park: GlaxoSmithKline; 2019.
42. Tudorza Pressair [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
43. Spiriva Handihaler [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2021.
44. Incruse Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2019.
45. Anoro Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020.
46. Trelegy Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020.
47. Kaplan A, Price D. Matching inhaler devices with patients: the role of the primary care physician. Can Respir J. 2018;2018:9473051. Published 2018 May 23. doi:10.1155/2018/9473051
48. Price D, Keininger DL, Viswanad B, et al. Factors associated with appropriate inhaler use in patients with COPD - lessons from the REAL survey [published correction appears in Int J Chron Obstruct Pulmon Dis. 2018 Jul 25;13:2253-2254]. Int J Chron Obstruct Pulmon Dis. 2018;13:695-702. Published 2018 Feb 26. doi:10.2147/COPD.S149404
49. Kher S, Landau H, Hon SM, et al. Inhaler use and education characteristics among English and non-English speaking patients: A pilot needs assessment survey. Patient Educ Couns. 2019;102(5):932-936. doi:10.1016/j.pec.2018.12.016
50. Usmani OS, Lavorini F, Marshall J, et al. Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes. Respir Res. 2018;19(1):10. Published 2018 Jan 16. doi:10.1186/s12931-017-0710-y
51. Nguyen TS, Nguyen TLH, Van Pham TT, et al. Pharmacists' training to improve inhaler technique of patients with COPD in Vietnam. Int J Chron Obstruct Pulmon Dis. 2018;13:1863-1872. Published 2018 Jun 11. doi:10.2147/COPD.S163826
52. Axtell S, Haines S, Fairclough J. Effectiveness of various methods of teaching proper inhaler technique. J Pharm Pract. 2017;30(2):195-201. doi:10.1177/0897190016628961
53. Cogan P, Sucher B. Appropriate use of pressurized metered-dose inhalers for asthma. US Pharm. 2015;40(7):36-41. Accessed August 16, 2022. https://www.uspharmacist.com/article/appropriate-use-of-pressurized-metereddose-inhalers-for-asthma
54. Qvar Redihaler [package insert]. Parsippany, NJ: Teva Pharmacceuticals USA, Inc.; 2021.
55. Haughney J, Price D, Barnes NC, et al. Choosing inhaler devices for people with asthma: current knowledge and outstanding research needs. Respir Med. 2010;104(9):1237-1245. doi:10.1016/j.rmed.2010.04.012
56. Choosing an inhaler device to suit the individual. National Asthma Council Australian Asthma Handbook. Accessed July 6, 2022. https://www.asthmahandbook.org.au/management/devices/device-choice
57. Gardenhire DS, Burnett D, Strickland S, Myers TR. A guide to aerosol delivery devices for respiratory therapists, 4th edition. American Association for Respiratory Care. 2017. Accessed July 6, 2022. https://www.aarc.org/wp-content/uploads/2018/03/aersol-guides-for-rts.pdf
58. Petite SE, Hess MW, Wachtel H. The role of the pharmacist in inhaler selection and education in chronic obstructive pulmonary disease. J Pharm Technol. 2021;37(2):95-106. doi:10.1177/8755122520937649
59. Price D, Chrystyn H, Kaplan A, et al. Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care. Allergy Asthma Immunol Res. 2012;4(4):184-191. doi:10.4168/aair.2012.4.4.184
60. Dekhuijzen PN, Lavorini F, Usmani OS. Patients' perspectives and preferences in the choice of inhalers: the case for Respimat or HandiHaler. Patient Prefer Adherence. 2016;10:1561-1572. Published 2016 Aug 18. doi:10.2147/PPA.S82857
61. Chrystyn H, van der Palen J, Sharma R, et al. Device errors in asthma and COPD: systematic literature review and meta-analysis. NPJ Prim Care Respir Med. 2017;27(1):22. Published 2017 Apr 3. doi:10.1038/s41533-017-0016-z
62. Navaie M, Dembek C, Cho-Reyes S, et al. Device use errors with soft mist inhalers: A global systematic literature review and meta-analysis. Chron Respir Dis. 2020;17:1479973119901234. doi:10.1177/1479973119901234
63. Price DB, Román-Rodríguez M, McQueen RB, et al. Inhaler errors in the CRITIKAL study: Type, frequency, and association with asthma outcomes. J Allergy Clin Immunol Pract. 2017;5(4):1071-1081.e9. doi:10.1016/j.jaip.2017.01.004
64. Weller T. Placebo inhaler devices and infection risks. Nursing Times.2005;101(42):50. Accessed August 16, 2022. https://www.nursingtimes.net/archive/placebo-inhaler-devices-and-infection-risks-18-10-2005/
65. Institute for Safe Medication Practices (ISMP). Correct use of inhalers: help patients breathe easier. July 14, 2016. Accessed July 6, 2022. https://www.ismp.org/resources/correct-use-inhalers-help-patients-breathe-easier

Screening, Brief Intervention and Referral to Treatment (SBIRT): An effective approach to identify persons at risk for substance use disorders

After completing this knowledge-based continuing education activity, pharmacists will be able to

· Discuss the prevalence and consequences of SUDs

· Describe the components of SBIRT

· Recognize motivational interviewing skills to promote readiness to change

· Discuss harm reduction and how it pertains to SUDs

· Describe barriers associated with the use of SBIRT in the community setting

After completing this knowledge-based continuing education activity, pharmacy technicians will be able to

· Discuss the prevalence and consequences of SUDs

· Describe the components of SBIRT

· Discuss harm reduction and how it pertains to SUDs

· Describe barriers associated with the use of SBIRT in the community setting

Hazardous use of alcohol and or opioids can result in harm. If not treated, this hazardous use could develop into a Substance Use Disorder (SUD). SUDs are associated with poor health related outcomes and increased healthcare costs. Screening, brief intervention and referral to treatment (SBIRT), is a public health approach to identify persons with at-risk behaviors and minimize the development of SUDs. The premise behind SBIRT is to promote early intervention with at-risk users and minimize harm. The screening process determines the severity and risk level of a person’s substance use and risk of misuse. Based on the results, healthcare professionals can perform a brief intervention and or a referral to treatment. Healthcare professionals such as pharmacists and pharmacy technicians can use SBIRT to identify and intervene on behalf of persons that are at risk of an SUD. Healthcare providers can perform SBIRT in many healthcare settings including community pharmacies, hospitals, and primary care offices.

Introduction

Substance Use Disorders (SUDs), continue to be a major concern in the United States. In 2017, nearly 20 million people reported an SUD because of alcohol or illicit drug use.¹ Costs associated with substance abuse are approximately $249 billion dollars for alcohol and $193 billion dollars for illicit drugs.^2-4

Alcohol use is second to nicotine for substance use among all substances misused.¹ In 2017, 140 million persons aged 12 and older reported alcohol use. A total of 16.7 million reported heavy alcohol use of five or more days over a 30-day timespan. Heavy alcohol use is defined as drinking four or more drinks on one occasion for females and five or more drinks in males. Heavy alcohol use can result in several health-related concerns, to include cirrhosis, depression, cancer, neuropathy, and pancreatitis to name a few.⁵

Typically, clinicians often treat people who have SUDs after they have developed the condition.^6,7 Other approaches include inpatient or outpatient treatment programs for those with SUDs and prevention programs to educate and inform the public of the dangers associated with substance use.

An alternative approach to these methods is to identify persons with at-risk behaviors for substance misuse and provide interventions to reduce long-term use and harm. This approach is called SBIRT. SBIRT stands for Screening, Brief Intervention, and Referral to Treatment.⁷ This evidence-based approach addresses harmful behaviors BEFORE they escalate to a full-blown SUD.

Who can perform SBIRT?

Many healthcare professionals can perform SBIRT, including doctors, nurses, pharmacists, pharmacy technicians, and behavioral health specialists. SBIRT is also adaptable to a team-based approach. Pharmacists and pharmacy technicians are in a particularly good position to perform SBIRT, as they are accessible, especially in community pharmacy settings.⁸ SBIRT can also be applied in several clinical settings, such as hospitals and ambulatory care clinics.

SBIRT’s first step involves the screening process. Using a universal screening approach is an important point of the screening process. A universal approach means screening everyone, regardless of who they are, or how they look or act. This makes sense because clinicians cannot determine if someone is using alcohol or other substances based on appearance and behavior. Pharmacists and pharmacy technicians can screen patients in any pharmacy setting to include community, hospital, and ambulatory care. In busy community settings, a targeted approach may be necessary. With targeted approaches, pharmacy teams might screen individuals who are on opioids, benzodiazepines, and other medications that have the potential for abuse. Ideally, however, the universal approach is better. If we focus only on certain populations, we may target individuals who don’t have an SUD and overlook someone who has an SUD but takes no prescription medications. The initial screening question is simple: a single yes/no question that determines if further screening is necessary.

PAUSE AND PONDER: When and where would you use SBIRT in your pharmacy practice?

How to Perform SBIRT in a Community Pharmacy Setting

Many pharmacy team members think that they cannot or should not perform SBIRT in their settings. With pharmacy teams expanding their responsibilities, it’s entirely possible to add SBIRT to the community pharmacy tool kit.

Community pharmacy teams need to note that they do not need to perform SBIRT in its entirety. In some cases, pharmacists and technicians may only perform the screening and then refer the patient to a provider for treatment. Pharmacists can perform a brief intervention if opioid misuse is a concern. For example, the pharmacist may access the prescription drug-monitoring program and recognize the patient is seeing multiple providers and using several pharmacies to fill opioid prescriptions. In this case, the pharmacist can perform a screening and brief intervention with the patient to discuss safe opioid use and possible referral to treatment.

Roberta is a 27-year-old female who presents to the pharmacy with a prescription for oxycodone. The pharmacy technician enters the prescription information and notices that Roberta picked up a 30-day supply two weeks ago. The technician informs the pharmacist about the early refill. The pharmacist refers to the prescription drug-monitoring program and notices that Roberta filled two other opioid prescriptions from different doctors at two different pharmacies. The pharmacist screens Roberta and provides a brief intervention.

Pharmacists can refer a patient to treatment or provide information on treatment centers based on the discussion. For example, while engaging with the patient the pharmacist may recognize that the patient is purchasing needles/syringes for illicit drug use. This is a perfect opportunity for the pharmacist to provide a referral to treatment.

When screening for alcohol and drugs, healthcare providers use pre-screening questions developed by the National Institute of Alcohol Abuse and Alcoholism for alcohol and the National Institute of Drug Abuse for drugs. Pre-screening questions determine whether additional screenings are necessary.

For alcohol the pre-screening question is, “Do you sometimes drink beer, wine, or other alcoholic beverages?” If the individual answers no, no further screening is necessary. If the individual answers in the affirmative or screens positive for alcohol, the screener would perform additional screening based on the Alcohol Use Disorders Identification Test (AUDIT) to evaluate alcohol use further.⁹

The same holds true for pre-screening for drug use. If an individual answers in the affirmative to the pre-screening question, “How many times in the past year have you used an illegal drug or a prescription medication for nonmedical reasons?” then the screener would use the Drug Abuse Screening Test (DAST-10) questionnaire to evaluate drug use further.¹⁰ (See Figure 1)

Figure 1. DAST-10 Questionnaire¹⁰

Let’s start with the AUDIT questionnaire. This 10-question screening tool addresses recent alcohol use, dependence symptoms, and harmful behaviors. (See Figure 2) Once the screening is complete, the scoring will determine next steps.

Figure 2. AUDIT Questionnaire⁹

Some key points to consider when using the AUDIT are the recommended drinking limits and size of the beverage. Did you know that the serving size of a glass of wine is five ounces, and that one bottle of wine typically contains five glasses? A serving of beer is 12 ounces, and a serving of spirits (hard liquor) is one and one-half ounces. The screener should explain serving sizes to the patient to ensure an accurate account of alcohol consumption and score of the AUDIT.

Recommended drinking limits for men are two drinks/day and no more than 14 drinks/week and for women one drink/day and no more than seven drinks/week. For those 65 or older, the recommended limits are similar to women: one drink/day and no more than seven drinks/week.¹¹ Consuming more than the recommended limits can result in binge drinking which is associated with greater harm and dependence. Binge drinking is five or more drinks for men or four or more drinks for women, and people who are 65 or older.¹²

The AUDIT score determines the severity and next steps that may include a brief intervention or referral to treatment. Individuals scoring between 0 and 7 are low risk and individuals scoring 20 or greater are considered dependent use and would benefit from a referral to treatment.

Pharmacy teams who are familiar with other screening methods may recall that a positive binge drinking finding would require an intervention using those methods. Using the AUDIT, binge drinking alone may not require an intervention. The intervention or referral to treatment would depend on the overall score of the AUDIT.

Scoring the AUDIT

Dependent Use (20+)

Harmful Use (16‒19)

At-Risk Use (8‒15)

Low Risk (0‒7)

The screening process for drugs is like that used for alcohol. The DAST-10 questionnaire assesses drug use in the past 12 months. (See Figure 1) Interpretation of the results determines the suggested action. Figure 3 describes screening results and suggested intervention. For example, a score of between 3 and 5 using the DAST-10 suggests harmful use and moderate degree of problems related to drug use.

Scoring the DAST-10

High Risk (6+)

Harmful Use (3‒5)

Hazardous Use (1‒2)

Abstainers (0)

Once the screener completes the screening, the score determines next steps for the patient. Next steps could include feedback, brief intervention, and or a referral to treatment. (See Figure 3.) For example, in persons with a low risk, feedback can include discussing the results of screening and risk of harm. A brief intervention is recommended in persons with risky or harmful behavior based on screening results.

Perform a screening for alcohol and drug use using a patient case

Joe is a 32-year-old man who hurt his back three years ago in a car accident. He has used opioids since the accident, but he still complains of pain. He supplements his medications by purchasing additional opioids online and on the street. Joe also has a history of alcohol use. He consumes three to four beers on most days. His family is concerned with his alcohol and drug use and recommends he seek help.

Below are his responses to the AUDIT and DAST-10 questionnaires. Based on his responses to the questions calculate his risk level for alcohol and drug use. See Tables 1 and 2.

Table 1. AUDIT Screening for Joe

Question	Answer	Score
How often do you have a drink containing alcohol?	Daily	4
How many drinks containing alcohol do you have on a typical day when you are drinking?	4	1
How often do you have six or more drinks on one occasion?	Once in awhile	1
How often during the last year have you found that you were not able to stop drinking once you had started?	Never	0
How often during the last year have you failed to do what was normally expected of you because of drinking?	Monthly	2
How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session?	Never	0
How often during the last year have you had a feeling of guilt or remorse after drinking?	Never	0
How often during the last year have you been unable to remember what happened the night before because of your drinking?	Never	0
Have you or someone else been injured because of your drinking?	No	0
Has a relative, friend, doctor, or other health care worker been concerned about your drinking or suggested you cut down?	Yes	4
Total Score		12

Based on Joe’s responses to the AUDIT what is his score and risk level?

Based on his responses to the questions Joe scored 12 on the AUDIT, which puts him as at-risk-use.

Table 2. DAST-10 Screening for Joe

Question	Answer	Score
Have you used drugs other than those required for medical reasons?	Yes	1
Do you abuse more than one drug at a time?	No	0
Are you unable to stop using drugs when you want to?	Yes– The pain gets too great	1
Have you ever had blackouts or flashbacks as a result of drug use?	No	0
Do you ever feel bad or guilty about your drug use?	No	0
Does your spouse (or parents) ever complain about your involvement with drugs?	Yes	1
Have you neglected your family because of your use of drugs?	No	0
Have you engaged in illegal activities in order to obtain drugs?	Yes	1
Have you ever experienced withdrawal symptoms (felt sick) when you stopped taking drugs?	Yes	1
Have you had medical problems as a result of your drug use (e.g., memory loss, hepatitis, convulsions, bleeding)?	No	0
Total Score		5

Based on Joe’s responses to the DAST-10 what is his score and risk level?

Based on his responses to the questions Joe scored a five, which indicates harmful use. We will come back to Joe and determine next steps for him.

Summary of screening

Screening is an important first step to determine the severity and risk level of substance use
Use a universal screening approach
Determine the level of risk and intervention based on screening results
Pharmacists and pharmacy technicians can successfully perform screenings

Brief Intervention (BI)

Following the screening process and based on the results, a BI may be necessary. A brief intervention, also referred to as a brief negotiated interview (BNI), can be performed by a healthcare professional such as a pharmacist, doctor, nurse, or behavioral specialist. Addiction experts recommend using a BNI for those with “at risk” or harmful level of risk based on screening results. During the BNI, the healthcare professional uses motivational interviewing (MI) to have a conversation with the patient and evoke the patient’s personal motivation for change.¹³Before we talk more about BNIs, let’s talk about the five stages of change.¹⁴ Change happens gradually, and individuals can move through the different stages depending on the situation and can move in and out of the different stages. In pre-contemplation, individuals may not be ready to make a change. Figure 4 depicts the five stages of change.

Figure 4. Stages of Change¹⁴

MI has several components, which can be overwhelming and confusing. Here is a brief outline of the components.

Components of MI

Key qualities of MI
Basic Principles of MI
BNI Process
OARS Framework

What is a brief intervention’s purpose and how do we use MI to evoke change? Motivational interviewing is an evidence-based approach to changing behaviors.^13,15

Key qualities of MI include¹³

Facilitate communication between the healthcare professional and patient, where information and guidance is given
Empower individuals to change based on what’s important to them
Respect patient’s autonomy to facilitate change

Healthcare professionals can use MI to engage the patient as an equal partner. Although the name motivational interviewing suggests the healthcare professional is motivating the patient, that isn’t the case. MI is not a way to change individuals, make demands of patient, or instruct them what to do or not do. MI is a way to help examine situations and options for patients. MI is not easy to learn and takes practice. Pharmacists may find MI difficult to apply because counseling and instructing patients is part of everyday practice. MI is different and recognizes that patients are responsible for their actions and taking action to make changes.

MI can be very useful when people

Have mixed feelings or are ambivalent about change
Have low confidence about making changes
May be uncertain about whether they want to make changes, creating low desire
Are not clear about the benefits of change and concerns related to the current situation, so do not deem change important

MI is based on four basic principles^15,16:

Express empathy
Develop discrepancy
Roll with resistance
Support self-efficacy

Expressing empathy is an important first step of the MI process. You do this by seeking to understand how the person feels without judgement. (See Side Bar-tips to express empathy)

Side Bar: Tips to Express Empathy

Maintain eye contact but avoid staring
Use reflective listening to hear and understand and repeat back the information
Avoid sympathy, “I’m sorry this happened to you”
Ask clarifying questions
Avoid passing judgement

Developing discrepancy

Using this principle, the provider discusses the discrepancy between the patient’s values and behavior. This involves discussing the good and the bad related to the behavior. Most patients are aware of the dangers related to substance misuse but are ambivalent about making a change. Discrepancy between the patient’s goals and current behavior motivates change.

Roll with resistance

During the BNI, patients may become defensive when talking about their substance use. This resistance is often because of a fear to change. To decrease resistance, the healthcare professional can redirect the discussion for the patient to understand the harm associated with the behavior. Last, the provider can explore the pros and cons of the patient’s behaviors. For example, a patient may enjoy the euphoria of heroin use (pro) but conversely contracts a cellulitis infection (con).

Support self-efficacy

This guiding principle focuses on supporting patient goals. Patients may feel that they cannot meet goals or expectations. It is important that the provider believe in the patient and promote confidence to support change.

Here is an example of a brief intervention.

Cynthia is at the pharmacy having a discussion with the pharmacist. She is concerned about her alcohol use. The pharmacy technician performs the AUDIT screening and provides the results to the pharmacist for discussion. AUDIT Score: 15 “At-risk use”

Cynthia: “I have been drinking more often over the last few months.”

Pharmacist: “Tell me more about that, Cynthia.” (Reflective listening)

Cynthia: “Work has been very stressful, and alcohol helps me relax. I used to drink only socially on the weekends with friends but now I drink almost every day. My teenage daughter sees me drink every night and she tells me I should stop because it’s not good for me. I don’t want to be a bad role model for her.”

Pharmacist: “So you are saying that you drink alcohol almost every day so that you can cope with the stress at work?” (Reflective listening)

Cynthia: “Yes. I am using alcohol to cope with stress at work.”

As you can see by the conversation above, the pharmacist reflects on Cynthia’s concerns regarding stress and work, which cause her to drink alcohol to cope. The pharmacist makes no judgement on whether the behavior is bad or that she should stop drinking. The pharmacist applies reflective listening and expresses empathy.

Developing discrepancy looks at current behaviors versus future goals. Let’s continue the conversation with Cynthia and apply this principle.

Pharmacist: “It sounds like you are having a hard time at work. But you also love your daughter and want to be a good role model for her. Is that right?” (Developing discrepancy)

Here the pharmacist emphasizes Cynthia’s concerns with her alcohol use and how that affects her daughter. This is the discrepancy. This allows Cynthia to recognize the pros and cons of her alcohol use so that she may change her behavior.

In roll with resistance, patients may pushback stating that they don’t have a problem, or their drinking or drug use is not a problem. In this case, it may require further discussion of current behavior and negative effects related to that behavior. The correlation of cause and effect can motivate the patient to change.

Last, support self-efficacy, where patients are responsible for deciding on actions they will make to support change. This is important because patients take the responsibility of making changes.

Regardless of the stage, MI encourages the patient to express the desire to change or what is referred to as “change talk.” In change talk, look at the following: desire, ability, reasons and need or acronym DARN. See the example below based on the conversation with Cynthia earlier.

Desire: “I need to drink less alcohol.”

Ability: “I could find healthier ways of coping with the stress at work, like yoga or meditation.”

Reasons: “I want my daughter to be proud of me.”

Need: “I might lose my daughter.”

This “change talk” can prepare the individual to make changes and act on those changes. As mentioned earlier, MI is a collaborative approach between the patient and healthcare professional providing the brief negotiated interview and involves four fundamental processes. Let’s talk about each of the processes.

Engage
Focus
Evoke
Plan

Engage

Having an honest and open conversation that engages the patient is the first step in the process. Listening without passing judgement or trying to fix the problem is important. The OARS framework includes interactive techniques to engage the patient. OARS stands for open questions, affirmations, reflections, and summaries. Table 3 describes each element of the framework and purpose.

Table 3. OARS framework¹⁵

Interview Skill	Description	Purpose
Open-ended questions	Ask the patient open-ended question vs. yes or no	Builds trust Gathers information
Affirmations	Show empathy for the patient Acknowledge the patient’s ability to make a change in their life Emphasize key points that are important to the patient.	Discuss/encourage patient’s abilities and healthy behaviors Build the patient’s confidence and self-efficacy
Reflections	Listen and understand what the patient is saying and repeating back to the patient	Repeat back what was said Incorporate unspoken feelings thoughts or behaviors
Summaries	Review key points of the conversation Use reflective listening	Help the patient see the big picture Create an action plan Emphasize key points of the conversation

Focus

During the conversation, focus on guiding patients to identify behaviors they struggle with or ambivalent to make a change. During the conversation, understand the patient’s dilemma or ambivalence. Asking what is important to them can help to identify the target and behavior that may inhibit them from reaching their goals.

Evoke

During the evoke process, we want patients to discuss their reasons for change and incorporate “change talk” during the conversation. Let’s go back to the conversation with Cynthia. Cynthia recognizes that she drinks alcohol to cope with the stress at work. She is also concerned that her drinking upsets her daughter and Cynthia wants to be a good role model. Her reason for change is that she wants to be a good role model for her daughter. Changing her behavior for her daughter is important to her.

Plan

The patient would commit to a plan of action that is simple, realistic, specific, and attainable. The patient should also set a timeline for the plan.

The incorporation of core skills is fundamental to MI. The acronym OARS, involves four interviewing skills to enhance motivation for change.¹⁵

Asking open-ended questions allows patients to provide more information and can provide insight to their feelings and thoughts. Close-ended questions only elicit a yes or no response with no further details. Here is an example of an open-ended versus close-ended question.

Close-ended question: Do you drink alcohol often?
Open-ended question: How much alcohol do you drink per week?

Affirmations

Statements of affirmation acknowledge the patient’s ability to make a change. Statements by the provider emphasize key points most important to the patient and support the patient to make changes.

Reflections

Reflections involve listening and understanding what the patient is saying. This can be as simple as repeating back the patient’s statements and incorporating the patient’s unspoken feelings or intent. Furthermore, reflections confirm with the patient that what you are repeating back is accurate. An example might be saying, “I heard you say that you have tried to stop drinking in the past and you have not been able to do it and I sense you are frustrated. Is that correct?” The latter statement incorporates the patient’s unspoken feelings and confirms an accurate account of the reflection.

PAUSE AND PONDER: Along the substance use continuum, with whom would you negotiate a reduction in use to lower risk levels?

Performing a BNI

A BNI uses MI to raise awareness in patients with risky or harmful substance use. Here are four important steps to follow when conducting a BNI.

Build rapport-raise the subject

Open the conversation by beginning with a general conversation and ask permission to discuss the topic of substance use. For example, you could say: “Thank you for meeting with me today. Would you mind speaking with me? Could I ask you some questions about your substance use?”

This engages the patient in the conversation. The conversation could highlight the patient’s substance use and explore the pros and cons of the situation. For example, with Cynthia, her alcohol use allows her to cope with stress at work. Conversely, her alcohol use makes her daughter upset and she wants to be a good role model for her. During the BNI, the provider should use open-ended questions to allow the patient to provide more information and further explore the patient’s substance use. Incorporating reflective listening, summarizing what the patient says, and weighing the pros and cons allows for decisional balance.

Provide feedback

After listening to the patient ask permission again to offer feedback based on the conversation. Review the screening results with the patient and connect consequences to substance use. Here is an example.

Karla is a 32-year-old mother of three children. She and her children are in the emergency department because of a car accident. Karla’s alcohol level is 0.09. (Blood alcohol levels ≥ 0.08% = legally impaired)

You perform a screening on Karla using the AUDIT. Her score reveals harmful use and when asked about her alcohol use causing injury, she states in the affirmative that she was under the influence of alcohol while driving with her children and feels extremely guilty and upset. During the conversation you ask permission to speak to Karla about her alcohol use and how this may be a direct cause of the accident. Karla may recognize the impact of her alcohol use and change her behavior.

Build readiness to change

Here we ask if they may be willing to make some changes. When doing so we can ask how willing they are or how ready they are to make a change. The provider can use a visual tool to assess willingness to change. This visual tool is a readiness ruler. (See Figure 5.) When approaching the patient, clinicians can use the readiness ruler in a way similar to that of a pain scale. For example, “On scale of 1 to 10, where 1 means you are not at all ready to change to 10 meaning you are very or completely ready to change. How ready are you to make a change about your substance use?”

Figure 5. Readiness Ruler¹⁵

PAUSE AND PONDER: What would be your response to a patient that states they are a 3 on the readiness ruler?

Negotiate a plan for change

Based on the screening results, the plan can vary. It may involve reducing risky use of substances and or a referral to treatment. The plan should be simple, realistic, specific, and attainable. Following up with patients to discuss changes and reinforcing the plan for change will promote long-term success.

Referral to Treatment

Patients diagnosed with an SUD by a provider or who have behaviors that are substance dependent (e.g., substance related injuries or inability to stop) or high-risk, such as increased frequency of substance use, require treatment. Healthcare professionals can easily refer the patient to treatment. Initiating the referral process by calling a trained treatment specialist on behalf of the patient to schedule an appointment can better assist the patient. Many resources are available to find treatment centers for patients. SAMHSA’s National Treatment Facility Locator is a helpful resource to locate a treatment center:¹⁷ http://findtreatment.samhsa.gov. Treatment options include counseling, medication assisted treatment, complimentary wellness, and support groups. The level of care is individualized and based on the severity of the substance use and comorbidities.

Key points for referral to treatment

Make a plan with the patient
Use a warm handoff
Decide how you will communicate with the provider
Confirm the plan with the patient

A warm handoff involves personally introducing the patient to the treatment provider. This helps build rapport and trust and increases the patient’s willingness to schedule an appointment. Warm handoffs are also more successful than passive referrals.

SBIRT in Practice

Healthcare professionals can utilize SBIRT in many areas of practice. Pharmacists and pharmacy technicians are one of the most accessible healthcare professionals, especially in community pharmacy settings. In this setting, pharmacists and pharmacy technicians can meet with patients to perform screenings, conduct a BNI, or refer to treatment, with the ultimate goal of reducing the risk of an SUD and patient harm.

Harm reduction is key to help to minimize adverse effects related to substance use.¹⁸ Harm reduction involves policies, programs, and practices that focus on the individual’s human rights. The goal of harm reduction is to keep people safe. Providers can reinforce positive changes in patients using MI. Examples of harm reduction include drug take back programs, access to naloxone, and syringe distribution.¹⁸ Distributing clean needles/syringes not only reduces harm for the persons using them but also contributes to community safety by reducing the spread of HIV, hepatitis, and other blood borne diseases.

Sadly, in community pharmacy settings, several barriers exist. Some include lack of privacy, lack of staffing, lack of time, and stigmas.^{19, 20}A stigma is an inaccurate belief against individuals based on a specific characteristic, race, or nation of people.^22,23 Often, we see this in patients with a mental illness. Stigma towards individuals with SUDs also exist and are one of the most challenging barriers because of a misconception that an SUD is not a disease or medical condition and individuals with an SUD are at fault.²³ You may hear people say, “They don’t want to get better” or “I don’t want those kinds of people in my pharmacy.” Stigmas can impede care and harm the patient.

It is important to recognize that an SUD is a medical condition and requires treatment. Stigmatizing language like “addict” or “junkie” has a negative connotation and can lead to barriers in care. Avoid using stigmatizing language. For example, an addiction is an SUD. Clinicians need to replace the words “addict” or “junkie” with the words “person with an SUD.” This recognizes the disease and not the person with the SUD.

Patient case Joe and brief intervention.

AUDIT score: 12-At risk use

DAST-10 score: 5-Harmful use

What recommendations are appropriate based on the screening results?

Joe’s alcohol screening score of 12 shows that he is at risk use and his DAST-10 score of 5 shows that his use of drugs is harmful. In Joe’s case, he would benefit from a brief intervention and referral to treatment.

A brief intervention would be helpful for Joe. Here is an example of an intervention between Joe and the pharmacist at the ambulatory care clinic.

Pharmacist: “Good morning, Joe. Would it be OK if I speak with you for a few minutes about your screening results that you took earlier?”

Joe: “I guess that would okay.”

Pharmacist: “Based on your screening results, your alcohol use puts you at risk for harm and your drug use is possibly already harmful for your health and for those around you.”

Joe: “I don’t know what you are talking about. I don’t have a problem.”

Pharmacist: “Let me ask you this. From your perspective what is your relationship with alcohol and drugs?”

Joe: “Well I guess I do drink every day and I am on oxycodone for the pain. I was in an accident a few years ago and the pain won’t go away. I need the oxy. My family thinks I need help.”

Pharmacist: “Thank you for opening up to me and telling me how you feel after your accident and that you’re still in pain. Tell me some of the things that are good about your alcohol and drug use and some things that are not good?”

Joe: “Well alcohol helps me forget about my problems for little bit. The drugs help my pain, but I feel guilty sometimes because I buy it off the street because my doctor won’t give me enough.”

Pharmacist: “What is it about your drug use that makes you feel guilty?”

Joe: “My family means a lot to me, and I am afraid that my wife might leave me and take the kids.”

Pharmacist: “It sounds like you love your family. What changes do you think you could make about your alcohol and drug use?”

Joe: “Well I guess I could cut back on my drinking and find some other ways to deal with my stress. I rely too much on the oxy so I don’t think I could cut back on that right now.”

Pharmacist: “That’s great that you are willing to cut back on your alcohol use. Tell me what that would look like?”

Joe: “I think I could limit myself to three beers a day instead of four or five. I can start there and see how it goes.”

Pharmacist: “That’s a great start. On a scale of 1-10 where 1 means that you are not at all ready to make this change and 10 meaning that you are completely ready where do you think you would put yourself on this scale?”

Joe: “I guess I would rate myself as being a 7.”

Pharmacist: “Joe, that’s great. A 7 is very close to being completely ready to make this change. Can I ask you what is holding you back from you being at a 10?

Joe: “I don’t think that I am completely ready to make a change. I am also afraid of failing.”

Pharmacist: That is a valid fear. Speaking with someone about your alcohol use and treatment can really help. Would you be willing to meet Dr. Smith here at the office and set up an appointment with him?”

Joe: “Sure. I could meet him now while I am at the clinic.”

The pharmacist walks Joe down the hall to meet Dr. Smith who is a behavioral specialist focusing on SUDs. The pharmacist performs a warm handoff, introducing Joe to Dr. Smith.

The pharmacist engaged Joe in the conversation and reflected on what Joe said and felt. During the conversation, the pharmacist asked open-ended questions to gain more insight into Joe’s alcohol and drug use and discussed his readiness to make a change. Joe rated himself as a 7 on the readiness scale. Discussing where they are on the readiness ruler can determine patients’ willingness to change, possible resistance, and potential fears. Joe recognized the pros and cons of his alcohol and drug use and made a plan to decrease his alcohol use and meet with a behavioral specialist about his drug use.

Conclusion

SBIRT is a public health approach to intervene with individuals at risk of an SUD. SBIRT is effective in reducing alcohol use by 40% and illicit drug use by 76%.²⁴ Applying universal screening and promoting change to reduce high-risk behavior before it escalates to an SUD can greatly reduce patient harm and minimize healthcare costs.

Depending on the setting, time constraints, day-to-day workload, and staffing, SBIRT may be a challenge to perform. Pharmacists and pharmacy technicians should be knowledgeable about SBIRT and treat persons with SUDs, where feasible, in a professional, caring manner. SBIRT can be a useful approach to identify those with at risk behaviors and apply early intervention methods to minimize harm and development of an SUD.

SBIRT Exam Questions
Pharmacist
After completing this continuing education activity, pharmacists will be able to
1. Discuss the prevalence and consequences of SUDs
2. Describe the components of SBIRT
3. Recognize motivational interviewing skills to promote readiness to change
4. Discuss harm reduction and how it pertains to SUDs
5. Describe barriers associated with the use of SBIRT in the community setting

1. SBIRT is a public health approach to identify persons at risk of a substance use disorder. For the acronym SBIRT, what does BI stand for?
A. Brief Interaction
B. Brief Intervention
C. Brief Intermediation

2. In the U.S., which of the following substances is most abused?
A. Nicotine
B. Alcohol
C. Oxycodone

3. Which of the following is used to screen for alcohol use?
A. AUDIT
B. DAST
C. ADST

4. Jim, a 42-year-old man, completed the alcohol screening questionnaire and scored 17. How would you rate his alcohol use?
A. At-risk use
B. Harmful use
C. Dependent use

Use patient case Sean for questions 5-7.
Sean is 42-year-old male who presents to the emergency department after a car accident. He scores 14 on the AUDIT questionnaire and the pharmacist performs a BNI. He has not worked since COVID and drinks to forget about his problems. The pharmacist discusses Sean’s drinking habits and related harm. Sean is defensive and states that he does not have a drinking problem.

5. Which of the following is an appropriate response to Sean’s statement, that he does not have a drinking problem?
A. “It seems to me you have a drinking problem. That’s how you ended up in the hospital.”
B. “You need to stop drinking or this will happen again. I’ve seen it time and time again.”
C. “Can we talk more about how you ended up in the emergency department today?”

6. The pharmacist reflects on Sean’s statements. Which is one of the following is example of reflective listening?
A. “Let’s create an action plan to decrease your alcohol use so you can have some goals to accomplish.”
B. “ I know that you don’t want to be here today, but can you see how important it is?”
C. “Thank you for sharing how you feel about losing your job. That must be hard for you.”

7. The pharmacist wants more information about Sean’s motivation to change behavior. Which of the following promotes the BEST response?
A. “Are you willing to cut back on your alcohol use?”
B. “What are some negative effects of your alcohol use?”
C. “Do you think your alcohol use contributed to the car accident?”
8. Fill in the blank. Harm reduction involves policies, programs, and practices to focus on the individual’s ________ ________.
A. Substance Use
B. Harmful Behaviors
C. Human Rights

9. Which of the following is an example of non-stigmatizing language?
A. He has a substance use disorder
B. He is addicted to drugs
C. He is heroin junkie

10. Which of the following is a barrier to providing SBIRT in a community pharmacy setting?
A. Cost of screening
B. Safety
C. Stigmas

Pharmacy Technician Post-test
After completing this continuing education activity, pharmacist technicians will be able to
1. Discuss the prevalence and consequences of SUDs
2. Describe the components of SBIRT
3. Discuss harm reduction and how it pertains to SUDs
4. Describe barriers associated with the use of SBIRT in the community setting

2. In the U.S., which of the following substances is most abused?
A. Nicotine
B. Alcohol
C. Oxycodone

3. Which of the following is used to screen for alcohol use?
A. AUDIT
B. DAST
C. ADST

4. Which of the following is an example of non-stigmatizing language?
A. He has a substance use disorder
B. He is addicted to drugs
C. He wants to be a junkie

5. Which of the following is associated with the distribution of clean needles/syringes?
A. Reduction of blood borne diseases
B. Increase in illicit drug use
C. Increase in drug overdoses

6. What are the recommended alcohol drinking limits for men who are younger than 65 years?
A. No more than 1 drink per day and no more than 7 drinks per week
B. No more than 2 drinks per day and no more 14 drinks per week
C. No more than 4 drinks per day and no more than 14 drinks per week

7. Which of the following is used to screen for drug use?
A. AUDIT
B. DAST
C. ADST

8. What is the goal of harm reduction?
A. Keeping people safe
B. Stopping drug use
C. Giving people free needles

9. Which of the following is a barrier to providing care to those with a SUD in a community pharmacy setting?
A. Cost of screening
B. Safety
C. Stigmas

10. SBIRT is effective in reducing alcohol use by___ %
A. 40%
B. 76%
C. 20%

References

1. Substance abuse and mental health services administration. 2017 NSDUH annual national report. Accessed June 9, 2021. Available at https://www.samhsa.gov/data/report/2017-nsduh-annual-national-report
2. Centers for Disease Control and Prevention. Excessive Drinking is Draining the U.S. Economy. Updated December 2019. Accessed June 21, 2021. https://www.cdc.gov/features/costsofdrinking/
3. National Drug Intelligence Center. National Drug Threat Assessment. Washington, DC: United States Department of Justice; 2011. Accessed June 21, 2021. www.justice.gov/archive/ndic/pubs44/44849/44849p.pdf
4. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal Costs of Prescription Opioid Abuse, Dependence, and Misuse in the United States. Pain Medicine. 2011; 12:657-667.
5. Rehm J, Room R, Graham K, et al. The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: An overview. Addiction. 2003; b;98(9):1209–1228.
6. Institute of Medicine (IOM). Broadening the base of treatment for alcohol problems. Washington, DC: National Academies Press; 1990.
7. Babor TF, McRee BG, Kassebaum PA, Grimaldi PL, Ahmed K, Bray J. Screening, Brief Intervention, and Referral to Treatment (SBIRT). Subst Abuse. 2007;28(3):7–30.
8. Shonesy BC, Williams D, Simmons D, Dorval E, Gitlow S, Gustin RM. Screening, Brief Intervention, and Referral to Treatment (SBIRT) in a retail pharmacy setting: The pharmacist’s role in identifying and addressing risk of substance use disorder. J Addict Med. 2019; 13(5):403-407.
9. WHO screening and AUDIT. Accessed June 9, 2021. http://www.who.int/substance_abuse/activities/sbi/en/
10. Smith PC, Schmidt SM, Allensworth-Davies D eta. A single-question screening test for drug use in primary care. Arch Intern Med. 2010; 170(13):1155−1160.
11. Centers for Disease Control and Prevention. Alcohol use and your health. Accessed June 9, 2021. Available at: http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm
12. National Institute of Alcohol Abuse and Alcoholism (NIAAA) for alcohol. Accessed June 9, 2021. Available at https://www.rethinkingdrinking.niaaa.nih.gov/how-much-is-too-much/is-your-drinking-pattern-risky/Drinking-Levels.aspx.
13. Miller WR, Moyers TB. Motivational Interviewing and the clinical science of Carl Rogers. J Consult Clin Psychol. 2017; 85(8):757-766. doi: 10.1037/ccp0000179.
14. Prochaska JO, Velicer WF, Rossi JS, et al. Stages of change and decisional balance for 12 problem behaviors. Health Psychol. 1994;13:39–46.
15. Miller WR, Rollnick S. Motivational Interviewing: Helping people to change (3rd Edition). Guilford Press; 2013.
16. Miller WR, Zweben A, DiClemente CC, Rychtarik RG. Motivational enhancement therapy manual: A clinical research guide for therapists treating individuals with alcohol abuse and dependence. Rockville, MD: National Institute on Alcohol Abuse and Alcoholism. Accessed June 9, 2021. Available at https://www.motivationalinterviewing.org/sites/default/files/MATCH.pdf
17. Substance Abuse and Mental Health Services Administration. Behavioral health treatment services. Accessed August 2, 2021. Available at https://findtreatment.samhsa.gov/
18. Harm reduction international. Accessed July 7, 2021. Available at https://www.hri.global/what-is-harm-reduction.
19. Hawk KF, Vaca FE, D'Onofrio G. Reducing fatal opioid overdose: Prevention, treatment and harm reduction strategies. Yale J of Biol and Med 2015;88(3):235–245.
20. Werremeyer A, Mosher S, Eukel H, et al. Pharmacists’ stigma toward patients engaged in opioid misuse: When “social distance” does not mean disease prevention. [published online ahead of print, 2021 March 22]. Subst Abuse. 2021;Mar 22; 1-8. doi: 10.1080/08897077.2021.1900988
21. Murphy A, Phelan H, Haslam S, Martin-Misener R, Kutcher SP, Gardner DM. Community pharmacists’ experiences in mental illness and addictions care: a qualitative study. Subst Abuse Treat, Prev, and Policy. 2016; 11:6 DOI 10.1186/s13011-016-0050-
22. Caddell J, Gans S. Verywellmind. What is stigma? Accessed August 5, 2021. Available at https://www.verywellmind.com/mental-illness-and-stigma-2337677
23. Fernandez L. Addiction or Substance Use Disorder? How Using the Right Language Helps Fight Stigma. Accessed August 12, 2021. Available at https://illuminaterecovery.com/blog/substance-use-disorder-stigma/
24. Aldridge A, Linford R, Bray J. Substance use outcomes of patients served by a large US implementation of Screening, Brief Intervention and Referral to Treatment (SBIRT). Addiction. 2017; Feb; 112 (Suppl. 2), 43–53 doi: 10.1111/add.13651.

Pain Management in Palliative Care

After completing this application-based continuing education activity, pharmacists will be able to

· Describe the principles of palliative and hospice care

· Discuss treatment options to manage the end-of-life symptoms of air hunger and/or pain

· Calculate appropriate opioid dose-equivalents

· Recognize risks of diversion in the hospice setting

After completing this application-based continuing education activity, pharmacy technicians will be able to

· Describe the principles of palliative and hospice care

· Identify treatment options to manage the end-of-life symptoms of air hunger and/or pain

· Recognize risks of diversion in the hospice setting

Palliative and hospice care mitigate suffering and maintain patients’ dignity and comfort throughout the course of disease. Palliative and hospice care are different, but related. Patients become eligible for hospice care (an insurance benefit) when they no longer wish to pursue curative therapies, and their prognosis is 6 months of life expectancy or less. Hospice teams practice comfort care. Palliative care is available throughout a patient’s life-threatening disease. Towards life’s end, many patients experience pain and/or dyspnea (e.g., shortness of breath or air hunger). Opioids can alleviate these symptoms, but healthcare professionals face many clinical decisions when choosing a pain control regimen. They use equianalgesic dosing to convert patients from one opioid formulation to another. Particular issues arise in different care settings; practitioners in hospitals must manage pain crises, while those in transitional facilities, such as hospice houses offering respite care, must select appropriate routes of administration. Patients may have misconceptions about medications in hospice; being well-versed in opioids’ uses and side effects allays these concerns. Palliative/hospice care should always put the patient’s comfort first.

INTRODUCTION

In 2020, The World Health Organization estimated that 40 million people need palliative care each year.¹ Palliative care is “an interdisciplinary care delivery system designed to anticipate, prevent, and manage physical, psychological, social, and spiritual suffering to optimize quality of life for patients, their families, and caregivers.”²As patients near the end of their lives, they may elect to pursue hospice care with a greater focus on maintaining their dignity and comfort.³ Such care is available in a variety of settings, including acute care hospitals, nursing homes, assisted living facilities, hospice houses, and the patient’s own home.⁴

A misconception—that palliative care is relevant only at the end of a patient’s life—is common. All patients contending with serious illnesses can benefit from palliative services.⁵ Patients with chronic diseases may choose to pursue both active treatment of their condition and palliative care for symptom management, working with a specialized, interdisciplinary team of healthcare professionals.⁴ This team collaborates with patients and their families to identify the patient’s treatment priorities and work to eliminate suffering throughout the course of the disease.⁶

Pharmacists are important members of the palliative care team and are involved with developing and implementing an individualized treatment plan for each patient.⁷ These plans “[require] specific patient goals with pharmacologic and nonpharmacologic management to improve quality of life while reducing costs and unnecessary medications.”⁷ Pharmacists provide valuable input to prescribers regarding medication selection, dosing recommendations, and nontraditional routes of administration, all of which will vary from patient to patient.^6,7

Pharmacy staff also have the opportunity to educate patients and their families directly regarding appropriate medication use and side effect management. Additionally, they may dispel myths about opioid use in palliative and hospice care and help identify allergies and adverse reactions. They are also well-placed to identify instances of medication diversion in both inpatient and outpatient settings.^6-8

Healthcare providers should feel comfortable managing patients pursuing palliative and hospice care, recognizing that medication is but one part of the care provided. The focus should be squarely on patients and their families and the goal of alleviating their suffering, no matter the stage of their disease.

PRINCIPLES OF PALLIATIVE/HOSPICE CARE

Palliative care is comprehensive in its management of the patient. According to the International Association for Hospice and Palliative Care, it⁹

Provides relief from pain and other distressing symptoms
Affirms life and regards dying as a normal process
Integrates the psychological and spiritual aspects of patient care
Offers a support system to help the family cope during the patient’s illness and in their own bereavement

Knowing that palliative care is not withdrawal or withholding of care is critical; it is simply a treatment with a different goal in mind: in this case, comfort, whether the patient is seeking cure or not. Palliative care comprises many components aside from medication; these may include varied offerings like mental health counseling, art therapy, and pastoral care, among others. All hospice care is palliative in nature, but not all palliative care is hospice care.¹¹

Table 1 compares both types of care.

Table 1. Characteristics of Palliative vs. Hospice Services^12-14
	Palliative Services	Hospice Services
When is it implemented?	As early as diagnosis; at any stage of disease	6-month life expectancy or less
Is it used along with active treatment/life-prolonging measures?	Yes	No
Where is it offered?	Usually an acute care facility or outpatient clinic, but may also be offered in nursing home, hospice house, or private residence	Various settings, including an acute care facility, nursing home, hospice house, private residence
Are psychosocial/emotional support services offered?	Yes	Yes
Does it involve treatment, including medication, for symptom relief?	Yes	Yes

Opioids in End-of-Life Care: Management of Pain and/or Dyspnea

Pain and dyspnea (also known as shortness of breath or air hunger) are common symptoms at the end of life.^15,16 This holds true even for patients without a respiratory causative diagnosis such as chronic obstructive pulmonary disease; patients with cancer (70%), AIDS (11% to 62%) and other terminal illnesses also experience difficulty breathing at the end of life.¹⁷ And in one study of 988 terminally ill patients, half experienced moderate or severe pain.¹⁸ Easing these symptoms reduces patient and family distress during the active dying process.

OPIOID PHARMACOLOGY

Opioids are the mainstay of therapy for pain and dyspnea in end-of-life care due to their multimodal mechanism of action.¹⁵ In the body, they bind to three different opioid receptor subtypes, known as mu-, kappa-, and delta-receptors.^16,19

Mu (μ) are responsible for analgesia, sedation, gastrointestinal distress, respiratory depression, euphoria, dependence
Kappa (κ) are responsible for analgesia, sedation, dyspnea and respiratory distress, euphoria
Delta (δ) are responsible for analgesia and spinal analgesia

These receptors are present in pain pathways in the central nervous system; by binding to them, opioids inhibit stimulatory neurotransmitters that conduct pain signals to the brain.²⁰

Dyspnea’s exact mechanism at the end of life is poorly understood; however, opioids’ ability to mitigate shortness of breath is possibly due to their secondary effects. Opioids may alter a patient’s ventilatory response to carbon dioxide, ease hypoxia, change inspiratory flow resistive loading, and improve oxygen consumption.²¹ In other words, opioids decrease respiratory drive, alter the perception of breathlessness, change peripheral opioid receptors’ activity in the lung, and decrease anxiety, all of which contribute to the sensation of dyspnea.²²Patients and caregivers perceive the shortness of breath as anxiety and often reach for the benzodiazepines to relieve this discomfort. However, opioids are the drug of first choice for dyspnea and may provide relief of the underlying cause thereby minimizing anxiety.

Selecting an Opioid

Consideration of patient-specific factors should guide the healthcare provider’s selection of opioid for pain and dyspnea.^23,24Opioids’ pharmacokinetic profiles differ, sometimes substantially, from one medication to another. ²⁵ Additionally, patients’ unique genetic identities may influence an opioid’s bioavailability, metabolism, and the patient’s physical response to the opioid.²³ Table 2 lists some questions clinicians should ask themselves when deciding on a pain management regimen.

Table 2. Clinical Considerations in the Selection of Opioids for a Patient Receiving Palliative Care²⁵
Consideration	Example
What kind of pain am I treating?	Breakthrough vs. chronic, neuropathic vs. skeletomuscular
What are the patient’s needs and goals?	Some patients may prioritize total pain relief; others may tolerate more pain in order to be less sedated
Is it practical and easy to administer the ordered dose?	Order reasonable, whole-number doses at even dosing intervals, i.e., avoid oxycodone 3 mg by mouth every 5 hours
Is the patient likely to derive meaningful relief from this regimen?	Consider renal and hepatic function, body composition, feasible routes of administration, drug interactions, etc.

Common Opioids Used in Palliative and Hospice Settings

Opioids are classified into four groups based on their chemical structure:

Phenanthrenes
Benzomorphans
Phenylpiperidines
Diphenylheptanes

The importance of these chemical structures will be discussed in the “Dispelling Common Hospice Myths” section.

Table 3 describes opioids commonly used in the palliative and hospice settings, and some of their pharmacokinetic and pharmacodynamic characteristics.

*Table 3. Opioids Commonly Used in the Palliative and Hospice Settings^15,16,26**
Opioid	Pharmacokinetic and Pharmacodynamic Characteristics
Morphine (Avinza, Kadian, MS Contin, Duramorph, MSIR)	Phenanthrene HydrophilicMetabolism: glucuronidation Highly protein-bound Mean elimination half-life: 2 hours
Hydrocodone (Norco, Hycet, Vicodin, Lorcet, Lortab) Note: only available in combination with non-opioid analgesics	Phenanthrene Metabolism: CYP2D6 enzyme Mean elimination half-life: 2.5-4 hours
Oxycodone (Oxycontin, OxyIR, Roxicodone, XTAMPZA, Percocet) Note: available on its own and in combination with non-opioid analgesics	Phenanthrene Metabolism: CYP2D6, CYP3A4 enzymes Mean elimination half-life: 2.5-3 hours
Hydromorphone (Dilaudid, Exalgo)	Phenanthrene HydrophilicMetabolism: glucuronidation Mean elimination half-life: 2-3 hours
Fentanyl	Piperidine Metabolism: CYP3A4 enzyme
Tramadol (Ultram, Ryzolt)	Mu-opioid agonist Metabolism: CYP2B6, CYP2D6 and CYP3A4 enzymes Mean elimination half-life: 6-8 hours

*Note: Methadone, a diphenylheptane synthetic opioid derivative, is also commonly used for palliative and hospice patients with severe pain who are not opioid-naïve. Its metabolism is non-linear and its dosing is complicated; this continuing education activity will not discuss methadone in detail.²⁶

Renal and Hepatic Dysfunction

Renal and hepatic metabolism affects multiple opioids. Table 4 discusses the use of these medications in instances of advanced kidney or liver disease and identifies drugs that should be avoided in these populations. In patients with impaired metabolism of opioids, providers should select the lowest effective dose and titrate cautiously to effect.

Table 4. Opioids in Organ Impairment^15,27,28,29

Safe	Use with Caution	Avoid
Renal Impairment
Hydromorphone Methadone Fentanyl	Hydrocodone Oxycodone Tramadol	Morphine
Hepatic Impairment
Hydromorphone Fentanyl Morphine	Hydrocodone Oxycodone Tramadol	Methadone

EQUIANALGESIC DOSE CONVERSIONS

It is common in palliative and hospice care for patients to require multiple opioids for symptom management.³⁰ As patients transition from the acute inpatient setting to outpatient care, clinicians should also consider converting parenteral opioid doses to oral forms whenever possible.^31,32 This aids patient comfort and eases administration, particularly when a caregiver, rather than a medical professional, is responsible for the patient’s medication management.

Equianalgesia refers to various opioids’ analgesic doses that are estimated to provide the same pain relief.³³Equianalgesic dose conversion charts and calculators are widely available as tools to help clinicians determine appropriate opioid dosages for patients; however, pharmacists should be aware that all conversion charts are approximations and are only to be used as guides.^34,35 Different sources may have slight variances in their conversion factors.³⁶ Clinicians may use these charts as a way to double-check their arithmetic by comparing the doses calculated using different tables. Table 5 is one example of an equianalgesic dose conversion chart. Additionally, because of patient-specific factors, the appropriate dose for a patient may not always be the one calculated based on a standardized ratio. There is no substitute for sound clinical judgment!

Table 5. Equianalgesic Opioid Dose Conversions ^15,37
Drug	Oral Dose	Parenteral Dose	Conversion Ratio (to oral morphine)
Morphine	30 mg	10 mg	3:1
Oxycodone	20 mg	--	2:3
Hydrocodone	20 mg	--	2:3
Hydromorphone	7 mg	1.5 mg	Oral hydromorphone: 1:4 Parenteral hydromorphone: 1:20

To convert from one parenteral or oral opioid dose to another, follow these steps^3,33,37,38:

1. Determine the total daily dose of current regimen in morphine equivalents

a. Add all doses of opioids the patient receives over a 24-hour period

b. Calculate equianalgesic morphine dose by multiplying the dose of the opioid you are switching from by the conversion factor*

2. Reduce the total daily dose of the new opioid by 25%-50% for incomplete cross tolerance*

3. Select the new dosing interval, accounting for short- and long-acting dosage forms

a. Convert the total daily dose (TDD) of the old opioid to the new opioid using a dose conversion chart

b. Determine the breakthrough/as-needed (PRN) dose of the new opioid by calculating 10-15% of the TDD for each PRN dose

Utilize short dosing intervals (every 1-3 hours) for PRN pain control in hospice/palliative care

* Incomplete Cross Tolerance

On occasion, clinicians may need to switch patients from one opioid to another when a patient develops tolerance (decreased pharmacologic response pursuant to repeated or prolonged drug exposure).³⁹Incomplete cross tolerance occurs when patients have developed some level of tolerance to opioids with pharmacologically similar structures. However, the extent of this tolerance varies, and clinicians may unintentionally overdose patients by over-estimating their ability to handle an equianalgesic dose of a new opioid.³⁹ To account for this phenomenon, clinicians should consider reducing the dose of the new opioid (i.e., the one you are switching to) by 25% to 50%.^39,40

Many patients experience decreased analgesia from their pain regimen over time and benefit from opioid rotation. Opioid rotation is the process of switching the patient to a novel opioid not currently part of their pain management plan.³³Of note, clinicians may also consider opioid rotation if patients experience intolerable side effects from a drug within the same class.

Example 1: Converting from the parenteral to the oral form of the same drug

Convert a patient on an IV morphine drip at 1 mg/hr, to an oral regimen or sustained-release morphine.

Convert from IV to PO formulation using conversion factor
- 24 mg IV morphine TDD * [3 mg PO morphine/1 mg IV morphine] = 72 mg PO morphine in 24 hours
Split total daily dose into two oral doses of the extended-release formulation
- 72 mg ÷ 2 = morphine sulfate ER 36 mg PO every 12 hours; but morphine sulfate ER is available in 30 mg tabs
- Final dose – morphine sulfate ER 30 mg PO every 12 hours
Calculate 10-15% of TDD for the breakthrough dose
- TDD = 60 mg
- 10% of TDD = 6 mg
- 15% of TDD = 9 mg
- Round to 10 mg PO morphine every 4-6 hours PRN; this dose was rounded up because we had to lower the around-the-clock dose due to the available dosage form.

Example 2: Converting from the parenteral form of one drug to the oral form of another drug

Convert hydromorphone 1 mg IV every 2 hours to a pain control regimen involving oxycodone extended release (ER) and oxycodone immediate release (IR) for breakthrough pain.

Calculate total daily dose
- Hydromorphone 1 mg IV every 2 hours = 12 mg IV hydromorphone/day
Convert to new opioid using conversion factor
- 12 mg IV hydromorphone x [20 mg oxycodone/1.5 mg IV hydromorphone] = 160 mg oxycodone/24 hours
Dose reduce by 25%
- 25% of 160 mg = 40 mg oxycodone
- 160 mg – 40 mg = 120 mg oxycodone/24 hours
Round to a reasonable, whole number dose and interval for long-acting formulation
- 120 mg oxycodone/24 hours = 60 mg oxycodone ER every 12 hours
Calculate 10-15% of the TDD for breakthrough dose
- 120 mg oxycodone TDD x 10 to 15% = 10 mg or 15 mg every 3-4 hours
- Use remaining 50% of total daily dose as short-acting formulation

Note that healthcare providers still need to use good clinical judgment when determining the final recommendation; there is no standardized dosing interval for short-acting opioids, although long-acting opioids are not given more frequently than every eight hours.^41,42

ROUTE-SPECIFIC CONSIDERATIONS

Intensol Formulations

Oral opioids are the formulation of choice for most patients pursuing palliative and hospice care.⁴³ At the end of life, many patients become frail and lose muscle tone, resulting in decreased swallowing ability; however, many of the most common medications used in hospice, including morphine, come in a highly concentrated intensol formulation. These concentrated products deliver sizable doses in very small liquid volumes.⁴⁴

Even in cases of severe pain and advanced illness, oral morphine remains an effective and suitable option; while inpatient facilities sometimes use morphine infusions, infusions are often unnecessary for patients at the end of life.^44,45To be most effective, clinicians should prescribe and administer morphine around the clock at consistent intervals to ensure steady pain control.⁴⁵

Concentrated morphine solution (Roxanol) is available in a 20 mg/1 mL solution, allowing effective delivery of the medication even in patients unable to swallow.⁴⁶ In this situation, the caregiver can prop the patient’s body to a 30-degree angle and instill up to 1 mL of the intensol solution into the buccal (cheek) area. This area serves as a “reservoir” for the medication as it slowly trickles down into the gastrointestinal tract where it is absorbed.⁴⁴

Transdermal Fentanyl Patches

Transdermal fentanyl patches may be a reasonable option for opioid-tolerant patients requiring around-the-clock pain control. Clinicians, however, should never employ transdermal fentanyl for immediate or intermittent pain relief as it takes approximately 24 hours (up to as much as 48 hours) for serum fentanyl concentrations to reach a constant state.⁴⁷ Package labeling also specifies that prescribers should only use fentanyl patches in patients who

are already receiving opioid therapy
have developed opioid tolerance, and
are receiving a total daily dose at least equivalent to [fentanyl] 25 mcg/hr.⁴⁷

Opioid tolerance, for the purpose of using a fentanyl patch, is defined as having been on at least 60 mg of morphine or its dosage equivalent daily for at least a week.⁴⁷

Proper application of the fentanyl patch is necessary to ensure optimal pain relief and reduce the likelihood of adverse reactions. Clinicians should communicate the following to patients prescribed transdermal fentanyl patches⁴⁷:

Each new fentanyl patch should be applied to a different skin site after removal of the previous one
The patch need not be applied to the area of discomfort or pain
Patients may tape the edges of the patch with first aid tape
If the patch falls off before 72 hours, dispose of it by folding it in half and flushing down the toilet
Fentanyl patches must never be cut
Never place a heating pad over a fentanyl patch

Do not escalate fentanyl patch doses more frequently than every two to three days. When a patch is first applied, serum fentanyl concentrations will increase with the first few applications.⁴⁷ Following several rounds of patch applications, serum concentrations eventually reach steady state, meaning that it is difficult to measure a patient’s pain relief accurately during the initiation of a new transdermal fentanyl dose.⁴⁷ Premature dose escalation may lead to overdose.

Additionally, body composition is an important clinical consideration when using transdermal fentanyl. This drug’s absorption is related to a patient’s body fat composition as fentanyl is lipophilic. Patients who are cachectic (wasting physically with weight and muscle mass loss due to disease) or suffer from profuse sweating, as many cancer patients do, will derive minimal benefit from transdermal fentanyl patches.^44,48Heat will increase the absorption of fentanyl from the patch, so heating pads must never be applied directly over the patch and patients with fever should have their patch removed and an alternate dosage form should be used.

It is appropriate to use fentanyl patches in conjunction with opioids given by other routes of administration. Judicious use of the patches may reduce the need for breakthrough pain doses by providing more consistent drug delivery over the 72-hour application period. Levy’s Rule (See Figure 1) provides the conversion factor to calculate equianalgesic transdermal fentanyl doses based on a patient’s total daily dose of oral morphine equivalents.⁴⁹

FIGURE 1

Levy’s Rule: Fentanyl patch dose (in mcg) = half of the TDD oral morphine

Managing a Pain Crisis

A pain crisis is a situation in which a patient’s pain is severe and uncontrolled, causing the patient, family, or both severe distress; the pain crisis may be sudden in onset or the result of worsening chronic pain.²⁵Clinicians should address this rapidly-escalating, uncontrolled pain promptly and aggressively. When patients are in pain crises, members of the treatment team, including nurses, pharmacists, and physicians, must work together to monitor their responses to opioid administration closely and make adjustments accordingly.⁵⁰

Clinicians should double the dose of the immediate-acting opioid every twenty minutes until the patient’s pain is controlled and conduct a review of the pain management plan thereafter to determine if dosage or administration frequency need to be changed.²⁵ Opioids have no maximum dosage limit; particularly in the palliative care setting, doses must be titrated to an appropriate level of pain relief that ensures a satisfactory result.

PAUSE AND PONDER: A patient is in pain crisis. You recommend doubling her dose of intravenous hydromorphone every 20 minutes, but her new nurse is nervous about increasing her dose so aggressively. How do you explain the treatment plan and alleviate his concern?

DISPELLING COMMON HOSPICE MYTHS

For many patients and their families, hospice is a difficult term to face at first. Pharmacists are in a unique position, both in the inpatient and outpatient settings, to speak to them as medication experts.⁷ Patients may express hesitation around opioid use related to a variety of factors.^3,51One study (N = 496) explored terminally-ill patients’ reasons for declining pain management; patients indicated that they feared addiction, found mental or physical side effects unwelcome, and resented the burden of medication in terms of number of doses.¹⁸ Table 6 lists some common misconceptions about opioid use in hospice care and suggests responses pharmacists can use to educate patients about these medications’ place in palliative care.

Table 6. Myths and Facts About Opioid Use in Hospice Care^3,52-55
Myth	Fact
“Opioids will make me die faster”	When used appropriately, opioids will not hasten death and can help relieve breathing discomfort many patients experience at the end of life.
“I will get addicted to opioids”	Patients may develop a tolerance to opioids, which occurs when they experience decreased pain relief compared to when they started taking the medication. This is a result of the way the drug works in the body. Patients may need higher doses to achieve the same effect. This is different from addiction. Addiction is a disease that involves a person’s repeated use of a drug despite experiencing negative consequences. Needing higher doses of an opioid does not mean a person is addicted.
“Going on hospice care and taking opioids means giving up”	Hospice provides care tailored to a patient’s dignity, comfort, and quality of life. It is not the same as withdrawing medical treatment; in fact, a multidisciplinary team of healthcare professionals manages patients in hospice. Medications, like opioids, are only one component of the care hospice patients receive.
“I get too constipated when I take opioids”	Constipation is a common opioid side effect that does not resolve over time, so clinicians need to prescribe appropriate laxatives for patients on opioids. Constipation in itself is not a contraindication to the use of opioids in palliative/hospice care.

Allergy vs “Allergy”

Another common misconception patients have regarding opioid use relates to allergies, as many opioid side effects mimic symptoms of true allergic reactions.⁵⁶ Palliative care clinicians need to be able to differentiate between a true allergy and an adverse reaction to determine appropriate pain regimens for patients safely.

True drug allergies, also known as type I hypersensitivity reactions, are due to immunoglobulin E (IgE)-mediated release of antibodies against the offending agent.⁵⁷This reaction, in its severest form presenting as anaphylaxis, occurs in less than 2% of patients.^56,57 While the gold standard for identifying a true drug allergy is drug provocation testing, achieved by exposing a patient to small doses of suspected drugs and monitoring for a reaction, clinicians rarely order drug provocation testing in practice and it is even less relevant in the hospice population.⁵⁸

In contrast to drug allergies, adverse reactions (see Table 7) are known or expected responses, different from the intended therapeutic effect, to a medication.⁵⁹ Such adverse reactions are commonly due to the parent opioid’s active metabolites.¹⁶

Table 7. Management of Common Opioid Adverse Reactions^56,62
Adverse Reaction	Do patients develop tolerance to this adverse reaction?	Management
Nausea/vomiting	Yes	May recommend use of prophylactic antiemetics (i.e., ondansetron, metoclopramide)
Constipation	No	Routinely recommend concomitant use of a stool softener (i.e., psyllium or docusate) or stimulant laxative (i.e., senna, bisacodyl)
Itching	Yes	May recommend use of prophylactic H1 or H2 histamine antagonist (i.e., diphenhydramine, loratadine, famotidine)

Patients may also demonstrate pseudo-allergy to an opioid, which is an adverse reaction that appears to mimic a true allergy but is unaffected by IgE.⁵⁶ These may include mild itching, skin redness, or bronchospasm but do not necessarily indicate an allergic reaction.⁶⁰Instead, they are more commonly due to a histamine-mediated response.⁶⁰Histamine release is related to the opioid’s potency; the more potent the opioid, the less histamine release and the lower the likelihood of a histamine-mediated reaction.

If a patient demonstrates any one of these symptoms or develops several that are mild in severity, it does not necessarily signal the patient has an immune-related allergy to opioids. Similarly, histamine-meditated adverse reactions do not mean opioids as a class are contraindicated for use in the affected patient. Clinicians in this scenario can opt to pre-medicate the patient with antihistamines or steroids before administering an opioid for a few days until the effect is minimized.⁶⁰They may also consider an alternative opioid in a different pharmacologic opioid class which may be more tolerable.⁶⁰

PAUSE AND PONDER: What questions would you ask patients to assess whether they are experiencing an allergy versus a side effect?

Cross-reactivity can occur when a chemical component of one medication is like that in another, resulting in an allergic reaction to both drugs.⁶¹ Understanding opioids’ chemical structures (see Table 8) allows clinicians to determine risk of cross-reactivity when they are concerned about a true allergy. Cross-reactivity may occur within the same class; for example, a patient with a true allergy to codeine should not take oxycodone. However, it is reasonable for a patient with an allergy to a drug in one class of opioids to take a medication from another class.⁶² The risk for cross-reactivity in this situation is low, but if the patient has a true allergic reaction, they should only take an opioid from another class under supervision of a healthcare professional until allergy to that product is ruled out.⁶²

Table 8. Chemical Classes of Opioids¹⁶

Phenanthrenes

Benzomorphans

Phenylpiperidines

Diphenylheptanes

Buprenorphine

Butorphanol

Codeine

Hydromorphone

Morphine

Nalbuphine

Oxycodone
Oxymorphone

Pentazocine

Alfentanil

Fentanyl

Meperidine

Sufentanil

Methadone

DIVERSION

Drug diversion is defined as “a criminal act or deviation that removes a prescription drug from its intended path from the manufacturer to the intended patient.”⁶³ The hospice setting is not immune to the risk of diversion. Given the estimate that more than 90% of hospice and palliative care patients receive a controlled pain medication, diversion is a very real concern.³⁰ One survey of 371 hospices revealed that 31% of facilities interviewed reported at least one case of confirmed diversion in the past quarter.⁶⁴

Palliative care presents unique diversion issues because it is often delivered in the patient’s home, rather than a facility. The home environment, while often the preferred site of care, is less closely monitored and controlled than in an inpatient setting, making it a susceptible site of opioid diversion.⁶⁵ Caregivers, family members, healthcare providers, and patients themselves may all divert opioids.⁶⁶

Identifying diversion

Providers should be able to identify instances of possible diversion and take reasonable steps to prevent it from happening.⁶⁷ State prescription drug monitoring programs (PDMPs) are one such way to monitor patient’s access to opioids.⁶⁸These programs vary from state to state, but all allow authorized providers to review a patient’s controlled substance fill history.⁶⁸Practitioners should make it a habit to review their state’s PDMP prior to filling a prescription for a controlled substance to determine whether a patient may seek out multiple prescribers or visit different pharmacies. Such behavior does not always indicate drug misuse or diversion but should prompt the pharmacist to identify any risky activity. Other common “red flags” that may signal a person is diverting medication:

□ Frequent or early refill requests from patient or caregiver

□ Inaccurate or missing record-keeping by pharmacy or hospice agency

□ Noncommunicative patients who appear to always be in severe pain/distress

□ Impaired caregivers, including both family members and home health staff

The University of Maryland, Baltimore, in conjunction with the Hospice Foundation of America, has developed 15 recommendations for preventing medication diversion and misuse in hospice care.⁶⁹ These include recommendations related to several care areas featured in Figure 2.

FIGURE 2

Hospice Prescriptions Transmitted by Facsimile

Federal and state laws regulate controlled substances dispensing for hospice patients. Specifically, prescribers may fax prescriptions for C-II medications to retail pharmacies without needing to subsequently furnish a hard copy as they would for a non-hospice patient.⁷⁰ The federal law regarding faxing C-II prescriptions for hospice patients states that “a prescription prepared in accordance with §1306.05 written for a Schedule II narcotic substance for a patient enrolled in a hospice care program certified and/or paid for by Medicare under Title XVIII or a hospice program which is licensed by the state may be transmitted by the practitioner or the practitioner's agent to the dispensing pharmacy by facsimile. The practitioner or the practitioner's agent will note on the prescription that the patient is a hospice patient. The facsimile serves as the original written prescription for purposes of this paragraph (g) and it shall be maintained in accordance with §1304.04(h).”⁷⁰ The faxed prescription must indicate that it is for a hospice patient in order to be filled legally—pharmacy teams should make note of this rule and ensure prescribers so annotate prescriptions.

Conclusion

Patients in palliative and hospice care have unique needs. Clinicians should be familiar with how the two types of care differ and their common characteristics. To manage a patient’s pain and dyspnea, healthcare providers should have a solid foundational knowledge of opioid medications and an understanding of how to select and tailor patients’ pain control regimens to their specific needs. There is no treatment algorithm for pain management, just as there is no standardized equianalgesic opioid dose conversion chart. Clinicians must account for patient- and drug-specific factors and use their own judgment when transitioning patients from one opioid to another to ensure adequate pain control. Certain formulations, such as intensol and transdermal patches, also have route-specific considerations. Pharmacists particularly are well-placed to educate other healthcare professionals as well as patients and their caregivers about opioids’ place in palliative/hospice care. They can “myth-bust” common hospice misconceptions, help identify allergies and adverse reactions, and inform treatment decisions related to acute situations (like pain crises) and transitions from inpatient to outpatient settings. They can also be closely involved in monitoring, documenting, and preventing issues related to medication diversion. Drug therapy is a significant component of palliative/hospice care. It requires a thorough and sensitive understanding by medical staff so that patients derive maximum benefit from it as they approach the end of their lives. Alleviation of suffering, and the protection of a patient’s dignity, should be at the core of any medication decisions made for these patients.

Pain Management in Palliative Care
Learning Objectives
• Describe the principles of palliative and hospice care
• Discuss treatment options to manage the end-of-life symptoms of air hunger and/or pain
• Calculate appropriate opioid dose-equivalents
• Recognize risks of diversion in the hospice setting

1. Which of the following is TRUE of palliative care?
a. It can hasten a patient’s death by using high doses of opioids and benzodiazepines
b. It is intended for patients with a life expectancy of six months or less
c. It is intended for any patient with a chronic disease, regardless of stage of illness

2. Your pharmacy receives a faxed prescription for KL. It has all the valid components of a legal prescription but does not specify “hospice patient” on it. Her family member confirms that KL is in fact pursuing hospice care. What should your next step be?
a. Fill the prescription as-is, indicating on the back of the fax that it is for a hospice patient; pharmacist documentation is sufficient
b. Call the physician’s office to request the prescription be re-transmitted with the necessary information documented on it
c. Contact your local DEA office to report your suspicion of medication diversion, as the prescription is a counterfeit

3. The hospitalist is preparing to discharge patient NM who has previously been on IV hydromorphone 1 mg q4h PRN, averaging four doses per day. He would like to send NM home on oral oxycodone at the same dosing interval (every four hours). What dose would you recommend?
a. Oxycodone 10 mg by mouth every 4 hours PRN
b. Oxycodone 5 mg by mouth every 4 hours PRN
c. Oxycodone 8.88 mg by mouth four times per day PRN

4. Which of the following is a step a home hospice agency could take to prevent diversion?
a. Designate one staff member to witness medication disposal after a patient dies
b. Conduct urine drug screens for new hires prior to an unsupervised home visit
c. Permit hospice staff to transport controlled substances via their personal vehicles

5. A man comes in with several prescriptions for his 98-year-old mother. He is concerned that the physician ordered morphine intensol, saying, “She was just in the hospital for pneumonia because she keeps inhaling her food when she eats. Won’t this cause the same problem?” How could you respond?
a. Tell him you will call the physician to have her change the order to morphine 10 mg/5 mL liquid
b. Advise him to crush her extended-release morphine tablets and use a small amount of water to make a paste she can swallow
c. Reassure him that morphine intensol is a concentrated liquid formulation that delivers drug in a very small volume

6. Which of the following might lead you to consider the possibility that a family member was diverting controlled substances for a hospice patient?
a. Family member claims patient needs morphine intensol for difficulty breathing, even though the patient isn’t dying from a lung disease
b. Family member provides prescriptions from several providers in different specialties and office locations
c. Family member claims patient needs morphine intensol for pain, even though the patient is on a high dose that should sedate her enough to be comfortable

7. Patient PW is a 67-year-old male admitted to your hospital with a past medical history of end-stage liver disease due to chronic alcoholism, congestive heart failure, and hypothyroidism. He elects to pursue inpatient hospice as death appears imminent. What is the most appropriate opioid medication for him?
a. Hydromorphone 2 mg IV every hour PRN
b. Oxycodone 5 mg by mouth every four hours PRN
c. Fentanyl 0.25 mcg IV every hour PRN

8. When converting a dose of one opioid to an equianalgesic dose of another, you must reduce your final calculated dose by 25-50%. Why is this?
a. To account for incomplete cross-tolerance and reduce the risk of overdosing the patient with the new opioid
b. To ensure the patient has less potent strengths of an opioid, thereby reducing the likelihood of diversion
c. To make it easier to round your calculated dose to a whole number so patients don’t have to split tablets

9. You are a pharmacist in a long-term care facility. You note that one of your patients is a good candidate for a fentanyl patch. He is currently on oxycodone ER 30 mg by mouth BID and oxycodone 5 mg by mouth every four hours as needed. He normally receives three breakthrough doses in a 24 hour-period. What would you recommend?
a. Fentanyl 75 mcg/hour patch, and continue the oxycodone 5 mg by mouth every four hours as needed
b. Fentanyl 100 mcg/hour patch, and discontinue the oxycodone 5 mg by mouth every four hours as needed
c. Fentanyl 50 mcg/hour patch, and continue the oxycodone 5 mg by mouth every four hours as needed

10. WN is a 45-year-old male recently diagnosed with ALS (Lou Gehrig’s Disease). He asks to meet with your hospital’s palliative nurse to discuss symptom management. Which of the following is true?
a. WN should exhaust all treatment options before pursuing palliative care
b. Palliative care can be administered alongside treatment
c. WE cannot explore palliative care until he is estimated to have a 6-month life expectancy or less

11. Patient RT has advanced lung cancer with metastases to the bone and brain. He comes to your hospital in a pain crisis, as his family has been unable to control his pain with medication at home. The hospitalist starts him on hydromorphone 1 mg IV every 5 minutes. RT receives four consecutive doses but is still in excruciating pain. What is the next step to recommend?
a. Increase the dose to hydromorphone 2 mg IV every 5 minutes
b. Transition the patient to an equianalgesic dose of oral hydromorphone
c. Initiate a long-acting opioid such as extended-release morphine or extended-release oxycodone

12. A pharmacy student uses two different equianalgesic dose conversion charts to calculate an oral hydromorphone dose and comes up with two different calculations: hydromorphone 3 mg by mouth every four hours vs. hydromorphone 4 mg by mouth every four hours. You advise that the 4 mg dose is the better option. Why is this?
a. The patient likely needs a higher dose for better pain control
b. It is a more feasible dose to administer due to the tablet size
c. You calculated the dose to be 4 mg based on the equianalgesic dose conversion chart you used

13. In what clinical situation would you consider opioid rotation?
a. In a patient who has developed unbearable constipation, despite taking medications to manage it
b. In a patient who was started on a fentanyl patch one day ago and has yet to show a response
c. In a patient who is responding well to the same pain regimen he has been on for the past two years

14. You receive a palliative care consult for a patient with chronic kidney disease who has now also developed acute renal failure. His creatinine clearance in the hospital is currently 24 mL/min. He has been receiving hydromorphone 8 mg by mouth every 6 hours. What is an appropriate recommendation?
a. Continue on the current dose
b. Reduce the dose to 4 mg every 6 hours
c. Increase the dose to 16 mg every 6 hours

15. Your patient BB has lost IV access. She was previously receiving morphine 1 mg IV every 2 hours PRN, averaging about 9 doses per day. What would an appropriate oral morphine dose administered every 4 hours PRN be?
a. Morphine 5 mg by mouth every 4 hours PRN
b. Morphine 1.5 mg by mouth every 4 hours PRN
c. Morphine 2.5 mg by mouth every 4 hours PRN

Pain Management in Palliative Care
Learning Objectives
After completing this CE activity, pharmacy technicians will be able to
• Describe the principles of palliative and hospice care
• Identify treatment options to manage the end-of-life symptoms of air hunger and/or pain
• Recognize risks of diversion in the hospice setting

3. A patient comes to your pharmacy with a prescription for methadone. You note she has an allergy to morphine listed in her profile. Which of the following is true?
a. Methadone is not likely to cause the same reaction based on the risk of cross-reactivity
b. You can assume it is probably not a true allergy as many patients report morphine allergy
c. This patient should not take methadone because of her allergy; she will have the same reaction to both

7. Your patient YP comes into your pharmacy to fill a prescription for oxycodone/acetaminophen 5/325 mg one tablet by mouth every four hours as needed. You see an allergy to morphine listed in his profile. When you ask him about it, he says, “It makes me so sick, I can’t stomach it.” How do you respond?
a. Tell him he should not take the oxycodone/acetaminophen, as he will also be allergic to it and will not be able to tolerate it
b. Tell him all opioids make people nauseous, and he should take morphine rather than oxycodone/acetaminophen since it isn’t a real allergy
c. Confirm with the pharmacist that YP can take the oxycodone/acetaminophen, as nausea is a side effect rather than an allergy

8. A patient hands you a prescription. She says, “My doctor had to increase my dose from 1 mg to 2 mg. I’ve been on it for a year but it doesn’t feel like it’s doing anything for me anymore.” What term best describes the phenomenon the patient is experiencing?
a. Tolerance
b. Addiction
c. Medication diversion

9. In what way does hospice care differ from palliative care?
a. Hospice uses no active treatment or life-prolonging measures
b. Hospice involves psychosocial and emotional support services
c. Hospice is only provided in a patient’s home or hospital

10. WN is a 45-year-old male recently diagnosed with ALS (Lou Gehrig’s Disease). He asks to meet with your hospital’s palliative nurse to discuss symptom management. Which of the following is true?
a. WN should exhaust all treatment options before pursuing palliative care
b. Palliative care can be administered alongside treatment
c. WN cannot explore palliative care until his estimated life expectancy less than 6 month

References

References
1. World Health Organization. Palliative Care Key Facts. World Health Organization website. August 5, 2020. Accessed May 3, 2021. https://www.who.int/news-room/fact-sheets/detail/palliative-care

2. National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care. 4th edition. Richmond, VA: National Coalition for Hospice and Palliative Care; 2018. Accessed April 14, 2021.https://www. nationalcoalitionhpc.org/ncp.

3. Clary PL, Lawson, P. Pharmacologic pearls for end-of-life care. Am Fam Physician. 2009;79(12):1059-1065.

4. National Institute on Aging. What are palliative and hospice care? U.S. Department of Health and Human Services website. May 17, 2017. Accessed May 3, 2021. https://www.nia.nih.gov/health/what-are-palliative-care-and-hospice-care#:~:text=Palliative%20care%20is%20a%20resource,from%20the%20point%20of%20diagnosis

5. American College of Surgeons Trauma Quality Improvement Program. Palliative care best practices guidelines. American College of Surgeons website. October 2017. Accessed May 3, 2021. https://www.facs.org/-/media/files/quality-programs/trauma/tqip/palliative_guidelines.ashx

6. Demler, TL. Pharmacist involvement in hospice and palliative care. US Pharm. 2016;41(3):HS2-HS5.

7. Barbee J, Kelley S, Andrews J, Harman A. Palliative care: the role of the pharmacist. Pharm Times. 2016;5(6). https://www.pharmacytimes.com/view/palliative-care-the-pharmacists-role

8. Walker KA, Scarpaci L, McPherson ML. Fifty reasons to love your palliative care pharmacist. Am J Hosp Palliat Care. 2010;27(8):511-513. doi: 10.1177/1049909110371096

9. What is palliative care? International Association for Hospice and Palliative Care website. Accessed May 6, 2021. https://hospicecare.com/what-we-do/publications/getting-started/5-what-is-palliative-care

10. Palliative care or hospice? National Hospice and Palliative Care Organization website. 2019. Accessed May 3, 2021. https://www.nhpco.org/wp-content/uploads/2019/04/PalliativeCare_VS_Hospice.pdf

11. Palliative care defined. Hospice Foundation of America website. 2018. Accessed May 7, 2021. https://hospicefoundation.org/Hospice-Care/Palliative-Care-Defined

12. Palliative care vs. hospice: what’s the difference? Vitas Healthcare website. Accessed May 3, 2021. https://www.vitas.com/hospice-and-palliative-care-basics/about-palliative-care/hospice-vs-palliative-care-whats-the-difference

13. Palliative care vs. hospice: similar but different. Centers for Medicare and Medicaid Services website. Accessed May 3, 2021. https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Downloads/infograph-PalliativeCare-%5BJune-2015%5D.pdf

14. Healthline. What’s the difference between palliative care and hospice? Healthline website. February 7, 2020. Accessed May 3, 2021. https://www.healthline.com/health/palliative-care-vs-hospice#how-to-decide

15. Groninger H, Vijayan J. Pharmacologic management of pain at the end of life. Am Fam Physician. 2014;90(1):26-32.

16. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133-S153.

17. Ross DD, Alexander CS. Management of common symptoms in terminally ill patients: part II. Am Fam Physician. 2001;64(6):1019-1027

18. Weiss SC, Emanuel LL, Fairclough DL, Emanuel EJ. Understanding the experience of pain in terminally ill patients. Lancet. 2001;357(9265):1311-1315. doi:10.1016/S0140-6736(00)04515-3

19. Vallejo R, Barkin RL, Wang VC. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician. 2011;14:E343-E360.

20. Trang T, Al-Hasani R, Salvemini D, Salter MW, Gutstein H, Cahill CM. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci. 2015;35(41):13879-13888. doi:10.1523/JNEUROSCI.2711-15.2015

21. Kamal AH, Maguire JM, Wheeler JL, Currow DC, Abernethy AP. Dyspnea review for the palliative care professional: treatment goals and therapeutic options. J Pall Med. 2012;15(1):106-114. doi:10.1089/jpm.2011.0110

22. Mahler, D. Opioids for refractory dyspnea. Expert Rev Respir Med. 2014;7(2):123-135. doi:10.1586/ers.13.5

23. NICE Clinical Guidelines, No. 140. Cardiff, UK; National Collaborating Centre for Cancer; 2012. National Collaborating Centre for Cancer (UK). Accessed April 20, 2021. https://www.ncbi.nlm.nih.gov/books/NBK115251/ .

24. Barnett M. Alternative opioids to morphine in palliative care: a review of current practice and evidence. Postgrad Med J. 2001;77:371-378. doi:10.1136/pmj.77.908.371

25. Moryl, N, Coyle N, Foley KM. Managing an acute pain crisis in a patient with advanced cancer. JAMA. 2008;299(12):1457-1467. doi:10.1001/jama.299.12.1457

26. Brown R, Kraus C, Fleming M, Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J. 2004;80(949):654-659. doi:10.1136/pgmj.2004.022988

27. Broadbent A, Khor K, Heaney A. Palliation and chronic renal failure: opioid and other palliative medications- dosage guidelines. Prog Palliat Care. 2013;11(4):183-190. doi: 10.1179/096992603225002627

28. Arnold R, Verrico P, Karnell A, Davison SN. opioid use in renal failure. Palliative Care Network of Wisconsin website. March 2020. Accessed May 3, 2021. https://www.mypcnow.org/fast-fact/opioid-use-in-renal-failure/

29. Oliverio C, Malone N, Rosielle DA. Opioid use in liver failure. Palliative Care Network of Wisconsin website. September 2015. Accessed May 3, 2021. https://www.mypcnow.org/fast-fact/opioid-use-in-liver-failure/

30. Cagle, JG. Strategies for detecting, addressing, and preventing drug diversion in hospice and palliative care. J Pain Symptom Manage. 2019;57(2):360. doi: 10.1016/j.jpainsymman.2018.12.023

31. Muller-Busch HC, Lindena G, Kietze K, Woskanjan S. Opioid switch in palliative care, opioid choice by clinical need and opioid availability. Eur J Pain. 2012;9(5):571. doi: 10.1016/j.ejpain.2004.12.003
32. Portenoy RK, Mehta Z, Ahmed E. Cancer Pain management with opioids: optimizing analgesia. UptoDate website. January 12, 2021. Accessed May 3, 2021. https://www.uptodate.com/contents/cancer-pain-management-with-opioids-optimizing-analgesia

33. Bhatnagar M, Pruskowski J. Opioid Equivalency. StatPearls Publishing;2020. Accessed April 19, 2021. https://www.ncbi.nlm.nih.gov/books/NBK535402/#_NBK535402_pubdet_.

34. Arnold R, Weissman DE. Calculating opioid dose conversions. Palliative Care Network of Wisconsin. May 2015. Accessed May 3, 2021. https://www.mypcnow.org/fast-fact/calculating-opioid-dose-conversions/

35. Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E. Equianalgesic dose ratios for opioids: a critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001;22(2):672-687. doi:10.1016/s0885-3924(01)00294-9

36. Anderson R, Saiers JH, Abram S, Schlicht C. Accuracy in equianalgesic dosing: conversion dilemmas. J Pain Symptom Manage. 2001;21(5):397-406. doi:10.1016/s0885-3924(01)00271-8

37. Periyakoil V. Equivalency table. Stanford School of Medicine Palliative Care website. Accessed May 3, 2021. https://palliative.stanford.edu/opioid-conversion/opioids/

38. Opioid prescribing guideline resources. Centers for Disease Control and Prevention website. February 2021. Accessed 4/19/2021. https://www.cdc.gov/drugoverdose/prescribing/guideline.html

39. Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10(4):537-551. doi:10.1208/s12248-008-9056-1

40. Pasternak GW. Preclinical pharmacology and opioid combinations. Pain Med. 2012;13:S4-S11. doi:10.1111/j.1526-4637.2012.01335.x

41. Vallerand AH. The use of long-acting opioids in chronic pain management. Nurs Clin North Am. 2003;38(3):435-445. doi: 10.1016/s0029-6465(02)00094-4.

42. Fine PG, Mahajan G, McPherson ML. Long-acting opioids and short-acting opioids: appropriate use in chronic pain. Pain Med. 2009;10(Supp 2):S79-S88. https://doi.org/10.1111/j.1526-4637.2009.00666.x

43. Kestenbaum MG, Messersmith S, Vilches AO, et al. Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Med. 2014;15(7):1129-1153. doi:10.1111/pme.12464

44. McPherson, ML, Kim, M, Walker, KA. 50 practical medication tips at end of life. J Support Onc. 2012;10(6):222-229. doi:10.1016/j.suponc.2012.08.002

45. Miller, KE. Continuous infusion of IV morphine for cancer pain. AM Fam Physician. 2003;67(2):416-417.

46. Morphine sulfate solution. Prescribing information. Boehringer Ingelheim; 2012. Accessed April 20, 2021. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Roxanol/Roxanol.pdf

47. Duragesic. Prescribing information. Janssen Pharmaceuticals, Inc; 2021. Accessed April 20, 2021. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DURAGESIC-pi.pdf

48. Clemens KE, Klaschik E. Clinical experience with transdermal and orally administered opioids in palliative care patients- a retrospective study. Jpn J Clin Oncol. 2007;37(4):302-309. doi:10.1093/jjco/hym017

49. Levy, MH. Pharmacologic treatment of cancer pain. N Engl J Med. 1996;335(15):1124-1132. doi: 10.1056/NEJM199610103351507

50. Ferrell B, Levy MH, Paice J. Managing pain from advanced cancer in the palliative care setting. Clin J Oncol Nurs. 2008;12(4):575-581. doi: 10.1188/08.CJON.575-581

51. Berger JM, Vadivelu N. Common misconceptions about opioid use for pain management at the end of life. Virtual Mentor. 2013;15(5):403-409. doi: 10.1001/virtualmentor.2013.15.5.ecas1-1305

52. Harrod CG, Mahler DA, Selecky PA et al. American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest. 2010;137(3):674-691. doi:10.1378/chest.09-1543

53. The NIDA Blog Team. Tolerance, Dependence, Addiction: What’s the Difference? NIH website. January 12, 2017. Accessed May 4, 2021. https://archives.drugabuse.gov/blog/post/tolerance-dependence-addiction-whats-difference

54. Dispelling Hospice Myths. Hospice Foundation of America website. Accessed May 4, 2021. https://hospicefoundation.org/Hospice-Care/Dispelling-Hospice-Myths

55. Albert RH. End-of-life care: managing common symptoms. Am Fam Physician. 2017;95(6):356-361.

56. Fudin, J. Opioid allergy, pseudo-allergy, or adverse effect? Pharmacy Times website. March 6, 2018. Accessed May 4, 2021. https://www.pharmacytimes.com/view/opioid-allergy-pseudo-allergy-or-adverse-effect

57. Abbas M, Moussa M, Akel H. Type I Hypersensitivity Reaction. Stat Pearls Publishing;2020. Accessed April 20, 2021. https://www.ncbi.nlm.nih.gov/books/NBK560561/ .

58. Li PH, Ue KL, Wagner A, Rutkowski R, Rutkowski K. Opioid hypersensitivity: predictors of allergy and role of drug provocation testing. J Allergy Clin Immunol Pract. 2017;5(6):1601-1606. doi:10.1016/j.jaip.2017.03.035

59. Coleman JJ, Pontefract SK. Adverse drug reactions. Clin Med (Lond). 2016;16(5):481-485. doi: 10.7861/clinmedicine.16-5-481

60. Woodall HE, Chiu A, Weissman DE. Opioid allergic reactions. Palliative Care Network of Wisconsin website. July 2015. Accessed April 20, 2021. https://www.mypcnow.org/fast-fact/opioid-allergic-reactions/

61. Jain S, Kaplowitz N. 9.16- Clinical Considerations of Drug-Induced Hepatotoxicity. In: Comprehensive Toxicology. 2nd ed. McQueen CA. Elsevier; 2010;369-381. https://doi.org/10.1016/B978-0-08-046884-6.01014-9.

62. Soljoughian, M. Opioids: allergy vs. pseudoallergy. US Pharm. 2006;6:HS5-HS9. https://www.uspharmacist.com/article/opioids-allergy-vs-pseudoallergy

63. Controlled substances drug diversion pharmacy technician toolkit. American Society of Health-System Pharmacists website. Accessed April 19,2021. https://www.ashp.org/Pharmacy-Technician/About-Pharmacy-Technicians/Advanced-Pharmacy-Technician-Roles-Toolkits/Controlled-Substances-Drug-Diversion-Pharmacy-Technician-Toolkit?loginreturnUrl=SSOCheckOnly

64. Cagle JG, McPherson ML, Frey JJ, et al. Estimates of medication diversion in hospice. JAMA. 2020;323(6):566-568. doi:10.1001/jama.2019.20388

65. Cagle JG, Ware OD. Preventing medication diversion in home health & hospice. HomeCare Magazine. October 8, 2019. Accessed April 20, 2021. https://www.homecaremag.com/october-2019/preventing-medication-diversions

66. Parker, J. Strategies to prevent drug diversion in hospice care. Hospice News. April 29, 2019. Accessed April 20, 2021. https://hospicenews.com/2019/04/29/strategies-to-prevent-drug-diversion-in-hospice-care/

67. Risk evaluation and mitigation tool-kit: strategies to promote the safe use of opioids. Virginia Association for Hospices and Palliative Care website. 2012. Accessed May 6, 2021. https://www.virginiahospices.org/assets/docs/REM_TOOLKIT/REM%20Tool%20Kit%204Website_2019.pdf

68. What States Need to Know About PDMPs. Centers for Disease Control and Prevention website. July 1, 2020. Accessed May 7, 2021. https://www.cdc.gov/drugoverdose/pdmp/states.html#:~:text=A%20prescription%20drug%20monitoring%20program,a%20nimble%20and%20targeted%20response.

69. Cagle JG, Ware OD. 15 recommendations for preventing medication diversion & misuse in hospice care. Hospice Foundation of America website. August 2019. Accessed April 20, 2021. https://hospicefoundation.org/hfa/media/Files/Preventing-Medication-Diversion-in-Hospice-Recommendations-10-28-2019.pdf

70. Office of the Federal Register. Part 1306- Prescriptions. Electronic Code of Federal Regulations website. May 4, 2021. Accessed May 6, 2021. https://www.ecfr.gov/cgi-bin/text-idx?SID=5ca5f28a5a2b14665924d3bef7178ebe&mc=true&node=se21.9.1306_111&rgn=div8

Sjogren’s Syndrome: How Dry Am I?

After completing this application-based continuing education activity, pharmacists will be able to

Discuss current theories postulating how Sjogren’s syndrome develops
Identify biomarkers used in diagnosis and patient classification
Interpret guidelines and evidence-based medicine to use best practices to manage Sjogren’s syndrome
Use elements of an integrated approach to care among specialists and other pharmacists

After completing this application-based continuing education activity, pharmacy technicians will be able to

Describe Sjogren’s syndrome’s basic pathology and symptoms
Outline prescription and non-prescription treatments used in Sjogren’s syndrome
Identify when to refer patients to the pharmacists for recommendations or referrals

Once considered a “dry eye-dry mouth-arthritis” illness, Sjogren’s syndrome (SjS) is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Systemic SjS is linked to autoimmune dysfunction that may eventually be irreversible. This disease affects about 2 to 4 million Americans, but every patient presents differently and symptoms mimic those of various other conditions, posing a challenge for diagnosis and treatment. SjS’s classic symptoms include sicca (ocular and oral dryness), arthralgia (joint pain), and fatigue. The pathogenesis of the disease is complex and multifactorial, but researchers are looking for a well-defined cause and modern understanding of SjS is improving. The search for biomarkers, therapeutic targets, and disease-modifying treatments for SjS is underway. Health care providers—including pharmacists and pharmacy technicians—who are up to date on current understanding and recently-updated guidelines will be better prepared to make evidence-based recommendations and appropriate referrals to improve care and outcomes for patients with SjS.

INTRODUCTION

The medical community’s understanding of Sjogren’s syndrome (SjS) has evolved a great deal since it was first recognized in the late 1800s. A surgeon reported the first clinical case of what is now called SjS in 1888, describing a male patient with painless bilateral swelling of the lacrimal, parotid, and submandibular glands (i.e., the glands that produce tears and saliva).¹ Following a series of case reports over about a century detailing a “dry eye-dry mouth-arthritis” illness, physicians pieced together and named the syndrome known today as SjS.^1,2

Epidemiologic data about SjS in the United States (U.S.) is limited. It is estimated to affect about 2 to 4 million Americans, but only about 1 million are definitively diagnosed.^3,4 Women are nine times more likely to have the condition, and it typically emerges around menopause (i.e., after age 50). SjS is the second most common rheumatologic disorder in the U.S. behind systemic lupus erythematous (SLE).⁵ Autoimmune conditions don’t discriminate; many famous people have historically battled them publicly. Selena Gomez postponed a concert tour to undergo treatment for SLE. Kim Kardashian suffers from psoriasis. SjS, as a rarer condition, doesn’t make the news quite as often as other autoimmune conditions, but here are a few people you may recognize who are battling the disease today^6-8:

Carrie Ann Inaba: In 2021, the 30-season judge of Dancing with the Stars and co-host of The Talk took a leave of absence from television to focus on her health and wellbeing. The chronic pain associated with her SjS, SLE, fibromyalgia, and rheumatoid arthritis forced her to stay in bed three days a week.
Shannon Boxx: This World Cup soccer player and Olympic gold medalist was diagnosed with SjS in 2002 and suffered from severe fatigue and joint pain. Ahead of the 2007 World Cup, she was put on corticosteroids to alleviate her symptoms and needed specific approval from the U.S. Anti-Doping Agency to take them while competing.
Venus Williams: While dominating the sport of tennis as the most decorated female tennis player to compete in the Olympic Games, she has also been in a battle against her own body. SjS-related fatigue caused her to pull out of the 2011 U.S. Open, and she was temporarily booted from the top 100 tennis players for the first time in 15 years.

As an autoimmune condition, SjS’s cause is unclear. Genetic, environmental, and hormonal factors likely work collaboratively to produce the cardinal symptoms of dry eyes and/or mouth, fatigue, and limb pain. Some patients experience additional manifestations in the lymph nodes, lungs, kidneys, muscles, nervous system, skin, teeth, and brain. Glandular and joint involvement is also possible, and constitutional symptoms (e.g., fever, involuntary weight loss, night sweats) can affect quality of life. Patients with SjS have an elevated risk of lymphoma, about 15 to 20 times higher than the general population.^9,10

PAUSE AND PONDER: Why are patients with SjS so difficult to identify and diagnose?

Clinical Presentation

SjS is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Since it impacts multiple systems in the body, SjS can manifest in various ways. Affected patients may have symptoms that cycle between mild and severe. Symptoms also tend to worsen as patients age and the function of the exocrine glands subsides.

SjS’s main symptoms are dry mouth and dry eyes (collectively, sicca). More than 95% of patients with SjS present with sicca symptoms, which are irritating and poorly tolerated.¹¹ About half of patients also have dermatologic involvement (i.e., dry skin or rashes).^3,12 Xerostomia (oral dryness) can substantially impact daily life, interfering with eating, speaking, or sleeping.⁴ When patients’ salivary volume decreases, they also lose saliva’s antibacterial properties. This can accelerate tooth decay, infection, and periodontal disease. Patients with dry mouth also report swallowing difficulties, halitosis (bad breath), and burning sensations in the mouth. Using artificial saliva products to manage dry mouth is time-consuming and ineffective for many patients with SjS.¹³

Patients with ocular dryness complain of itchy, gritty, sore, or dry sensations in the eyes despite appearing physically normal.⁴ Decreased tear production over time can cause chronic irritation and destruction of conjunctival epithelium that lines the inside of the eyelids and covers the sclera (whites of the eyes).

Patients may also experience symptoms elsewhere in the body, including

Dry cough
Fatigue
Joint and muscle pain
Numbness or tingling of the hands and feet
Vaginal dryness

Patients who develop musculoskeletal symptoms may have difficulty remaining active. About 53% of patients experience arthralgias (joint stiffness) and 22% experience myalgias (muscle pain).⁴ SjS-associated arthralgia occurs primarily in small joints, sometimes asymmetrically. Providers may confuse these symptoms with SLE or rheumatoid arthritis.

Disease Classification and Severity

Experts classify SjS as primary or secondary (see Table 1). Primary SjS (pSjS) is an autoimmune disease that causes immune cells to mistakenly attack and destroy healthy cells in the glands that produce tears and saliva. SjS can also be secondary to other autoimmune diseases (e.g., SLE, rheumatoid arthritis, scleroderma), as is the case for about 60% of patients.⁴

Table 1. American-European Consensus Group Criteria for the Classification of SjS¹⁴

Primary SjS Criteria

Secondary SjS Criteria

SjS Exclusion Criteria

At least 4 of the following, including at least criterion 5 or 6:

1. Ocular symptoms (dry eyes for ≥ 3 months, foreign-body sensation, use of tear substitutes > 3 times daily)

2. Oral symptoms (dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing)

3. Ocular signs (Schirmer test* performed without anesthesia [< 5 mm in 5 minutes], positive vital dye staining results)

4. Oral signs (abnormal imaging of salivary glands, unstimulated salivary flow < 1.5 mL in 15 minutes)

5. Positive minor salivary gland biopsy findings

6. Positive anti-SSA or anti-SSB antibody results

In the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5 for primary SjS.

Any of the following:

· AIDS

· Graft versus host disease

· Hepatitis C virus infection

· Past head-and-neck radiation

· Prior lymphoma

· Sarcoidosis

· Use of anticholinergic drugs

*Schirmer test is used to determine whether the eye produces enough tears to keep it moist; AIDS = acquired immunodeficiency syndrome; SjS = Sjogren’s syndrome; SSA = Sjogren's syndrome A; SSB = Sjogren’s syndrome B

There is a broad range of disease severity in SjS. Some patients experience mild glandular dryness and constitutional symptoms while others have severe glandular involvement and various manifestations throughout the rest of the body, including systemic autoimmune features. Mild SjS has a good prognosis, but patients often have difficulty managing their symptoms and moderate-to-severe disease can severely impact quality of life.¹⁵ SjS symptoms cause considerable psychological distress. About one third of patients with the condition have clinically significant anxiety and half have diagnosable depression.¹⁶

Measuring Systemic Disease Activity

The European League Against Rheumatism (EULAR) created a disease activity index for primary SjS (ESSDAI) to measure systemic disease activity.^17,18 The ESSDAI includes 12 domains: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathic, and biological. Each domain is divided into three or four levels of activity, and patients are scored based on that domain’s severity (i.e., 0 indicates no activity and 3 or 4 indicates high activity).¹⁸

Each domain’s weight reflects its relative importance to disease activity, and the score for each domain is equal to the level of activity multiplied by the domain’s weight. A final ESSDAI score (i.e., the sum of all the domain scores) could theoretically be between 0 and 123. Patients’ disease activity based on ESSDAI score is as follows^17,18:

0 = no activity
1 to 4 = low activity
5 to 13 = moderate activity
14 or greater, or high activity in any domain with a definition of high activity = severe activity

Measuring Patient-Reported Outcomes

EULAR also created the SjS patient reported index (ESSPRI) to assess patient-reported outcomes in pSjS.¹⁸ This scale focuses solely on the three major manifestations of SjS: dryness, fatigue, and musculoskeletal pain. Patients rank each of these domains on a scale of 0 to 10, and the total ESSPRI score is the mean (average) of those scores. A “patient acceptable symptom state” is defined as an ESSPRI score of less than 5, and clinicians and researchers define “minimally clinically important improvement” as an increase in ESSPRI score 1 point or more or 15%.¹⁸

PAUSE AND PONDER: How would your daily life change if you had SjS? What hardships might you face?

Recognition and Treatment are Inadequate

SjS’s variable symptoms are not always present at the same time, leading providers—including physicians, dentists, and ophthalmologists—to treat each symptom individually, unaware of the systemic disease’s presence. Patients suffer from SjS symptoms an average of 10 years before obtaining a diagnosis.^4,19 The condition has historically been misdiagnosed because providers consider symptoms minor or vague and they often mimic other diseases. Up to 30% of people 65 years or older, with SjS or not, report dryness of the eyes and mouth.¹⁹ Sicca and/or parotid gland enlargement can result from various other conditions, including¹⁹

Alzheimer’s disease
anxiety and depression
Bell’s palsy
bulimia
chronic conjunctivitis or blepharitis (inflammation of the membrane on the eye or the eyelid, respectively)
chronic pancreatitis
complications from contact lenses
dehydration
diabetes mellitus
hepatitis C
Parkinson’s disease
rosacea
viral infections (e.g., cytomegalovirus, influenza, mumps)

About half of patients with SjS lack a definitive diagnosis, so undertreatment is considerable.⁴ For those who are diagnosed, treatment guidelines have historically been unclear and available treatments are limited and often unsuccessful. Recently, evidence-based treatment guidelines have emerged (discussed below) to help providers make decisions regarding SjS care. SjS is incurable; targeted, disease-modifying therapies are needed.

DISEASE MECHANISMS AND BIOMARKERS

pSjS’s pathogenesis is complex and multifactorial. Underlying genetic predisposition, epigenetic mechanisms (i.e., things that cause changes that affect the way your genes work), and environmental factors contribute to disease development.²⁰ There is no identified causal agent for SjS and it presents with multiple organ involvement. This makes the pursuit for defining an etiology and identifying biomarkers all the more important.

Researchers historically considered SjS a specific, self-perpetuating immune-mediated loss of exocrine tissue as the main cause of glandular dysfunction.²⁰ Today, with more sophisticated research methods, experts believe this fails to fully explain several SjS-related phenomena and experimental findings.

Genetics and Epigenetics

Genetic studies are a powerful tool for discovering new pathogenic pathways. Scientists have made great strides in studying genetic susceptibility to pSjS, but the evidence still does not match that of other autoimmune conditions.²⁰ Several genome-wide association studies in pSjS have shown that the strongest association lies within human leukocyte antigen (HLA) genes.

The non-HLA genes IRF5 and STAT4 (relevant to the innate and adaptive immune systems) also show consistent associations but on a smaller scale.²⁰ These genes activate interferon (IFN) pathways as part of the innate immune system. Epigenetic mechanisms (e.g., DNA methylation) also play a role in pSjS pathogenesis by modulating gene expression without altering DNA sequences. This may serve as a dynamic link between the genome and SjS manifestation.

Chronic Immune System Activation

Chronic immune system activation is central to SjS pathophysiology. Innate (“nonspecific”) immunity is the defense system people are born with to protect them from all antigens (foreign substances) that enter the body. Unlike the innate immune system, which attacks based on identification of general threats, the adaptive immune system is activated by pathogen exposure. Adaptive immunity uses its “memory” to learn about the threat and enhance the immune system accordingly over time. The adaptive immune system relies on B cells and T cells—otherwise known as lymphocytes—to function.

IFNs exert antiviral, antimicrobial, antitumor, and immunomodulatory effects as part of the innate immune system. Literature widely recognizes the SjS-associated “IFN signature,” as increased IFN levels activate multiple IFN-responsive genes involved in immune activities.²¹ Research indicates that type 1 IFN dysregulation is a major pathogenic mechanism in many autoimmune conditions, including SjS.^21,22 It is also suggested that “crosstalk” between the type 1 IFN pathway and B-cell activation causes a vicious cycle of immune activation where type 1 IFNs drive production of autoantibodies (made against substances formed by a person's own body) which further promotes IFN production.²¹ Toll-like receptors (TLRs) also play key roles in the innate immune system.²¹ Research suggests that TLR-dependent IFN expression may contribute to immune system activation and autoimmunity development in pSjS.²¹

In patients with SjS, lymphocytes infiltrate the salivary and lacrimal glands and other glands of the respiratory and gastrointestinal tracts and vagina.⁴ T cells in this infiltrate produce interleukin (IL)-2, IL-4, IL-6, IL-1β, and tumor necrosis factor while the B cells cause hypergammaglobulinemia (overproduction of immunoglobulins/antibodies) and produce autoantibodies.⁴ Some of these autoantibodies target cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. About 60% of patients with SjS also express non-organ-specific autoantibodies, including rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes Ro/SS-A and La/SS-B.⁴ These processes eventually lead to glandular dysfunction that manifests as dry eyes and mouth and enlargement of major salivary glands.

B-cell activating factor (BAFF) may also contribute to pSjS development. BAFF is usually an active part of the innate immune system, but B cells, T cells, and epithelial cells in the salivary glands also release BAFF in response to IFNs.²¹ This suggests that epithelial cells are not only passive victims of pSjS autoimmunity but also contributors to immune system overactivation. This also shows that BAFF serves as a link between the innate and adaptive immune systems in pSjS and could also represent an important therapeutic target in pSjS.²¹

Other Theories

Research into a well-defined cause of SjS is ongoing. Additional theories include a potential viral trigger, neuroendocrine abnormalities, and autoimmune epithelitis. Evidence for a viral trigger in pSjS development is conflicting, but studies have been unable to replicate an association between SjS and Epstein-Barr virus, hepatitis C virus, retroviruses, or Coxsackie A virus.²¹ Researchers think that the microbial stimuli driving pSjS development could be diverse or that the initiating viral stimulus is no longer detectable once the disease manifests.

The classic triad of symptoms in pSjS is sicca, arthralgia, and fatigue. Pathogenic mechanisms producing fatigue remain unknown, but neuroendocrine dysfunction may play a key role in the process.²¹ Studies show that patients with pSjS have decreased hormone levels (e.g., cortisol) compared with healthy individuals, indicating dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is suggested to promote fatigue and depression in patients with pSjS.

The Search for Biomarkers

Disclosing a disease’s etiology allows researchers to identify biomarkers (i.e., a biological molecule in the body that is a sign of an abnormal process) for diagnosis and assessment of disease process and treatment response. It also stimulates discovery of treatment targets. Researchers have been hard at work searching for biomarkers for SjS. Biomarkers can drive more precise diagnosis and may be used to measure disease severity or see how well the body responds to treatment. Scientists have discovered potential biomarkers, but studies have yet to validate their utility in SjS diagnosis and treatment.

Novel tissue-specific autoantibodies (TSAs) have been described in the early stages of pSjS, including salivary protein-1, parotid secretory protein, and carbonic anhydrase 6.²³ These are detectable even before the classic autoantibodies Ro/SS-A and La/SS-B. Further studies are needed to determine the utility of TSAs in screening patients with dry eye for SjS.

Some researchers hope to look beyond blood for reliable biomarkers for pSjS, more specifically in tears or saliva. They have studied tear proteins LACTO and LIPOC-1 as potential biomarkers for pSjS and one study shows they are more accurate indicators than traditional clinical tests for disease detection.²³ Other studies have examined salivary levels of S100A8/A9 as a potential biomarker for lymphoma development in patients with pSjS. Imaging biomarkers are also gaining attention. Salivary gland ultrasounds, for example, are non-invasive and valuable for studying the morphology (structure) of major salivary glands.²³

EVIDENCE-BASED TREATMENT STRATEGIES

SjS has no cure, and treatment varies from person to person based on their symptoms. Until recently, guidelines were unavailable to help clinicians manage Sjogren’s syndrome rationally.

In 2019, EULAR released evidence-based guidelines on which to rely, but clinicians may be unaware of its availability.¹¹ Medication is the cornerstone of these recommendations, so pharmacists and pharmacy technicians should be prepared to make evidence-based recommendations and appropriate referrals to improve care for patients with SjS. It is important to remember that no therapy is explicitly approved for SjS disease modification. Rather, providers use therapies indicated for each symptom separately—and some off-label (i.e., for a non-FDA-approved indication)—on a trial-and-error basis based on available evidence from small trials that sometimes include a subset of patients with SjS.

Sicca

Glandular dysfunction—the cause of sicca symptoms—appears to be stable for long periods of time (up to 12 years) and has a chronic course in patients with pSjS.¹¹ No therapeutic intervention can reverse or slow the progression of glandular dysfunction, so sicca symptoms cannot be cured. EULAR guidelines state that the first therapeutic approach to sicca symptoms should be symptomatic relief using topical therapies (e.g., saliva substitutes, artificial tears).¹¹ This minimizes the risk of adverse effects (AEs) seen with systemic therapies.

Finding the optimal lubrication is a matter of trial and error, so pharmacy staff should be prepared to set realistic expectations for patients seeking relief of sicca symptoms. They should also help patients recognize when it may be time to talk to their prescriber about stepping up to pharmacologic treatment.

Oral Dryness

Treatment of oral dryness depends on the severity of salivary gland dysfunction (Figure 1).¹¹ No evidence indicates any non-pharmacologic stimulant is better than another, so patients with mild glandular dysfunction should use a trial-and-error approach to find one that works for them. If these therapies don’t help or patients do not wish to use non-pharmacologic stimulants, providers should move on to pharmacologic stimulation. Muscarinic agonists’ main AE is excessive sweating.¹¹ To avert this, EULAR recommends increasing the dose progressively up to 15 to 20 mg/day when possible.

Cevimeline and pilocarpine are cholinergic agents, meaning they activate muscarinic receptors in the parasympathetic nervous system (which controls bodily functions when a person is at rest) to stimulate saliva production. Patients with SjS take cevimeline 30 mg by mouth three times daily or pilocarpine 5 mg by mouth four times daily to treat dry mouth.^24,25 The most common AEs of cevimeline and pilocarpine are excessive sweating, nausea, rhinitis (stuffy nose), and diarrhea.

The ideal saliva substitute will have a neutral pH mimicking natural saliva composition and contain fluoride and other electrolytes.¹¹ Gel formulations are ideal for patients with acceptable salivary flow output, especially those with oral dryness at night. However, patients often dislike these formulations due to their sticky mouthfeel. Pharmacists can recommend that patients dilute oral gel formulations to reduce this phenomenon for better adherence. Thinner preparations are preferred for patients with better-preserved glandular function.¹¹

Some experts feel that all patients with oral dryness should use salivary substitutes regardless of the degree of glandular dysfunction.¹¹ Whether patients use these formulations or not, all patients with salivary dysfunction should use a neutral pH sodium fluoride gel to prevent extensive caries (i.e., cavities).

Ocular Dryness

Reflex tears are the tears we produce when we cry, while we produce basal tears continuously to lubricate the ocular surface (the surface layers of the eye, namely the cornea and conjunctiva).²⁶ While tears may taste like salt water, their composition is more complex. Both types of tears contain water, but they also contain mucin, lipids, proteins (lysozyme, lactoferrin, lipocalin, immunoglobulins, and peroxidase), electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, and calcium), growth factors (epidermal growth factor), cytokines, and glucose.

Artificial tears and ocular gels/ointments are first line therapies for volume replacement and lubrication for ocular dryness.¹¹ While many people refer to over-the-counter (OTC) drops, gels, ointments, and lubricants as artificial tears, these products lack the biologically active components found in natural tears.²⁷ Their primary role is to supplement the patient’s natural tear production and provide sufficient lubrication to avoid eye complications.

Many artificial tear formulations are available, so patients may need assistance navigating the options. Table 2 lists common ingredients in artificial tears and their functions. A major difference between OTC products is the presence of chemical formulations that increase viscosity (thickness/stickiness) and adhesion and facilitate even distribution across the ocular surface.²⁷ As a general rule, drops are the lowest viscosity products, ointments have the highest viscosity, and suspensions fall in between. Lubricants with a polymeric base or viscosity agent are preferred for patients with SjS to¹¹

Add volume to the tear lake
Increase the time the lubricant remains on the ocular surface
Cushion the ocular surface to reduce friction between the eye and the eyelid

Table 2. Artificial Tear Ingredients and Their Functions^27-30

Ingredient Class	Function	Examples
Astringent	Precipitate protein to clear mucus from outer eye surface	zinc sulfate
Buffering agent	Maintain normal tear film pH	bicarbonate, phosphate
Demulcent	Protect and lubricate mucous membrane surfaces	carboxymethylcellulose sodium, dextran, gelatin, glycerin, hydroxyethyl cellulose, hypromellose, methylcellulose, polyethylene glycol, polysorbate, polyvinyl alcohol, povidone, propylene glycol
Lipid formulations	Improve gland function and increase tear film stability	castor oil, phospholipids, triglycerides
Preservatives	Prevent bacterial contamination	benzalkonium chloride (BAK), ethylenediaminetetraacetic acid (EDTA), polyquaternium-1, sodium chlorite, sodium perborate

Not all artificial tear products are equal, and different products work better for different patients. The optimal artificial tear offers long-lasting, effective symptom relief. It should also have low blur and be comfortable to administer.³¹ Surface tension, pH, viscosity, duration of action, and preservative presence or absence affect these factors.

OTC eye drops commonly include preservatives to prevent bacterial contamination. Repeated use of preservative-containing eye drops is associated with ocular allergies and toxicities, which can lead to product nonadherence and worsening symptoms.²⁷ Benzalkonium chloride (BAK)—the most common preservative used in eye formulations—is an epitheliotoxin and a toxic detergent.^28,29 It attracts monocytes and lymphocytes to the conjunctiva, worsening inflammation and thickening the tissue. This effect is cumulative; the more the eye is exposed to BAK, the greater the negative effects.²⁹ As a rule-of-thumb, pharmacists should always recommend products without BAK as a preservative.²⁸

EULAR recommends that all patients with SjS who present with ocular dryness use artificial tears containing methylcellulose or hyaluronate at least twice daily.¹¹ They should increase frequency as symptoms reappear as often as hourly. Individuals who use artificial tears four or more times daily should always use preservative-free products. Patients who experience overnight dryness should consider ophthalmic ointments before bedtime, as they remain in the eye longer. These are not recommended for daytime use because they blur vision.

Patients who are refractory to artificial tears and ointments—those who do not improve after maximum use—should see an ophthalmologist for prescription treatment. Short-term non-steroidal anti-inflammatory drug (NSAID) or corticosteroid eye drops are indicated for a maximum of two to four weeks.¹¹ This is due to the potential for AEs with long-term use, including

NSAIDs: corneal-scleral melts, perforation, ulceration, severe keratopathy
corticosteroids: infections, increased intraocular pressure, cataract worsening or development

Cyclosporine 0.05% is another therapeutic option for patients who are refractory to or do not tolerate artificial tears and ointments and those with severe ocular dryness requiring multiple courses of a glucocorticoid eye drop.¹¹ Cyclosporine is a calcineurin inhibitor that prevents T cell maturation.³² This counteracts SjS’s vicious cycle of inflammation. Patients administer the drug in the eyes twice daily, and the most common AEs are eye burning, stinging, and irritation. Of note, a small trial investigating topical tacrolimus showed promising results, but larger trials are needed to confirm the role of this drug for SjS-associated ocular dryness. Some providers also use lifitegrast ophthalmic solution or varenicline nasal spray off-label to treat SjS-associated dry eye, but EULAR makes no recommendation for their use.

Serum eye drops are blood-derived eye drops that may be autologous (uses the patient’s own blood) or allogenic (the blood comes from a donor).²⁶ These are compounded; a specialized pharmacy collects the patient’s blood, then clots, centrifuges, and dilutes it with sterile saline. The serum drops also contain increased concentrations of proteins, growth factors, vitamins A and C, antioxidants, and electrolytes found in natural tears.²⁶ This is meant to mimic natural basal tears’ biochemical properties to heal the cells of the ocular surface.

Small uncontrolled studies have examined serum eye drops for SjS patients, and results are inconsistent.¹¹ Nevertheless, ophthalmologists may use this option for patients with severe symptoms who are refractory to topical cyclosporine drops. When considering serum eye drops, individuals should consider storage needs, as they should be frozen until use (up to six months) and then refrigerated once opened for up to one week. Contamination during and after the compounding process is also possible.¹¹

Studies have investigated the utility of other therapies—hydroxychloroquine, immunosuppressive agents, and rituximab—for SjS-related ocular dryness, but EULAR does not recommend any of them for ocular dryness alone based on available clinical data.

Fatigue and Pain

Patients with pSjS often present with general non-inflammatory joint/muscle pain and fatigue/weakness. After ruling out potential concomitant conditions (e.g., osteoarthritis, hypothyroidism, vitamin deficiencies, depression), providers should evaluate whether the patient is experiencing joint pain (arthralgia) or joint inflammation (arthritis, tenosynovitis).¹¹ The ESSDAI score defines low articular activity level as arthralgia in the hands, wrists, ankles, and feet accompanied by morning stiffness longer than 30 minutes, always ruling out concomitant osteoarthritis.¹⁷ Objective inflammation (i.e., redness, heat, and swelling) in one or more joints is considered arthritis, and the ESSDAI score classifies arthritis severity based on the number of joints involved. Management of arthritis is covered under systemic disease treatment, and Table 3 outlines EULAR recommendations for non-arthritis musculoskeletal pain.

Table 3. EULAR-Recommended Management of SjS-Associated Musculoskeletal Pain*¹¹

Acute Pain

Frequent Acute Pain

Chronic, Daily Pain

· Acetaminophen or NSAIDs for symptomatic relief for up to 7 to 10 consecutive days

· Topical diclofenac may be effective for local pain with fewer adverse effects

· Consider hydroxychloroquine in patients with articular pain based on its evidence for use in other SAD

· Off-label use of biologics (even as rescue therapy) is not recommended

· Emphasize non-pharmacologic management (e.g., physical activity) before medications

· Goal is to avoid repeated use of NSAIDs or glucocorticoids

· Musculoskeletal: antidepressants and anticonvulsants

· Neuropathic: gabapentin, pregabalin, or amitriptyline

· Opioids are not recommended

*Providers must first rule out concomitant osteoarthritis (i.e., objective inflammation in 1 or more joints); NSAID = non-steroidal anti-inflammatory drug; SAD = systemic autoimmune diseases

Systemic Disease

EULAR defines systemic SjS as disease involvement that affects or has affected any of the organs/systems included in the ESSDAI score (i.e., all domains except biological).¹¹ Systemic disease is linked to autoimmune dysfunction that may eventually become irreversible. Providers should limit systemic therapies to patients with active systemic disease following careful evaluation of symptom severity and organ damage. Clinicians should consider systemic therapy on an individual basis, as not all patients with active systemic disease will require it.¹¹

EULAR makes a few general recommendations regarding systemic therapy¹¹:

Consider systemic therapies for most patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score (i.e., greater than 5).
Therapeutic response is considered a reduction of 3 or more points in the global ESSDAI score.
Providers should follow a sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics to treat organ-specific systemic manifestations.
Use glucocorticoids at the minimum dose and duration necessary to control active systemic disease.
Use synthetic immunosuppressive agents (e.g., azathioprine, cyclophosphamide, leflunomide, methotrexate, mycophenolate) mainly as glucocorticoid-sparing agents in patients requiring long-term glucocorticoid therapy (i.e., those with severe organ impairments).
Consider B-cell targeted therapies (e.g., belimumab, rituximab) in patients with severe, refractory systemic disease.

Evidence regarding the use of glucocorticoids for SjS is weak and studies report high rates of AEs.¹¹ Guidelines recommend administering pulses of methylprednisolone followed by doses of 0.5 mg/kg daily or less as induction therapy in patients with severe disease and lower doses in patients with less severe disease. The goal is to withdraw glucocorticoids in patients whose SjS becomes inactive as soon as possible or at least target a maintenance dose of 5 mg daily or less with the aid of steroid-sparing immunosuppressive agents.¹¹ Studies of immunosuppressive agents are lacking, so EULAR does not recommend one agent over another, except in the case of patient characteristics or comorbidities. Dose, route of administration, and duration of treatment are not established given the lack of clinical data, so physicians should follow similar dosing schedules to other systemic autoimmune diseases.¹¹

EULAR guidelines also include algorithms for each ESSDAI domain based on available trial data and the clinical experience of the individuals on the EULAR task force.¹¹ Figure 2 summarizes these recommendations, including standard of care, second line, and third line recommendations.

Considering Comorbidities

More than 20% of people with SjS are older than 65 years, making them more likely to have pulmonary, liver, kidney, or heart-related comorbidities.¹⁹ It is especially important to consider alternative causes of sicca in older patients since many conditions and drugs produce oral and ocular dryness. Older people are nearly twice as likely to suffer from dry eyes than younger individuals.¹⁹ Older age is also associated with decreased salivary flow rate. Dry mouth is more than a bothersome symptom. Addressing dry mouth in older adults is vital because worsening oral health increases risks of malnutrition, social isolation, care dependency, and frailty that tend to affect this population.¹⁹

An estimated 45% to 80% of the older adult population reports some pain, most commonly musculoskeletal.¹⁹ Treatment plans for these patients should emphasize non-pharmacologic relief rather than medications as first-line therapy. Also, despite the lack of available evidence, experts suggest that topical NSAID formulations may be effective for local SjS-related pain in older adults with fewer AEs than oral NSAIDs.¹⁹

Treating systemic symptoms in this population also requires special considerations. Older adults are more likely to experience AEs from glucocorticoids—including blood clots, osteoporosis, and bone fractures—than younger individuals.¹⁹ Pharmacists should also consider the greater frequency of hepatic and renal impairment in older patients. For example, renal function decline and decreased folate stores may increase methotrexate-related toxicity.¹⁹ Studies suggest that disease-modifying antirheumatic drugs (including some biologics) have similar effects on younger and older patients while maintaining favorable AE profiles.¹⁹ Older people, therefore, should not be excluded from the use of these agents for systemic disease where appropriate.

Autoimmune conditions increase the risk of lymphoma, cancer stemming from the lymph nodes.³³ More specifically, pSjS is the autoimmune disease associated with the highest risk of B-cell lymphoma, occurring in 5% to 10% of patients.³³ This risk increases by 2.2% per year of age in this population.³³ In patients with pSjS, chronic stimulation of autoimmune B cells leads to development of B-cell lymphoma. Screening for lymphoma is an important part of a comprehensive treatment plan given the increased risk. Similar to other autoimmune conditions, SjS also increases patients’ risk for atherosclerosis and coronary artery disease.²²

Research Continues

Researchers continue to define new therapeutic targets and investigate new treatments for SjS. Targeting B cells appears to be the most promising therapeutic approach for this condition.¹⁸ Studies are evaluating anti-CD20 antibodies and antibodies targeting the BAFF signaling pathway to target B cells and anti-CD40 antibodies to block the crosstalk between T cells and B cells.¹⁸ So far, two agents have met their primary outcome—improvement in systemic disease activity—in pSjS clinical trials: anti-BAFF receptor antibodies and anti-CD40 antibodies.

BAFF receptors are exclusively expressed on B cells, so targeting these receptors effectively depletes B cells to blunt the autoimmune response in pSjS. Clinical trials have assessed an anti-BAFF receptor antibody, ianalumab (VAY736) in patients with pSjS with positive results.^34,35 In the phase 2b study, patients experienced improved ESSDAI scores from baseline to week 24 and improvement in stimulated saliva flow rate.³⁵ This is a promising option for a future disease-modifying pSjS treatment, and phase 3 trials are ongoing.

The interaction between CD40 and the CD40 ligand (CD40L) is important for B cell development, antibody production, and optimal T cell-dependent antibody responses. Patients with pSjS have increased expression of CD40L compared to healthy individuals, which suggests that CD40-CD40L interactions could be a practical target for pSjS treatment.¹⁸ Phase 2 studies have shown promising results for iscalimab, an anti-CD40 antibody, to treat pSjS. Patients treated with intravenous iscalimab experienced a mean ESSDAI score decrease of 5.21 points, a significant improvement over patients in the placebo group.³⁶ Phase 3 studies of this therapy are forthcoming. A phase 2 trial of another anti-CD40L antibody is also underway.³⁷

Additional therapeutic targets under investigation include¹⁸

Bruton’s tyrosine kinase, an important molecule in B cell receptor signaling
plasmacytoid dendritic cells, which secrete type 1 IFNs
downstream type 1 and 2 IFN signaling (using Janus kinase inhibitors)
IL-12 signaling pathway and induction of T helper 1 cells, which secrete type 2 IFNs (using ustekinumab)

PAUSE AND PONDER: How often do you encounter patients asking for help choosing artificial tear products? What could you improve about your ability to assist them?

MULTIDISCIPLINARY TEAM CARE IS IDEAL

EULAR guidelines recommend a multidisciplinary approach to SjS treatment.¹¹ This is the second strongest recommendation included in the 2020 guidelines, with only a recommendation for patients who develop B-cell lymphoma to receive individualized treatment receiving a stronger grade. SjS’s overall prevalence in the general population is low and the condition presents differently in every patient, making it difficult for any one provider to ensure in-depth expertise in managing it. At minimum, the SjS care team should include a primary care provider (PCP), a rheumatologist, a dentist, and an ophthalmologist. Pharmacy staff should understand the roles and responsibilities of each provider to better recognize their own place on the care team.

Rheumatologist

Rheumatologists are usually the “lead” of the medical team for SjS and have the primary responsibility for managing it.³⁸ The rheumatologist should verify the diagnosis, including looking for disease mimics and screening and monitoring for coexisting rheumatologic or autoimmune conditions. They should also screen for lymphoma risk factors and common comorbidities. They may collaborate with the patient’s PCP for comorbidity monitoring and management. Rheumatologists also provide treatment for systemic features of SjS.³⁸

Primary Care Provider

The PCP should provide routine, comprehensive health care addressing a wide range of issues, including patients’ mental health.³⁸ They should collaborate with the patient’s rheumatologist to establish who is responsible for overlapping areas of practice (e.g., comorbidities, immunizations, nutrition concerns). Screening for comorbidities—including cardiovascular disease, osteoporosis, sinusitis, and others—is an important task for PCPs, but they may be unaware of the increased risk of these conditions in patients with SjS. Pharmacy teams should encourage patients to advocate for themselves, and direct patients to www.sjogrensadvocate.com for advice on how to do so effectively.³⁸

Ophthalmologist

Ophthalmologists are responsible for managing severe dry eye.³⁸ Occasionally, the ophthalmologist is the first provider to suspect SjS and refers patients to rheumatology for general management. They perform diagnostic tests (e.g., Schirmer’s test, ocular staining score, tear breakup time) to determine the severity of SjS ocular symptoms and blood tests to screen for biologic signs of SjS. These clinicians also provide routine dry eye management, including prescription medications/drops and recommendations for OTC therapies.

Dentist

Many patients with SjS require extensive dental care exceeding the recommended checkups every 6 months for otherwise healthy individuals.³⁸ Preventative dental visit frequency depends on patients’ level of dryness and decay. At every checkup, dentists should examine the entire oral region, including palpating (i.e., feeling with the fingers) salivary glands, face, and neck for swelling and masses.³⁸ They should also provide dental caries prevention, screening, and treatment.

Where Pharmacy Fits In

Most often, pharmacy technicians will encounter patients with SjS at the pickup counter, so they should be prepared to refer patients to the pharmacist when appropriate. Sometimes, patients request assistance finding the eye care aisle for OTC drops. Before pointing them in the right direction, pharmacy technicians should refer patients to the pharmacist for counseling if they indicate they are new to using artificial tears (e.g., asking your opinion about product selection).

Technicians can also help patients locate products based on pharmacist recommendations and provide informational handouts about proper administration technique (see Sidebar). While cost is an important factor in therapy adherence, consider recommending name brand products rather than store brand generics whenever feasible. While the active ingredients may be consistent across proprietary and store brand products, the concentration of these components is often less than 5% of each drop.³⁹ The amount of inactive ingredients (i.e., “filler”) differs from brand to brand.

Sidebar: Don’t Leave Patients High and Dry^40,41

To provide maximum relief, patients must administer eye formulations correctly. Many patients struggle with this, especially older patients, and joint pain in SjS can make it even more difficult. Counseling patients on proper eye drop and ointment instillation is crucial to improving outcomes.

Eye Drop Administration

Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses unless the product is specifically designed for use with contact lenses. If using a suspension, shake well.
Tilt head back, gently grasp the lower eyelid below lashes and pull away from the eye to create a pouch.
Look up and administer a single drop into the pouch without touching the tip of the container to the eye.
As soon as the drop is instilled, release the eyelid slowly. Close eyes gently for 3 minutes and position the head downward (gravity pulls the drop onto the ocular surface). Minimize blinking or squeezing the eyelid.
Use a finger to gently apply pressure to the opening of the tear duct (inner corner of the eye) to prevent medication from draining through the tear duct and increase medication contact time in the eye.
If additional ophthalmic therapy is indicated, wait 5 to 10 minutes in between. Also, wait 5 to 10 minutes before reinserting contact lenses, if applicable.

Pro-Tip: tell patients, “If you have a hard time deciphering whether you’ve successfully installed eye drops, refrigerate the solution before administration to detect the drops more easily on your eye’s surface. Do NOT use this trick with a suspension.”

Eye Ointment Administration

Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses unless the product is designed for use with contact lenses specifically.
Tilt head back, gently grasp the lower eyelid below lashes, and pull away from the eye to create a pouch.
Look up, and with a sweeping motion, place a strip of ointment ¼ to ½ inch wide inside the lower eyelid by gently squeezing the tube (avoid touching the tube tip to any tissue surface).
Release the eyelid slowly and close eyes gently for 1 to 2 minutes.
Vision may blur temporarily, so avoid activities that require good visual acuity until vision improves. Also, wait 15 minutes before reinserting contact lenses, if applicable.

Clearly, a medication expert needs to contribute to patient and provider education and oversee prescribed and OTC medications. Pharmacists can offer various clinical pearls to help patients with SjS avoid dry eyes, mouth, and skin.

Lifestyle modifications⁴²:

Avoid windy or drafty environments and wear sunglasses outdoors
Use a humidifier indoors to keep the air moist
Practice good oral hygiene (e.g., chew sugarless gum, stay well hydrated, see a dentist three times a year)
Consciously remember to blink when working at a computer or reading extensively
Avoid wearing eye makeup
Consider smoking cessation and avoid smoky environments
After showering, pat dry gently and apply an emollient to damp skin within three minutes

Separation and timing^40,41:

Separate administration of multiple eye drops by at least 5 minutes to ensure the first drop is not flushed away by the second and the second drop is not diluted by the first
If using multiple products, use them in order of least viscous to most viscous to ensure efficacy of all treatments
If using drops and ointment, administer drops at least 10 minutes before ointment so the ointment does not create a barrier to the drops’ absorption
If using a suspension with another dosage form, use the suspension last because its retention time in the tear film is longer

Pharmacists and pharmacy technicians should also be aware of medications that could worsen symptoms of dryness (Table 4). Technicians should refer patients with SjS to the pharmacist when they see these at the pick-up counter. They should also stay up to date on available eye care formulations and discuss new products with the pharmacist. Pharmacists should counsel patients with SjS about which OTC products to avoid and offer to contact prescribers to recommend prescription therapy changes.

Table 4. Medications That Cause or Worsen Ocular Dryness^19,25,28

Medication/Class	Examples	Rx/OTC	Mechanism for Ocular Dryness
Anticholinergics	benztropine trihexyphenidyl	Rx	Blocking acetylcholine blurs vision and stops the signals that normally tell the eyes to produce tears
Antihistamines (especially first-generation)	cetirizine chlorpheniramine diphenhydramine loratadine	OTC	Dry secretions (including tears) and produce anticholinergic adverse effects
Beta-blockers	atenolol metoprolol propranolol	Rx	Cause the body to make less of a protein present in tears, and can lower pressure in the eyes, affecting the amount of water in the tears
Decongestants	phenylephrine pseudoephedrine	OTC	Decrease nasal/mucosal mucus production (including the eyes), which decreases tear production
Diuretics	furosemide hydrochlorothiazide	Rx	Help the body eliminate water and salt, which can alter tear composition
Hormones	estrogen/progesterone and other hormones used for contraception, infertility, or hormone replacement	Rx	Unknown
Isotretinoin	N/A	Rx	Lessens oil production by certain glands to treat acne, but some of those glands are in eyelids, decreasing oil in tears
Tricyclic antidepressants	amitriptyline amoxapine clomipramine imipramine maprotiline	Rx	Anticholinergic adverse effect stops the signals that normally tell the eyes to produce tears

OTC = over-the-counter; Rx = prescription only

CONCLUSION

SjS is a complex, multifactorial condition that impacts patients’ quality of life substantially. Providing optimal care for this disease requires a multidisciplinary team, on which pharmacists and pharmacy technicians provide a link between all providers to ensure continuity of care. Recognizing patients with SjS in the pharmacy is crucial to prevent polypharmacy, ensure patients know how to use eye care formulations, assist patients in finding OTC products to address symptoms, and refer to other providers when necessary. This will improve care and outcomes for patients with SjS.

Pharmacists Post-test

Upon completion of this activity, pharmacists will be able to
1. DISCUSS current theories postulating how Sjogren’s syndrome develops
2. IDENTIFY biomarkers used in diagnosis and patient classification
3. INTERPRET guidelines and evidence-based medicine to use best practices to manage Sjogren’s syndrome
4. USE elements of an integrated approach to care among specialists and other pharmacists

1. Which gene(s) shows the strongest association with primary SjS?
A. STAT4
B. IRF5
C. HLA

2. Which of the following is associated with SjS pathogenesis?
A. Interferon signature
B. T-cell activating factor
C. Epstein-Barr virus

3. Which sentence describes the potential role of BAFF in primary SjS development?
A. It is an unexplored and unreliable therapeutic target for SjS treatment
B. It proves that epithelial cells are passive victims of SjS autoimmunity
C. It serves as a link between the innate and adaptive immune systems

4. Which of the following biomarkers may be more accurate than traditional clinical tests for SjS detection?
A. TSAs
B. LACTO and LIPOC-1
C. S100A8/A9

5. Which is TRUE about the ESSDAI score?
A. A 14 is the highest score possible
B. It measures disease activity in 12 domains
C. It assesses patient-reported outcomes

6. A patient consults with you about her SjS-induced dry mouth symptoms. She has been using a gel saliva substitute for a week. It works well, but she finds it annoyingly sticky and is hoping to find an alternative. She tells you her rheumatologist says she has mild gland dysfunction and acceptable saliva output. What is the best recommendation for this patient?
A. Dilute the saliva substitute with water
B. Switch to xylitol-free chewing gum
C. Talk to your rheumatologist about trying cevimeline

7. A patient is using artificial tear drops for SjS-related ocular dryness, but he complains that he must use them every 2 hours because they wear off. Which of the following is the best recommendation for this patient?
A. Switch to an artificial tear suspension containing hyaluronate
B. Switch to an artificial tear ointment containing BAK
C. Talk to your ophthalmologist about prescription therapies

8. A patient with SjS complains of visible redness, considerable heat, and ample swelling in three of his joints. He brings acetaminophen and ibuprofen to your pharmacy counter and asks which one will work better. Which of the following is the best recommendation for this patient?
A. Ibuprofen is the better choice because it is anti-inflammatory
B. A topical NSAID like diclofenac is a better choice because it is locally-acting
C. Talk to your rheumatologist about systemic hydroxychloroquine with NSAIDs

9. A patient presents to your pharmacy to buy artificial tears. She mentions that her ophthalmologist recommended that she see a rheumatologist because she thinks the patient has SjS. She doesn’t understand why that’s necessary when she can just use OTC drops to lubricate her dry eyes, and she doesn’t plan to see another provider. Which of the following is the best response?
A. You can use OTC drops as long as you choose a product with methylcellulose and no benzalkonium chloride
B. SjS affects your whole body, not just your eyes, so you may need additional treatment from a rheumatologist
C. Your ophthalmologist can prescribe prescription therapies for your dry eye symptoms, so you don’t need to see a rheumatologist

10. A patient’s neurologist prescribed propranolol for migraine prevention. He presents to your pharmacy to pick up the prescription along with a facewash for acne and artificial tear drops for SjS. What should you do?
A. Offer to contact the patient’s neurologist for an alternative migraine prevention therapy
B. Recommend a suspension, not drops, to prevent blurred vision that could worsen his migraines
C. Advise him to avoid the acne facewash as it could worsen his SjS-related dry eye symptoms

Pharmacy Technician Post-test

Upon completion of this activity, pharmacy technicians will be able to
1. DESCRIBE Sjogren’s syndrome’s basic pathology and symptoms
2. OUTLINE prescription and non-prescription treatments used in Sjogren’s syndrome
3. IDENTIFY when to refer patients to the pharmacists for recommendations or referrals

1. Which is the most common symptom of SjS?
A. Arthralgia
B. Fatigue
C. Sicca

2. Which of the following sentences accurately describes SjS symptoms?
A. Symptoms are the same in every patient
B. Symptoms may cycle between mild and severe
C. Younger patients have worse symptoms than older patients

3. Which gene(s) shows the strongest association with primary SjS?
A. STAT4
B. IRF5
C. HLA

4. Which of the following should ALL patients with SjS-related dry mouth use?
A. Gel formulation saliva substitute
B. Prescription muscarinic agonists
C. Neutral pH sodium fluoride gel

5. Which of the following has the lowest viscosity?
A. Eye drops
B. Eye suspensions
C. Eye ointments

6. Which prescription therapy does EULAR recommend for SjS-related ocular dryness?
A. Hydroxychloroquine oral tablets
B. Cyclosporine ophthalmic solution
C. Lifitegrast ophthalmic solution

7. Which of the following is used to treat frequent acute SjS-associated articular pain?
A. Hydroxychloroquine
B. Biologics
C. Amitriptyline

8. Which of the following does EULAR recommend for patients with SjS who present with ocular dryness?
A. Use artificial tears containing methylcellulose of hyaluronate at least twice daily
B. Use artificial tears containing benzalkonium chloride at least four times daily
C. Use artificial tear ointments during the day because they last the longest in the eyes

9. A patient is picking up a pilocarpine prescription for SjS-induced dry eyes. She mentions that she has daily, throbbing pain in her back. She is also purchasing naproxen (an NSAID) that she hopes will help with the pain and OTC artificial tears for her dry eyes. Why should you refer this patient to the pharmacist?
A. Acetaminophen is a better choice for this patient’s pain
B. The patient should not use artificial tears with pilocarpine
C. This patient may require prescription treatment for her pain

10. Which of the following patients with SjS should you refer to the pharmacist?
A. A 74-year-old male purchasing topical diclofenac for local, acute pain
B. A 52-year-old female purchasing artificial tears, cevimeline, and phenylephrine
C. A 33-year-old female purchasing artificial tears and insulin for diabetes

References

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2. Jonsson R, Brokstad KA, Jonsson MV, et al. Current concepts on Sjögren's syndrome - classification criteria and biomarkers. Eur J Oral Sci. 2018;126(Suppl 1):37-48. doi:10.1111/eos.12536
3. Sjogren’s syndrome. National Institute of Dental and Craniofacial Research. Updated July 2018. Accessed June 1, 2022. https://www.nidcr.nih.gov/health-info/sjogrens-syndrome
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6. Venus Williams stands up for Sjogren’s awareness. Sjogren’s Foundation. April 30, 2022. Accessed June 1, 2022. https://www.sjogrens.org/blog/2022/venus-williams-stands-up-for-sjogrens-awareness
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8. Ramirez CD. Carrie Ann Inaba announces leave of absence from The Talk to focus on her health. April 26, 2021. Accessed June 1, 2022. https://people.com/tv/carrie-ann-inaba-taking-leave-of-absence-from-the-talk-to-focus-on-health/
9. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a metaanalysis. Arch Intern Med. 2005;165:2337-2344.
10. Lazarus, M.N.; Robinson, D.; Mak, V.; Møller, H.; Isenberg, D.A. Incidence of cancer in a cohort of patients with primary sjogren’s syndrome. Rheumatology. 2006;45:1012-1015.
11. Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3-18. doi:10.1136/annrheumdis-2019-216114
12. Kittridge A, Routhouska SB, Korman NJ. Dermatologic manifestations of Sjögren syndrome. J Cutan Med Surg. 2011;15(1):8-14. doi:10.2310/7750.2010.09033
13. Engel GL. The clinical application of the biopsychosocial model. J Med Philos. 1981;6(2):101-123. doi:10.1093/jmp/6.2.101
14. Tzioufas AG, Voulgarelis M. Update on Sjögren's syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol. 2007;21(6):989-1010. doi:10.1016/j.berh.2007.09.001
15. Carsons SE, Patel BC. Sjogren Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 2, 2021. https://www.ncbi.nlm.nih.gov/books/NBK431049/
16. Valtýsdóttir ST, Gudbjörnsson B, Lindqvist U, Hällgren R, Hetta J. Anxiety and depression in patients with primary Sjögren's syndrome. J Rheumatol. 2000;27(1):165-169.
17. Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide. RMD Open. 2015;1(1):e000022. Published 2015 Feb 20. doi:10.1136/rmdopen-2014-000022
18. Seror R, Nocturne G, Mariette X. Current and future therapies for primary Sjögren syndrome. Nat Rev Rheumatol. 2021;17(8):475-486. doi:10.1038/s41584-021-00634-x
19. Retamozo S, Baldini C, Bootsma H, et al. Therapeutic recommendations for the management of older adult patients with Sjögren's syndrome. Drugs Aging. 2021;38(4):265-284. doi:10.1007/s40266-021-00838-6
20. Jonsson R. Disease mechanisms in Sjögren's syndrome: What do we know? Scand J Immunol. 2022;95(3):e13145. doi:10.1111/sji.13145
21. Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol. 2013;9(9):544-556. doi:10.1038/nrrheum.2013.110
22. Skarlis C, Raftopoulou S, Mavragani CP. Sjogren's syndrome: recent updates. J Clin Med. 2022;11(2):399. doi:10.3390/jcm11020399
23. Cafaro G, Croia C, Argyropoulou OD, et al. One year in review 2019: Sjögren's syndrome. Clin Exp Rheumatol. 2019;37 Suppl 118(3):3-15.
24. Evoxac [prescribing information]. Daiichi Pharmaceutical Co.; 2006. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020989s008lbl.pdf
25. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014;157(4):799-806. doi:10.1016/j.ajo.2013.12.023
26. Dang VT, Hoyle B. Autologous serum tears: an overlooked treatment for dry eye. Modern Optometry. July 2020. Accessed June 1, 2022. https://modernod.com/articles/2020-july-aug/autologous-serum-tears-an-overlooked-treatment-for-dry-eye?
27. Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) artificial tear drops for dry eye syndrome. Cochrane Database Syst Rev. 2016;2:CD009729. doi:10.1002/14651858.CD009729.pub2
28. Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015;112(5):71-82. doi:10.3238/arztebl.2015.0071
29. Benzalkonium chloride (BAK). Not a Dry Eye. Accessed June 13, 2022. https://www.notadryeye.org/all-about-dry-eye-syndrome/treatments-for-dry-eye-syndrome-and-related-conditions/lubricating-eye-drops/glaucoma-eyedrops-a-fresh-look-at-preservatives/
30. CFR—Code of Federal Regulations Title 21. U.S. Food and Drug Administration. Updated March 28, 2022. Accessed June 13, 2022. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=349
31. Horton M, Horton M, Reinhard E. Master the maze of artificial tears. Review of Optometry. November 20, 2018. Accessed June 13, 2022. https://www.reviewofoptometry.com/article/master-the-maze-of-artificial-tears
32. Gupta PK, Asbell P, Sheppard J. Current and future pharmacological therapies for the management of dry eye. Eye Contact Lens. 2020;46 Suppl 2:S64-S69. doi:10.1097/ICL.0000000000000666
33. Nocturne G, Pontarini E, Bombardieri M, Mariette X. Lymphomas complicating primary Sjögren's syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford). 2019;60(8):3513-3521. doi:10.1093/rheumatology/kez052
34. Dörner T, Posch MG, Li Y, et al. Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019;78(5):641-647. doi:10.1136/annrheumdis-2018-214720
35. Dörner T, Bowman SJ, Fox R, et al. Ianalumab (VAY736), a dual mode of action biologic combining BAFF receptor inhibition with B cell depletion, reaches primary endpoint for treatment of primary Sjogren’s syndrome [abstract OP0302]. Ann Rheum Dis. 79(Suppl 1);187-188 (2020).
36. Fisher BA, Szanto A, Ng WF, et al. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study. Lancet Rheumatol. 2(3);e142-e152 (2020).
37. Safety, tolerability, pharmacokinetics, and therapeutic efficacy of SAR441344 in primary Sjögren's syndrome (pSjS) (phaethuSA). ClinicalTrials.gov identifier: NCT04572841. Updated May 12, 2022. Accessed June 1, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04572841
38. For the newly diagnosed. Sjogren’s Advocate. Updated June 10, 2022. Accessed June 13, 2022. https://www.sjogrensadvocate.com/newly-diagnosed
39. So many choices…what drops are best for my dry eyes? Summit Eye Center. March 5, 2019. Accessed June 13, 2022. https://www.summiteyekc.com/blog/eye-drop-overload-at-the-pharmacy
40. Evans K, Madden L. Recommended dry eye treatments in community pharmacy. The Pharmaceutical Journal. August 2, 2016. Accessed June 13, 2022. https://pharmaceutical-journal.com/article/ld/recommending-dry-eye-treatments-in-community-pharmacy
41. Fiscella RG, Jensen MK. Ophthalmic disorders. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs. 19th ed. Washington, DC: APhA Publications;2018:545-566.
42. Wick JY. Sjogren’s syndrome: dry as a desert. Pharmacy Times. February 18, 2014. Accessed June 13, 2022. https://www.pharmacytimes.com/view/sjogrens-syndrome-dry-as-a-desert

Diabetic Nephropathy: Slowing Decline and Preventing Mortality

After completing this application-based continuing education activity, pharmacists will be able to

1. List the classifications of chronic kidney disease

2. Describe the unmet medical needs, clinical practice guidelines, and scientific evidence in renal disease for patients with T2DM

3. Review emerging information about COVID-19’s impact and optimal management of patients with chronic kidney disease

4. Identify medications that are nephrotoxic and treatments that slow or prevent CKD

5. Apply patient counseling skills to improve awareness of condition and adherence to treatment

After completing this application-based continuing education activity, pharmacy technicians will be able to

1. List the basic pathology and symptoms of renal disease and diabetes

2. Recall treatments used in patients who have comorbid renal disease and diabetes

3. Identify when to refer patients to the pharmacists for recommendations or referrals

Kidney disease’s main risk factor is diabetes. Approximately one in three patients with diabetes have chronic kidney disease (CKD). Hypertension and smoking also increase risk and speed of its progression. Healthcare providers have primarily directed prevention at strict blood pressure control, use of renin-angiotensin-aldosterone-system blockers, adequate glycemic control, and cardiovascular risk factor control. Patients rarely exhibit symptoms until CKD is advanced, making diagnosis and treatment a challenge. Early screening for renal disease prompts earlier intervention and delays progression. Pharmacists can apply guideline recommendations that intersect with their scope of practice and recognize the advantage of renal protective medications. Seemingly harmless over the counter medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), can cause acute kidney injury. Technicians can take advantage of frequent patient interactions at the point of sale, screen for inappropriate NSAID use, and refer patients for pharmacist consultation. Pharmacy teams also need to be aware of coronavirus’s implications for patients with diabetes and offer support when appropriate.

Introduction

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder resulting from insulin resistance requiring lifelong management.¹ Managing comorbidities involves a multifaceted approach to care. Diabetic kidney disease (DKD) is a leading cause of morbidity and mortality.²

This home-study will use both terms, DKD and chronic kidney disease (CKD). The Kidney Disease: Improving Global Outcomes (KDIGO) guideline avoids using DKD because it implies all kidney disease is caused by diabetes pathophysiology. However, KDIGO also deems the term DKD appropriate when clinicians recognize the limitation of diabetes causing kidney disease.³

Epidemiology, Risk Factors, and Symptoms

Worldwide, more than 450 million people have diabetes. This number is expected to exceed 700 million by 2045.⁴ Forty percent of these patients develop DKD and may go on to develop kidney failure requiring renal replacement therapy (RRT).⁴ Of note, rap musician Freeway, comedian Tracy Morgan, and actress Lucy Davis all have diabetes—and kidney disease.⁵

Unfortunately, CKD may be present at diagnosis of T2DM.⁶ It can markedly increase cardiovascular risk and health care costs.⁶ Reducing DKD’s prevalence requires management efforts and support for patients.⁷

Demographic factors associated with development and progression of CKD among patients with T2DM include^7,8

African American race
Hispanic ethnicities
Male sex
Older age

Clinical factors include^7,8

Acute kidney injury (AKI)
Cardiovascular disease (CVD)
Family history of CKD, diabetes
Hyperlipidemia
Hypertension
Obesity
Smoking

Each kidney has about 1 million nephrons. Humans’ large physiologic reserve make slow loss unnoticeable. Often patients are asymptomatic until more than three quarters of kidney function is lost (usually stage 4 or 5), leading them to refrain from taking measures to treat the disease.^9,10 Eventually, CKD progresses to end stage renal disease (ESRD).¹¹

Unfortunately, patients do not realize they have renal dysfunction until symptoms begin to present. Examples of symptoms include¹²

Bleeding
Cold intolerance
Fatigue
Itching
Loss of appetite
Mental confusion
Nausea and vomiting
Peripheral neuropathies
Shortness of breath
Weakness

Pathogenesis

Located below the rib cage in the middle of the back, each kidney is about the size of a closed fist and shaped like a kidney bean (Figure 1).¹³ The kidneys’ regulatory and excretory functions maintain balance. Regulatory function controls the blood’s composition and volume. The kidneys also maintain stable sodium, potassium, and calcium concentrations, along with acid-base balance. The excretory function removes metabolic wastes (e.g., uremia) and produces urine.⁸ The tubule returns needed and useful substances to blood, and waste and extra water becomes urine.¹⁴

The kidneys have other functions. Their hormonal function produces renin for blood pressure (BP) control, generates erythropoietin that stimulates marrow production of red blood cells, and activates vitamin D needed for bone health. The kidneys also have metabolic functions contributing to glucose generation and metabolism of drugs and substances derived internally (e.g., insulin).⁸

DKD’s natural history starts with hyperglycemia. The kidneys begin to filter too much blood and the glomerular filtration rate (GFR) increases. The glomerulus acts as a filter and increased permeability allows albumin to cross the glomerulus into the urine. Higher albumin levels within the tubule may exacerbate kidney damage by exceeding the tubules’ ability to reabsorb.¹⁰ After years of working hard to filter more blood, the kidneys start to leak, and protein is lost in the urine (e.g., albuminuria).^2,14 Albuminuria may be the first sign of DKD.⁸ Overtime, GFR slowly declines. Ultimately, the kidneys fail at ESRD.²

Increased pressure and flow within the glomerulus may damage nephrons and decrease nephron mass.^8,12 The remaining nephrons then compensate using autoregulation. Renin release increases and converts angiotensin I to angiotensin II (ATII). ATII is a potent vasoconstrictor of afferent (e.g., brings blood to the glomerulus) and efferent (e.g., drains blood away from the glomerulus) arterioles – but preferentially affects efferent arterioles. This increases pressure within the glomerulus. More fluid reaches the kidneys and passes into the tubules. Consequently, tubular reabsorption increases.¹²

This compensatory mechanism may be adaptive and beneficial, but over time it can diminish the number of functioning nephrons. High pressure in the glomerulus impairs the size-selective function of the filter, resulting in more albumin in urine. Furthermore, ATII may mediate CKD progression through nonhemodynamic effects which ultimately results in further inflammation and fibrosis.¹² Hypertension and obesity also contribute to high glomerular pressure and enlargement in T2DM.² Metabolic changes, such as hyperglycemia, alter kidney hemodynamics and promote inflammation and fibrosis.²

Measuring Kidney Function

GFR is equal to the sum of the filtration rates in all functioning nephrons. An estimation of GFR (eGFR) uses the serum creatinine (SCr) level to measure the number of functioning nephrons roughly. eGFR does not actually measure the GFR. It estimates the measured GFR within +/- 85%. Small fluctuations in GFR are common and do not necessarily indicate disease progression.¹⁷ KDIGO guidelines consider progression at a minimal percentage change of at least 25%.¹⁷ Creatinine-based kidney function estimates have limitations. Results can be inaccurate with rapidly changing creatinine levels (e.g., in AKI), extremes in muscle mass or body size, or altered diet patterns, medications that interfere with SCr measurement, and use of creatine supplements.⁸ Medications associated with a false increase in SCr include antibiotics such as⁹

cefaclor
cefazolin
cefoxitin
cephalexin
clavulonic acid

Clinicians should measure SCr when antibiotic concentrations are at the lowest (at the end of dosing interval) to minimize this false increase.⁹Additionally, medications can alter SCr through inhibition of active tubular secretion of creatinine. These include⁹

amiodarone
cimetidine
cobicistat
dolutegravir
pyrimethamine
rilpivirine
trimethoprim

Approaches to estimate kidney function include Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).¹⁰ Equations estimating renal function are less reliable if the patient has good kidney function. Estimates of kidney function are difficult to interpret in older patients because kidney function naturally declines with age.⁸“Normal” serum creatinine levels listed on lab reports do not account for muscle mass, age, sex, and race.⁸

Each approach has limitations. Researchers developed the Cockcroft-Gault formula based on only 249 men aged 18 to 92.¹⁰ Women tend to have less muscle mass, thus, the equation assumes females would have a creatinine clearance 15% lower than men with the same SCr.¹⁰ MDRD and CKD-EPI are most widely used; the equations include adjustments for SCr, age, race, sex, and body surface area (see Table 1).¹⁰ KDIGO recommends using CKD-EPI for reporting eGFR in adults because the equation is more precise and accurate than MDRD, especially at GFR 60 mL/min/1.73m² or greater.¹⁷

Table 1. Comparison of Equations Used to Estimate Kidney Function^{H#,J#,O#,X1#,G2#,H2#}
Name	Equation	Sex^§	Race^§
Cockcroft-Gault (mL/min)	= (140 – Age in years) * (IBW in kg)^† (72 * SCr in mg/dL)	0.85 if female	N/A
MDRD (mL/min/1.73 m²)	= 175 * (SCr in mg/dL)^-1.154* (Age in years)^-0.203	0.742 if female	1.212 if African American
CKD-EPI (mL/min/1.73 m²)	= 141 * min (SCr in mg/dL /κ, 1)^α * max(SCr in mg/dL /κ, 1)^-1.209* 0.993^Age^{in years} κ = 0.7 for females and 0.9 for males, α = -0.329 for females, -0.411 for males, min = minimum of Scr/κ or 1 max = maximum of Scr/κ or 1	1.018 if female	1.159 if African American
^§Multiplier; ^†Use ABW if ABW < IBW; use AdjBW when ABW > 130% IBW ABW = actual body weight (in kg); AdjBW = adjusted body weight (in kg); IBW = ideal body weight; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; MDRD = Modification of Diet in Renal Disease

Unjustly, applying a racial multiplier delays recognition of CKD. The multiplier can falsely increase eGFR by as much as 21%, even in patients identical in every other way.¹⁸Race is not a biologic characteristic, and application of a racial multiplier delays necessary treatments (e.g., dialysis or renal transplantation) and promotes inappropriate medication dosing.^18,19 The National Kidney Foundation and the American Society of Nephrology Task Force now recommend the immediate removal of race as a variable in eGFR estimations because of its potential adverse consequences.^19,20

Measuring kidney function is also vital when using medications that require renal dose adjustments. Clinicians should adjust doses of renally cleared drugs as described in their package inserts.²¹ The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Laboratory Working Group recommends using eGFR (mL/min/1.73m²) or creatinine clearance (mL/min) for drug dosing.²² The NIDDK suggests performing a dosing conversion equation for very large or very small patients.slow²²This equation converts eGFR to units of mL/min.²²

eGFR (mL/min) for drug dosing = eGFR (mL/min/1.73m²) x BSA/1.73

The KDIGO guidelines define CKD as abnormalities of kidney structure or function, present for more than three months, with implications for health.¹⁷KDIGO classifies CKD (see Figure 2) based on cause, GFR category (G1-G4), and albuminuria category (A1-A3).²³A patient lacking evidence of kidney damage could not be classified as having CKD.²⁴ Markers of kidney damage include²³

albuminuria (albumin excretion rate greater than or equal to 30 mg/24 hours)
electrolyte and other abnormalities due to tubular disorders
histologic abnormalities detected by histology
history of kidney transplantation
structural abnormalities detected by imaging
urinary sediment abnormalities

Screening/Monitoring & Diagnosis

DKD’s typical presentation includes retinopathy (which is often the first microvascular complication from long-standing of diabetes), albuminuria without visualized blood in the urine, and gradually progressive eGFR decline.⁶

Healthcare providers diagnose DKD based on the presence of albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage.⁶Urine albumin-to-creatinine ratio (UACR) is a test to estimate 24-hour albumin excretion. UACR is a continuous variable and can increase temporarily from heart failure, episodic hyperglycemia, exercise within 24 hours, fever, infection, menstruation, and serious hypertension.⁶ Normal UACR is less than 30 mg/g.⁸eGFR less than 60 mL/min/1.73m² is considered kidney disease, and less than 15 mL/min/1.73m² is kidney failure.⁸

Clinicians should assess patients with T2DM at least annually for CKD. Depending on the disease severity and progression, assessing more than four times annually may be necessary. The American Diabetes Association (ADA) recommends screening for urine albumin with UACR (on a spot urine specimen) and eGFR at least annually.⁶Providers need to monitor patients with diabetes and urinary albumin exceeding 300 mg/g creatinine and/or an estimated glomerular filtration rate 30 to 60 mL/min/1.73m² twice annually to guide therapy.⁶ Diagnosis of kidney injury requires confirmation with a second test within a three-to-six-month period.^6,8

Pharmacists should closely monitor patients with eGFR less than 60 mL/min/1.73m² to verify appropriate medication dosing, minimize exposure to nephrotoxins (e.g., NSAIDs and iodinated contrast), and evaluate potential CKD complications.⁶ Complications become prevalent at stage 3 and become more common and severe as CKD progresses. Elevated BP, volume overload, electrolyte abnormalities, metabolic acidosis, anemia, and metabolic bone disease are possible complications.⁶ At every clinical contact, clinicians should assess BP and volume status if possible. The ADA guidelines encourage clinicians to evaluate laboratory results every six to 12 months for stage 3 CKD, and more frequently for progressive stages, or as indicated to reassess symptoms or changes in therapy.⁶

Nephrology Referral

Physicians should refer patients to a nephrologist to assist with diagnostic or therapeutic challenges related to CKD complications (e.g., resistant hypertension, anemia, abnormal mineral metabolism and bone disorders, electrolyte disturbances).⁶ Nephrologists can help manage AKI, rapidly increasing albuminuria or nephrotic syndrome, and rapidly decreasing eGFR.^6,8 Diagnosis of advanced kidney disease (eGFR less than 30 mL/min/1.73m²) warrants a referral to discuss RRT for ESRD.⁶

At CKD stage 5, dialysis or kidney transplantation become essential for survival.²⁵ The first human was dialyzed in 1924. Eventually, dialysis became more common and in addition to the growing number of patients initiating treatment, a significant number of patients required ongoing therapy. By the early 1960s, a finite number of nephrologists and facilities offering dialysis led to dialysis rationing (restricting the number of patients who could receive it).²⁶ The federal government established an ESRD Medicare program in 1972 in response. Before that year, an anonymous committee selected patients for dialysis partly based on their social worth. The committee judged applicants based on their potential to remain, or become, productive community members. Determinants of social worth included level of education, marital status, net worth of patients, work performance and history, and number of dependents.²⁷

Managing Renal Disease

Treatment’s goal is to delay or prevent progression of CKD and its associated complications.¹² Early detection and early intervention minimizes adverse outcomes.¹¹ Reaching blood glucose (BG) and BP goals are the best ways to slow and prevent DKD.²⁸ When interpreting glucose parameters, clinicians should remember that hemoglobin A1C (HbA1C) values may be falsely low in patients with CKD. HbA1C is measured based on assumed red blood cell life span of 90 days. However, in patients with CKD, the red blood cell life span is shorter.¹²

Interventions for reducing urine albumin—controlling BP, reducing sodium intake, reducing weight if obese, reducing protein intake if excessive, and achieving tobacco cessation—may lower risk of progression.⁸

CVD Risk Reduction

To reduce cardiovascular risk, statins, beta blockers (BB), angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), and antiplatelet drugs are standard of care.¹² The following section provides information on ACEi/ARB. Statins do not appear to slow CKD, but they may reduce urine protein and significantly reduce all-cause CVD mortality.²⁹

Inhibition of RAAS

In 1934, Harry Goldblatt brought recognition to kidneys’ importance in BP control with his experiment in dogs. Goldblatt clamped the renal arteries, which precipitated chronic hypertension. This discovery led to investigation of the pressor substance. Two separate research groups in Argentina and America simultaneously identified the pressor substance that increases BP in response to renin. The pressor identified was later named “angiotensin.”³⁰Key trials helped scientists acknowledge that renin-angiotensin-aldosterone-system (RAAS) antagonists slow kidney disease progression independent of their effects on BP.^{4,31,32,33,34} The Ramipril Efficacy In Nephropathy trial demonstrated a renoprotective effect that exceeds the protection expected for the degree of BP lowering.³¹ Ramipril was well tolerated in advanced renal disease, continuing to prevent additional renal impairment.³¹ A study conducted in China found patients with SCr levels exceeding 3 mg/dL tolerate benazepril.³⁴ The Irbesartan Diabetic Nephropathy Trial noted the mechanism responsible for renoprotection of ARB includes restriction of intrarenal angiotensin activity.³² The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study extrapolated observed data, estimating losartan delayed dialysis or transplantation by about two years.³³

Antihypertensive medications such as ACEi and ARB block the RAAS and lower urine albumin. ACEi have names ending with “-pril” and may have a side effect of dry cough. ARB have names ending with “-sartan.” KDIGO guidelines suggest physicians titrate ACEi or ARB to the highest approved dose tolerated.⁴ The NIDDK recommends monitoring patients closely using ACEi or ARB for hyperkalemia and increases in SCr.^10,12 KDIGO advises monitoring serum potassium and SCr levels within two to four weeks of initiation or when doses change.⁴ If hyperkalemia develops, clinicians may consider moderating patient potassium intake or introducing a loop diuretic to increase urinary potassium excretion.^4,29 NIDKK emphasizes individualizing dietary potassium restriction for each patient to achieve and maintain a safe serum potassium (less than 5 mEq/L).²⁹Practice guidelines recommend continuing therapy despite minor increases in SCr (less than 30%).⁴ Guidelines encourage dose reductions or discontinuation for symptomatic hypotension, uncontrolled hyperkalemia, and AKI.⁴

Table 2. Available SGLT-2i
Medication	Medication	Renal Considerations
canagliflozin	· 100 mg daily, titrated to 300 mg daily taken before first meal of the day · Patients with eGFR 30-59 mL/min/1.73m² should receive maximum 100 mg daily · Dose adjustment required when taken concomitantly with UGT inducers (rifampin, phenytoin, phenobarbital, ritonavir)	· Initiation not recommended, and likely ineffective for glycemic control with eGFR < 30 mL/min/1.73m² · Contraindicated in dialysis
dapagliflozin	· 5 mg daily, titrated to 10 mg daily	· Likely ineffective for glycemic control with eGFR < 45 mL/min/1.73m² · Initiation not recommended with eGFR < 25 mL/min/1.73m² · Contraindicated in dialysis
empagliflozin	· 10 mg daily, titrated to 25 mg daily as tolerated · Taken in the morning with or without food	· Do not use when eGFR < 30 mL/min/1.73m² · Contraindicated in dialysis
ertugliflozin	· 5 mg daily, titrated to 15 mg daily as tolerated · Taken in the morning with or without food	· Initiation not recommended in patients with an eGFR 30-59 mL/min/1.73m² · Continued use not recommended in patients with an eGFR consistently < 60 mL/min/1.73m² · Contraindicated in eGFR < 30 mL/min/1.73m², ESRD, or dialysis
eGFR = estimated glomerular filtration rate; ESRD = end stage renal disease; SGLT-2i = sodium glucose co-transporter 2 inhibitors; UGT = uridine 5’-diphosphate glucuronosyltransferase

Phlorizin, a natural product derived from the root bark of apple trees, provided the chemical starting point for modification and achievement of selective sodium-glucose transporter 2 inhibitors (SGLT-2i).³⁵ Currently, four SGLT-2i are approved: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin (Table 2).^39,40SGLT-2i, along with metformin, are the recommended therapy for patients with T2DM, CKD, and eGFR greater than or equal to 30 mL/min/1.73m².⁴ Trials have reported consistent reductions in cardiovascular events and CKD progression.⁴ SGLT-2i provide an HbA1C reduction of 0.5-1% and 1 t0 5 kg of weight loss from visceral fat (not muscle mass loss).³⁹ They also reduce systolic BP by 3 to 4 mmHg and diastolic BP by 1 to 2 mmHg.³⁹

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed canagliflozin, in addition to RAAS blockade, preserves renal function and improves cardiovascular outcomes.^41,42 SGLT-2i benefits appear independent of their BG decrease.⁴¹ Their effects may be mediated by natriuresis and glucose-induced osmotic diuresis, reducing intraglomerular pressure.⁴² The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial was designed to assess dapagliflozin’s long-term efficacy and safety.⁴² Researchers found a sustained decline in eGFR.⁴² In contrast to the CREDENCE trial, the DAPA-CKD trial included patients without T2DM and an eGFR below 30 mL/min/1.73m².⁴² Patients treated with SGLT-2i, as expected, experience an initial dip in eGFR, followed by a stabilization of kidney-function decline.⁴²

SGLT-2i reduce tubular glucose reabsorption.^6,39 An insulin-independent mechanism lowers BG.³⁹ As renal impairment continues, the efficacy of SGLT-2i decreases because the amount of glucose that reaches the proximal tubules declines as GFR declines.³⁹

SGLT-2i are second line therapy in the ADA algorithm, and third line in the American Association of Clinical Endocrinology/American College of Endocrinology (AACE/ACE), guideline.^6,39 Older adults with stage 4 or 5 CKD are poor candidates because of their typically diminished renal function and poor thirst response when dehydrated.³⁹

Pharmacists have an opportunity to educate patients starting SGLT-2i about the secondary effects of modest volume contraction, BP reduction, and weight loss.⁴ Patients who are on diuretics are already at risk for hypovolemia.⁴ Lowering the diuretic dose and monitoring for orthostatic hypotension is recommended.^4,39

The most common adverse effect is genitourinary infection, which is not dose dependent.³⁹ Another side effect, symptomatic hypotension, occurs more frequently in patients with eGFR less than 60 mL/min/1.73m².³⁹

Post-marketing research has linked SGLT-2i and euglycemic diabetic ketoacidosis in case reports.³⁹ Risk factors are dehydration, long standing T2DM, and serious illness.³⁹ Ensuring patients are well hydrated before starting therapy and temporarily stopping if serious illness occurs is important.³⁹ Patients using insulin should not decrease the dose when initiating SGLT-2i.³⁹ Hypoglycemia is uncommon with SGLT-2i unless used in combination with sulfonylureas, meglitinides, or insulin.³⁹

GLP-1RA

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have positive effects on cardiovascular and renal events in DKD.⁴³ They also offer potential adequate glycemic control in multiple stages of DKD, without increased hypoglycemic risk.⁴³ GLP-1RA prevent macroalbuminuria’s onset and slows GFR decline.⁴³ Additional benefits include weight reduction (1 to 2 kg) and lower HbA1C 0.5 to 1.5% when used as monotherapy.^1,39,43

GLP-1RA increase insulin secretion in response to nutrients, particularly glucose (incretin effect), and suppress inappropriately high postprandial glucagon secretion from the pancreas. Reduced postprandial glucose levels follow.⁴³ Weight loss results from increased satiety signals, slowed gastric emptying, and appetite reduction.³⁹

The incretin effect is an increased insulin secretion in response to an oral glucose stimulus that promotes the pancreas to secrete insulin. Patients with T2DM have an incretin effect approximately half of that seen in nondiabetic patients.³⁹

Hypoglycemia is an uncommon side effect because GLP-1RA enhance insulin secretion in a glucose dependent manner. Low BG is more common when combined with a sulfonylurea or insulin.¹

GLP-1RA have beneficial direct and indirect effects. Reducing hyperfiltration, inflammation, oxidative stress, glomerular atherosclerosis, and ATII and renin concentrations are the direct effects.⁴³ Improved glycemic control, increased insulin sensitivity, decreased plasma insulin levels, weight loss, and improved BP (1-2 mmHg) are the indirect effects.⁴³

KDIGO recommends long-acting GLP-1RA for patients not reaching glycemic targets or those unable to use SGLT-2i.⁴ The AACE/ACE and ADA guidelines recommend GLP-1RA as second line therapy.³⁹

Researchers took almost 20 years from identification of endogenous glucagon-like-peptide-1 to the first therapeutic GLP-1RA approval. Surprisingly, the first GLP-1RA approved was a peptide originally isolated from lizard venom (exenatide).⁴⁴GLP-1RA consists of two groups: incretin mimetics (exedin-4 analogs) and human GLP-1RA.⁴³ Daily exenatide, weekly exenatide, and lixisenatide are approved exedin-4 analogs.⁴³ Liraglutide, semaglutide (oral and subcutaneous), and dulaglutide are approved human GLP-1RA.⁴³

Human GLP-1RA and weekly exenatide are long acting. The longer half-life contributes to suppressing glucagon overnight and improves fasting glucose.³⁹ Patients taking long acting GLP-1RA experience less nausea due to a lower impact on gastric emptying.³⁹ Nausea upon initiation appears to be dose-related and prescribers should titrate doses (Table 3).³⁹ Gastrointestinal adverse effects decrease over time.³⁹ Longer acting GLP-1RA are contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (higher risk of C-cell tumors).³⁹

Table 3. Available GLP-1 RA ^{D1#,F1#,G1#,H1#,I1#,J1#,K1#,L1#}
Medication	Dosing and Administration	Renal Considerations
dulaglutide	· 0.75 mg SC once weekly; increase to 1.5 mg once weekly · Maximum 4.5 mg after at least 4 weeks on previous dose · Administer with or without food · Administer a missed dose as soon as possible if at least 3 days (72 hours) until next scheduled dose	None
exenatide	· 5 mcg SC twice daily and titrate to 10mcg twice daily in 1 month · Inject up to 60 minutes before morning and evening meals. If patient does not eat breakfast, administer first injection of the day at lunch (at least 6 hours between doses). · Skip missed dose and resume with the next scheduled dose	Avoid in patients with CrCl < 30 mL/min; caution when initiating or escalating doses in patients with CrCl 30-50 mL/min
exenatide extended release	· 2 mg SC every 7 days without regards to meals · Administer missed dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose	Not recommended if eGRF < 45 mL/min/1.73m²
liraglutide	· 0.6 mg SC daily (nontherapeutic to minimize side effects), then increase to 1.2 mg daily · Maximum dose 1.8 mg/day · Skip missed dose and resume with next scheduled dose. If more than 3 days elapsed since last dose, reinitiate, and titrate per prescriber	None
lixisenatide	· 10 mcg SC once daily for 14 days, then increase to 20 mcg daily · Administer 1 hour before first meal · Missed dose administered 1 hour prior to next meal	Avoid in patients with ESRD
semaglutide (injectable)	· 0.25 mg SC once weekly without regards to meals; increase to 0.5 mg after 4 weeks. May increase to 1 mg 4 weeks later · Administer within 5 days of missed dose; if more than 5 days have passed, skip missed dose and administer on the next regularly scheduled day	None
semaglutide (oral)	· 3 mg PO daily for 30 days, then increase to 7 mg daily. Maximum 14 mg daily at least 30 days after 7 mg dose · Take 30 minutes before first food, beverage, or other oral medications with no more than 4 oz plain water · Skip missed dose and resume taking the following day	None
GLP-1 RA = glucagon-like peptide-1 receptor agonists SC = subcutaneously ESRD = end stage renal disease CrCl = creatinine clearance eGFR = estimated glomerular filtration rate PO = by mouth

Daily exenatide and lixisenatide are short acting and demonstrate a more pronounced decrease in postprandial glycemia.⁴³ More nausea is associated with shorter acting GLP-1RA.³⁹ Patients can limit nausea by eating slowly and stopping when full.³⁹

Potentially, protein and peptide medications are immunogenic, meaning they can trigger an unwanted immune response against themselves. Thus, antibody formation may occur in patients taking GLP-1RA. The incidence of antibodies cannot be directly compared between products. Antibody formation has not been associated with reduced efficacy or increased side effects from GLP-1RA.³⁹ The exception is extended release exenatide: patients may have an attenuated HbA1C response.⁵¹ Local injection site reactions are prominent in antibody positive patients. Prescribers can consider alternative therapy if patients experience worsening glycemic control or failure to achieve target glycemic control.³⁹

Pause and Ponder: What would you tell a patient concerned about experiencing nausea upon starting GLP-1RA?

Glycemic Control

Hyperglycemia is T2DM’s hallmark feature. Glycemic control is fundamental to disease management.⁶ Glomeruli filter glucose which is then almost completely reabsorbed by proximal tubules.²⁹ Glucose in the urine (glucosuria) occurs when the tubules’ ability to reabsorb glucose is exceeded. The renal threshold for glucose is 180-200 mg/dL.²⁹

A lag time of at least two years exists between intensive glucose control and attenuated renal function decline.⁵² Intensive control early in diabetes offers a long-lasting, favorable effect on the risk of DKD development. Irreversible damage from hyperglycemia can be prevented.²

The AACE/ACE recommend targeting more stringent goals for glycemic control (HbA1C less than 6.5%) in younger patients with a shorter duration of diabetes, absence of complications, and longer life expectancy.⁵³ The AACE/ACE encourages less stringent goals (H1A1C less than 8%) for older patients with longstanding diabetes, micro- and macrovascular complications, and limited life expectancy.^2,29,53 KDIGO guidelines recommend preventing or delaying progression of diabetes’ microvascular complications by targeting HbA1C to about 7%. Providers should avoid treating patients at risk for hypoglycemia, such as those with DKD, to HbA1C less than 7%.² The ADA agrees that tightfisted goals are inappropriate for patients at risk for hypoglycemia.⁶

Tight glucose control does not slow progression once patients have established DKD since circulating levels of insulin are higher due to reduced catabolism.²⁹ Hypoglycemia risk increases as CKD advances: physicians should discontinue or adjust medications accordingly.²⁹ For example, they should discontinue metformin at eGFR less than 30 mL/min/1.73m².²⁹ Renal function status does not restrict insulin doses, allowing titration upwards to reach glycemic goals.⁷Unexplained eGFR improvement or increased hypoglycemia may indicate CKD is progressing.²⁹

BP Control

Controlling BP is key to slowing progression of CKD, breaking a potentially vicious cycle associating hypertension and CKD.¹⁷ The ADA endorse a target BP less than 140/90 mmHg.⁶ A baseline systolic BP greater than 140 mmHg in patients with T2DM has been associated with higher risk of ESRD and death.²The American College of Cardiology/American Heart Association (ACC/AHA) 2017 guidelines recommend a BP goal of 130/80 mmHg for all patients.⁵⁴ Uncontrolled hypertension (systolic BP greater than 160 mmHg) is a major challenge and becomes an issue when elevated albuminuria goes unresolved.²⁹

The ACC/AHA recommends introducing medication at a systolic BP greater than or equal to 130 mmHg or diastolic BP greater than or equal to 80 mmHg.⁵⁴ Patients often require multiple medications to control BP.^29,54 Drugs that reduce cardiovascular events include ACEi, ARB, thiazide-like diuretics, and calcium channel blockers (CCB).⁴³ Combination of ACEi with ARB is harmful and should be avoided.⁴The ACC/AHA advises initial antihypertensive treatment with a thiazide diuretic, CCB, and ACEi or ARB.⁵⁴ In the Black population, ACC/AHA recommend initial treatment with a thiazide diuretic (especially chlorthalidone) or CCB.⁵⁴ Physicians should assess patients one month after starting therapy to optimize medication adherence and consider treatment intensification.⁵⁴ Physicians can reassess patients who have met their BP goal in three to six months.^4,54

PRO TIP: Ask patients if they are interested in having their blood pressure checked at the pharmacy.

Diet

Weight loss induces a significant and rapid reduction in urine protein.⁴³

Limiting salt and sodium is the first step to improve diet and enhances RAAS antagonists’ effects on lowering urine albumin.^28,29 Even small reductions in sodium intake lowers BP.²⁹ Less than 2300 mg of sodium each day can help control BP.¹⁴ For reference, about one teaspoon of salt has roughly 2300 mg of sodium.²⁹

How can patients achieve such a seemingly difficult goal?²⁹

Buy fresh. Prepared and packaged foods usually have added sodium.
Cook food at home instead of eating frozen dinners or restaurant prepared food – control what goes into meals.
Use spices, herbs, and sodium-free seasonings to add flavor instead of salt.
Minimize salt by rinsing canned foods with water.

Heart-healthy foods (lean meats, fish, beans, vegetables, low-fat milk/yogurt/cheese, poultry without skin) minimize fat accumulation in the blood vessels, heart, and kidneys.^14,29 Individuals should strive to keep both saturated fats and added sugar at less than 10% of total calories. Patients can grill, broil, or roast instead of frying. Using nonstick cooking spray minimizes the fat from using butter.²⁹ Alcohol consumption should be in moderation (up to one drink/day for women and two for men).²⁹ One drink is 12 ounces beer, 5 ounces wine, or 1.5 ounces liquor.²⁹

As kidney function declines, patients may need to eat food with less phosphorus and potassium.¹⁴ In CKD, phosphorus accumulates in blood and pulls calcium from bones.¹⁴ Bones become thin, weak, and more likely to break.¹⁴ High levels of phosphorus cause noticeable symptoms, namely itchy skin, and bone and joint pain.¹⁴ Healthcare providers may add a prescription phosphate binder with meals to help remove excess phosphorus.¹⁴

How can patients limit phosphorus and potassium intake?¹⁴

Ask a butcher to help choose fresh meats without added phosphorus.
Choose food lower in phosphorus: fresh fruits and vegetables, breads, pasta, rice, rice milk (not enriched), corn and rice cereals, light-colored sodas.
Stay away from food higher in phosphorus: meat, poultry, fish; bran cereals and oatmeal, dairy foods, beans, lentils, nuts, dark-colored soda.
Read the label – salt substitutes may be high in potassium.
Choose foods lower in potassium: apples, peaches, carrots, green beans, white bread and pasta, white rice, rice milk (not enriched), cooked rice and wheat cereals, grits, apple/grape/cranberry juice.
Avoid food higher in potassium: oranges, bananas, orange juice, potatoes, tomatoes, brown and wild rice, bran cereals, dairy foods, whole-wheat bread and pasta, beans, and nuts.

Patients may find it beneficial to visit a registered dietician for medical nutrition therapy.⁸ Registered dieticians can assist with HbA1C lowering.⁸

Uncommonly known, any juice treats hypoglycemia.²⁹ If patients are taking ACEi or ARB, discuss using glucose tabs or low-potassium juice to treat low BG.²⁹Juices with lower potassium content than the typically recommended orange juice include grapefruit, pineapple, grape, apple, cherry, and cranberry cocktail (from most to least potassium).²⁹

Exercise

Physical inactivity is associated with increased mortality in CKD.²⁹ Researchers agree that although data is limited, recommending activity may be beneficial. Since the risk of hypoglycemia is amplified during and after exercise, counseling patients on how to best manage hypoglycemia symptoms is necessary.²⁹

Avoiding Nephrotoxins and OTC Recommendations

All patients with CKD have an increased AKI risk.¹⁷

Frequently, patients take ACEi or ARB, a diuretic, and start a non-steroidal anti-inflammatory drug (NSAID). This is known as a “triple whammy.”⁵⁵ This combination causes a problem because the ACEi or ARB vasodilate the efferent arteriole and diuretics decrease blood volume, limiting perfusion.⁵⁵ Adding an NSAID prevents vasodilation of the afferent arteriole, so very little perfusion within the glomerulus causes reduced glomerular pressure, reduced filtration, and AKI.⁵⁵

NSAIDs are universally accessible and disrupt blood flow to the kidneys.⁵⁵ Upon discontinuation of NSAIDs, SCr may decrease and eGFR may increase.²⁹ Pharmacy technicians have an opportunity to identify patients purchasing over the counter (OTC) NSAIDs and refer them to the pharmacist for consultation. Pharmacists can identify patients with advanced kidney disease based on their medication profile. Typically, patients are taking ACEi or ARB, phosphate binders (calcium acetate, sevelamer carbonate, lanthanum carbonate), vitamin D analogues (calcitriol, paricalcitol, doxercalciferol), calcimimetics (cinacalet), and erythropoiesis stimulating agents (epoetin alfa, darbepoetin alfa).⁵⁵

Patients seeking relief for their headaches, pain, fever, or colds may unknowingly be taking NSAIDs because products are sold under many different brand names. Technicians can monitor purchasing of AKI inducing products containing naproxen, ibuprofen, and aspirin.¹⁴ A technician PRO TIP: call the pharmacist over for patients purchasing OTC pain and cold medications. This quick and easy intervention can have a meaningful impact on clinical outcomes. It is an opportunity to counsel on self-care products and direct the patient to safer alternatives.⁵⁵ Pharmacists can direct patients to cold medications without NSAIDs. The National Kidney Foundation supports using oral acetaminophen for fever or pain.⁵⁶ Pharmacists can suggest patients try OTC topical analgesics such as lidocaine or capsaicin (available as cream or patches) for pain.⁵⁷ Patients may wish to try nonpharmacologic interventions such as transcutaneous electrical stimulation, topical heat and cryotherapy (warm and cold compresses), massage, acupuncture, and exercise.⁵⁷

Pause and Ponder: What OTC medications would you suggest for patients who cannot take NSAIDs?

Healthcare providers can remember additional nephrotoxic medications by the acronym CARNIVAL CAMP; calcineurin inhibitors, ACEi/ARB, radiocontrast, NSAIDs, ifosfamide, vancomycin, aminoglycosides, lithium, cisplatin, amphotericin B, methotrexate, and penicillins.⁵⁸ Although ACEi and ARB can be nephrotoxic, they are proven to be renoprotective for patients with DKD and urine albumin excretion greater than 30 mg/24 hr.⁵⁸ They lower albuminuria.⁵⁸

Patients feeling unwell or dehydrated need medical advice to develop a sick plan. Dehydration, in combination with some medications, worsens kidney function.⁵⁹ The sick plan temporarily discontinues drugs excreted by the kidneys.^12,59 These include digoxin, diuretics, lithium, metformin, NSAIDs/COX II inhibitors, RAAS blockers, SGLT-2i, and sulfonylureas.^12,59

Empowering Patients and Improving Adherence

CKD remains under diagnosed.¹⁰ The Centers for Disease Control and Prevention reports as many as 90% of adults with CKD do not know they have CKD.⁶⁰Patients report feeling “fine” and symptoms may not be obvious until disease is advanced.²⁹ Self-management of diabetes and hypertension can slow kidney disease progression, making patient awareness important. Guidelines for CKD and national programs recommend patient education as a critical component of care.⁶¹ Pharmacist counseling empowers patients in self-management of their CKD risks, improves well-being, and optimizes quality of life.^61,⁶² Patients with CKD must understand their condition to participate in care decisions and planning.⁶¹ Pharmacists can provide education to minimize long-term complications.

Pharmacists can also play a part in diagnosis by discussing risk with T2DM patients and communicating the importance of testing for CKD. Pharmacists can identify these patients by scanning their medication profile for metformin (first line medication).³⁹ PRO TIP: Use the pharmacy’s technology, or even a sticky note, to flag metformin prescriptions that are ready for pick-up for patient counseling. Many patients have little to no knowledge of diagnosis or dialysis. This poses a challenge when initiating treatment to delay disease progression. Pharmacists can educate patients regarding complications (e.g., heart disease), CKD’s progressive nature, treatment basics, and terminology (e.g., GFR).^10,29 Patients require repetition to integrate the information learned.⁶³Fortunately, pharmacists are accessible to provide the repeated emphasis patients desire.

Pause and Ponder: What other health conditions present minimal symptoms until they have advanced?

As CKD advances, prevalence of medication-related problems and significant costs to the healthcare system increase because medication use increases. Clinicians prescribe six to eight medications, on average, for patients with stage 3 and 4 CKD. Patients with stage 5 are prescribed about 12 medications to treat five or six chronic medical conditions.¹⁰ Pharmacists can identify and resolve drug therapy problems between visits with providers.² Failure to do so could accelerate disease progression.⁶⁴Pharmacists can monitor medication profiles for interactions and adjust doses based on kidney function.¹² Additionally, pharmacists and patients need to discuss hypoglycemia risk, cost, and side effects.⁶⁵ Communication ensures treatment satisfaction when patients are weighing their options and buying into adherence of their chosen regimen to help manage CKD.^64,66

COVID-19 and T2DM

The relationship between coronavirus disease 2019 (COVID-19) and diabetes has been described as “the interaction of two pandemics.”⁶⁷ Diabetes is the most common non-communicable chronic disease globally, and, one of the major comorbidities in patients with COVID-19.⁶⁷ As many as 40% of the COVID fatalities–120,000 Americans–have been people with diabetes.⁶⁸ Even if patients are not affected by infection, they still face challenges introduced by the virus. A new nationwide survey conducted by the ADA in partnership with Thrivable and the Diabetes Daily community uncovered the crisis Americans with diabetes are facing during the pandemic. The results of the survey acknowledge COVID-19 has created dangerous hurdles to accessing health care such as⁶⁸

delaying routine medical care because patients fear exposure to COVID-19
financial constraints limiting technology and insulin supplies
disruptions in health insurance resulting from lost jobs
reduced food access

Living with T2DM is a risk factor associated with developing more severe COVID-19 and increased risk of death.⁶⁹ It is also associated with neurological complications.⁷⁰ Furthermore, these patients are at increased risk for multi-organ dysfunction. Amid the burden on healthcare systems, clinicians must recognize these risks and focus on individualized treatment to avoid poor prognosis.⁶⁹

Experts mostly consider COVID-19 a respiratory illness, but the kidneys may be one of its targets. The virus enters cells through angiotensin-converting enzyme 2 receptors, found abundantly in the kidney. Information on kidney involvement in COVID-19 is limited but evolving rapidly.⁷¹COVID-19 directly attacks pancreatic islets and deteriorates glycemic control in patients with diabetes.⁶⁷ Tight glucose monitoring and careful considerations of potential drug interactions are paramount to optimize outcomes for critically ill and hospitalized patients.⁶⁷ Insulin is the safest choice for antihyperglycemic treatment because of the uncertainty of using some oral medications with COVID-19 infection.⁶⁹

Continuing ACEi, statins, and oral or inhaled and intranasal corticosteroids prescribed for comorbid conditions after diagnosis of COVID-19 is crucial.⁷⁰

Conclusion

Pharmacy teams can benefit from advanced knowledge to manage patients with DKD. The more routinely healthcare professionals screen patients for renal disease, the earlier progression can be delayed. Pharmacists can recommend renoprotective medications such as ACEI, ARB, SGLT-2i, and GLP-1RA to patients when appropriate. Technicians can take advantage of frequent patient interactions and advise them to consult with the pharmacist. Screening at the point of sale can discourage use of nephrotoxic OTC medications. Recurrent patient engagement translates into self-awareness, allowing for earlier intervention. Ultimately, clinicians can enhance patient care with better adherence, satisfaction of treatment, and improved quality of life.

Pharmacist Post-test

After completing this continuing education activity, pharmacists will be able to
• Describe the unmet medical needs, clinical practice guidelines, and scientific evidence in renal disease for patients with T2DM.
• List the classifications of chronic kidney disease.
• Review emerging information about COVID-19’s impact and optimal management of patients with chronic kidney disease.
• Identify medications that are nephrotoxic and treatments that slow or prevent CKD.
• Apply patient counseling skills to improve awareness of condition and adherence to treatment.

1. Which medication is nephrotoxic?
A. vancomycin
B. levofloxacin
C. azithromycin

2. Which eGFR category is associated with kidney failure?
A. G1
B. G5
C. G0

3. What is the SAFEST choice for antihyperglycemic treatment in T2DM patients with COVID-19?
A. insulin
B. glipizide
C. sitagliptin

4. A patient tells you he does NOT want to start a GLP1-RA because he is worried about experiencing nausea. What can you recommend?
A. Eat slowly and stop when full
B. Use a shorter acting GLP1-RA
C. Eat small meals very quickly

5. Which patient should use a long acting GLP-1RA according to KDIGO guidelines?
A. A patient achieving glycemic targets
B. A patient who cannot use SGLT-2i
C. A patient with significant hypotension

6. According to the AACE/ACE guidelines, when should clinicians consider an SGLT-2i?
A. first line
B. second line
C. third line

7. Which of the following statements about diabetic nephropathy is FALSE?
A. Symptoms of renal dysfunction include fatigue, weakness, shortness of breath, and itching.
B. Statins slow CKD progression and reduce all-cause cardiovascular disease mortality.
C. Controlling a patient’s BP with an ACEi or ARB is key to slowing CKD progression.

8. Patient AD has T2DM and CKD. She was prescribed dulaglutide. AD is also having a difficult time managing her postprandial glycemia. What recommendation can you make to her provider?
A. Replace with lixisenatide
B. Replace with semaglutide
C. Replace with weekly exenatide

9. Patient DN has T2DM and kidney function classified as G2A1. He is reluctant to continue treatment with canagliflozin ever since he heard it can cause symptomatic hypotension. What can you tell DN to help him adhere to treatment?
A. Symptomatic hypotension occurs more frequently in patients with eGFR < 60 mL/min/1.73m2. B. Symptomatic hypotension occurs more frequently in patients with eGFR < 90 mL/min/1.73m2. C. Symptomatic hypotension occurs more frequently in patients with eGFR > 60 mL/min/1.73m2.

10. What is the HbA1C target recommended by KDIGO guidelines to prevent or delay progression of the microvascular complications of diabetes?
A. Less than 8%
B. About 6.5%
C. About 7%

11. EM approaches the pharmacy counter to pick up her prescriptions for metformin, losartan, and furosemide. She also wants to purchase naproxen for headache. How can you help Emma with her OTC choice?
A. Recommend Emma try acetaminophen since naproxen is an NSAID.
B. Counsel Emma to use aspirin since it will not be absorbed systemically.
C. Advise Emma to try ibuprofen since it is a stronger NSAID than naproxen.

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to
• List the basic pathology and symptoms of renal disease and diabetes.
• Recall treatments used in patients who have comorbid renal disease and diabetes.
• Identify when to refer patients to the pharmacists for recommendations or referrals.

1. Which statement is TRUE about treatments used in patients who have comorbid renal disease and diabetes?
A. GLP-1RA increase blood pressure
B. SGLT-2i cause loss of muscle mass
C. SGLT-2i reduce CKD progression

2. A patient you know has T2DM approaches the counter and wants to purchase an OTC item. Which of the following medications would flag you to ask the pharmacist for a consultation?
A. Acetaminophen
B. Naproxen
C. Lidocaine

3. Which symptom corresponds with more than three quarters of kidney function lost?
A. Constipation
B. Cough
C. Itching

4. Which medication is an example of a short acting GLP1-RA ?
A. lixisenatide
B. semaglutide
C. dulaglutide

5. A patient is picking up her prescriptions for calcitriol, sevelamer carbonate, and losartan. The patient has a headache and is also purchasing OTC aspirin. What should you do?
A. Complete the transaction, aspirin is safe for the treatment of headaches in patients with advanced kidney disease.
B. Refer the patient to the pharmacist; aspirin is an NSAID that should not be taken by patients with advanced kidney disease.
C. Recommend the patient try ibuprofen because it is the best alternative for patients with advanced kidney disease.

6. What contributes to glomerular hyperfiltration in T2DM?
A. Hypertension
B. Diarrhea
C. Rhinorrhea

7. Patient KD approaches the pharmacy counter and asks you to explain what eGFR is and why it is important. What do you tell him?
A. eGFR is a direct measure of your glomerular filtration rate. It is important because it estimates the number of functioning nephrons in your kidneys.
B. eGFR is an estimation of your glomerular filtration rate. It is important because it estimates the number of functioning nephrons in your kidneys.
C. eGFR is the filter in your kidneys. It is important because it returns useful substances to blood, and waste and extra water becomes urine.

8. Which medication is a SGLT-2i?
A. metformin
B. exenatide
C. canagilflozin

9. What is an adverse event associated with SGLT-2i?
A. Genitourinary infections
B. Antibody formation
C. Gastrointestinal symptoms

10. What is a benefit of using GLP-1RA?
A. Weight loss of 3-5 kg
B. Lower HbA1C 2-2.5%
C. Weight loss of 1-2 kg

References

1. Benjamin N Gross, Vidhi Shah, and Michelle Z Farland, (2017), "Diabetes mellitus," PharmacotherapyFirst: A Multimedia Learning Resource. Accessed May 13, 2021. https://doi.org/10.21019/pharmacotherapyfirst.dm_overview
2. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045. doi:10.2215/CJN.11491116
3. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115. doi:10.1016/j.kint.2020.06.019
4. Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes management in chronic kidney disease: synopsis of the 2020 KDIGO clinical practice guideline. Ann Intern Med. 2021;174(3):385-394. doi:10.7326/M20-5938
5. Famous People and Kidney Disease. Renal Support Network. Updated July 9, 2021. Accessed July 22, 2021. https://www.rsnhope.org/rsn-blog/famous-people-and-kidney-disease/
6. American Diabetes Association Diabetes Care 2020 Jan; 43(Supplement 1): S135-S151. https://doi.org/10.2337/dc20-S011
7. Wu B, Bell K, Stanford A, et al. Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns-NHANES 2007-2012. BMJ Open Diabetes Res Care. 2016;4(1):e000154. doi:10.1136/bmjdrc-2015-000154
8. Chronic Kidney Disease Nutrition Management Training Program. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated September 2013. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/professionals/education-cme/management-training-program
9. Dowling TC. Evaluation of kidney function. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. McGraw-Hill; Accessed May 13, 2021. https://usjezproxy.usj.edu:2608/content.aspx?bookid=1861§ionid=134127006
10. Chronic Kidney Disease Management for Pharmacists. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated January 2020. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/professionals/education-cme/chronic-kidney-disease-management-pharmacists
11. Fatema K, Abedin Z, Mansur A, et al. Screening for chronic kidney diseases among an adult population. Saudi J Kidney Dis Transpl. 2013;24(3):534-541. doi:10.4103/1319-2442.111049
12. Hudson JQ, Wazny LD. Chronic kidney disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. McGraw-Hill; Accessed May 13, 2021. https://usj-ezproxy.usj.edu:2608/content.aspx?bookid=1861§ionid=134127380
13. Kidney Beginnings. American Association of Kidney Patients (AAKP). Published 2017. Accessed May 15, 2021. https://aakp.org/wp-content/uploads/2019/09/KB-Book_2017_FINAL_online_version.pdf
14. Chronic Kidney Disease (CKD). National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated October 2016. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/kidney-disease/chronic-kidney-disease-ckd/all-content
15. Cockcroft-Gault Formula. National Kidney Foundation. Updated 2021. Accessed September 20, 2021. https://www.kidney.org/professionals/kdoqi/gfr_calculatorcoc
16. Estimating Glomerular Filtration Rate. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Accessed September 20, 2021. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate/estimating
17. Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825-830. doi:10.7326/0003-4819-158-11-201306040-00007
18. Morris H, Mohan S. Using race in the estimation of glomerular filtration rates: time for a reversal?. Curr Opin Nephrol Hypertens. 2020;29(2):227-231. doi:10.1097/MNH.0000000000000587
19. Eneanya ND, Yang W, Reese PP. Reconsidering the Consequences of Using Race to Estimate Kidney Function. JAMA. 2019;322(2):113–114. doi:10.1001/jama.2019.5774
20. Delgado C, Baweja M, Crews D, et al. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease [published online ahead of print, 2021 Sep 23]. J Am Soc Nephrol. 2021;ASN.2021070988. doi:10.1681/ASN.2021070988
21. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487-1496.
22. CKD & Drug Dosing: Information for Providers. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated April 2015. Accessed September 20, 2021. https://www.niddk.nih.gov/research-funding/research-programs/kidney-clinical-research-epidemiology/laboratory/ckd-drug-dosing-providers
23. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. 2013;3(1):262-265. doi:10.1038/kisup.2013.30
24. Levey AS, Eckardt KU, Dorman NM, et al. Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference. Kidney Int. 2020;97(6):1117-1129. doi:10.1016/j.kint.2020.02.010
25. Stage 5 of Chronic Kidney Disease (End Stage Renal Disease). Fresnius Kidney Care. Updated 2020. Accessed July 16, 2021. https://www.freseniuskidneycare.com/kidney-disease/stages/stage-5
26. Schreiner GE. How end-stage renal disease (ESRD)-medicare developed. Am J Kidney Dis. 2000;35(4 Suppl 1):S37-S44. doi:10.1016/s0272-6386(00)70229-0
27. Savage T, Browne T. Dialysis rationing and the just allocation of resources: a historical primer. J. Am. Soc. Nephrol. 2012;36(Winter 2012):37-42. Accessed July 22, 2021. https://www.kidney.org/sites/default/files/v36b_a4.pdf
28. Diabetic Kidney Disease. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated February 2017. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/diabetic-kidney-disease
29. Helping Diabetes Educators Care for Patients with Kidney Disease. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated September 2014. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/professionals/education-cme/helping-diabetes-educators-kidney-disease
30. Bernstein KE, Ong FS, Blackwell WL, et al. A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme [published correction appears in Pharmacol Rev. 2013;65(1):544]. Pharmacol Rev. 2012;65(1):1-46. Published 2012 Dec 20. doi:10.1124/pr.112.006809
31. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibitors in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;354:359-364.
32. Lewis EJ., Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonists irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
33. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
34. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-140.
35. Beitelshees AL, Leslie BR, Taylor SI. Sodium-glucose cotransporter 2 inhibitors: a case study in translational research. Diabetes. 2019;68(6):1109-1120. doi:10.2337/dbi18-0006
36. Invokana. Prescribing information. Janssen Pharmaceuticals, Inc.; 2019. Accessed May 15, 2021. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf
37. Farxiga. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021. Accessed May 15, 2021. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0be9cb1b-3b33-41c7-bfc2-04c9f718e442/0be9cb1b-3b33-41c7-bfc2-04c9f718e442_viewable_rendition__v.pdf
38. Jardiance. Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc.; 2020. Accessed May 15, 2021. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf
39. Triplitt CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. McGraw-Hill; Accessed May 18, 2021. https://usj-ezproxy.usj.edu:2608/content.aspx?bookid=1861§ionid=146065891
40. Steglatro. Prescriber information. Merck & Co., Inc,;2021. Accessed June 11, 2021. https://www.merck.com/product/usa/pi_circulars/s/steglatro/steglatro_pi.pdf
41. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744
42. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
43. Górriz JL, Soler MJ, Navarro-González JF, et al. GLP-1 receptor agonists and diabetic kidney disease: a call of attention to nephrologists. J Clin Med. 2020;9(4):947. doi:10.3390/jcm9040947
44. Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest. 2017;127(12):4217-4227. doi:10.1172/JCI97233
45. Victoza. Prescribing information. Novo Norodisc; 2020. Accessed May 15, 2021. https://www.novo-pi.com/victoza.pdf
46. Trulicity. Prescribing information. Eli Lilly and Company; 2021. Accessed May 15, 2021. https://uspl.lilly.com/trulicity/trulicity.html#pi
47. Byetta. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021. Accessed May 15, 2020. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/ce8afab9-2b45-436d-957c-a73978d09e93/ce8afab9-2b45-436d-957c-a73978d09e93_viewable_rendition __v.pdf
48. Ozempic. Prescribing information. Novo Norodisc; 2021. Accessed May 15, 2021. https://www.novo-pi.com/ozempic.pdf
49. Adlyxin. Prescribing information. Sanofi-aventis U.S. LLC;2019. Accessed May 15, 2021. https://products.sanofi.us/adlyxin/adlyxin.pdf
50. Rybelsus. Prescribing information. Novo Norodisc; 2021. Accessed May 15, 2021. https://www.novo-pi.com/rybelsus.pdf
51. Bydureon Bcise. Prescribing information. AstraZeneca Pharmaceuticals LP; 2020. Accessed May 15, 2021. https://www.azpicentral.com/bydureon_bcise/bydureon_bcise.pdf#page=1
52. Wieczorek-Surdacka E, Surdacki A, Świerszcz J, Chyrchel B. Novel antidiabetic drugs in diabetic kidney disease accompanying type 2 diabetes - a minireview. Folia Med Cracov. 2020;60(4):97-101
53. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. 2015;21 Suppl 1(Suppl 1):1-87. doi:10.4158/EP15672.GL
54. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines [published correction appears in J Am Coll Cardiol. 2018 May 15;71(19):2275-2279]. J Am Coll Cardiol. 2018;71(19):e127-e248. doi:10.1016/j.jacc.2017.11.006
55. Counseling Patients on NSAID Use to Prevent Acute Kidney Injury. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Updated February 2020. Accessed May 15, 2021. https://www.niddk.nih.gov/health-information/professionals/education-cme/counseling-patients-nsaid-use
56. Pain Medicines (Analgesics). National Kidney Foundation Inc (NKF). Updated February 25, 2021. Accessed July 16, 2021. https://www.kidney.org/atoz/content/painmeds_analgesics
57. Pham PC, Khaing K, Sievers TM, et al. 2017 update on pain management in patients with chronic kidney disease. Clin Kidney J. 2017;10(5):688-697. doi:10.1093/ckj/sfx080
58. Jennifer Bailey, Asha Tata, Laura Waite, and Ryan G. D’Angelo, (2017), "Chronic kidney disease," PharmacotherapyFirst: A Multimedia Learning Resource. Accessed May 13, 2021. https://doi.org/10.21019/pharmacotherapyfirst.ckd_overview
59. Sick Day Plan. Kidney Health Australia. Updated May 2017. Accessed June 25, 2021. https://kidney.org.au/uploads/resources/Acute-Kidney-Injury-Sick-Day-Plan-for-healthcare-professionals-sheet.pdf
60. Chronic Kidney Disease in the United States, 2021. Centers for Disease Control and Prevention (CDC). Updated March 4, 2021. Accessed July 16, 2021. https://www.cdc.gov/kidneydisease/publications-resources/ckd-national-facts.html
61. Narva AS, Norton JM, Boulware LE. Educating patients about CKD: the path to self-management and patient-centered care. Clin J Am Soc Nephrol. 2016;11(4):694-703. doi:10.2215/CJN.07680715
62. Foucault-Fruchard L, Bizzoto L, Allemang-Trivalle A, Renoult-Pierre P, Antier D. Compared benefits of educational programs dedicated to diabetic patients with or without community pharmacist involvement. Prim Health Care Res Dev. 2020;21:e49. doi:10.1017/S1463423620000390
63. Jang SM, Cerulli J, Grabe DW, et al. NSAID-avoidance education in community pharmacies for patients at high risk for acute kidney injury, upstate New York, 2011. Prev Chronic Dis. 2014;11:E220. Published 2014 Dec 18. doi:10.5888/pcd11.140298
64. Zhu L, Fox A, Chan YC. Enhancing collaborative pharmaceutical care for patients with chronic kidney disease: survey of community pharmacists. Can J Hosp Pharm. 2014;67(4):268-273. doi:10.4212/cjhp.v67i4.1370
65. Kleinaki Z, Kapnisi S, Theodorelou-Charitou SA, Nikas IP, Paschou SA. Type 2 diabetes mellitus management in patients with chronic kidney disease: an update. Hormones (Athens). 2020;19(4):467-476. doi:10.1007/s42000-020-00212-y
66. de Boer IH, Caramori ML, Chan JCN, et al. Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment. Kidney Int. 2020;98(4):839-848. doi:10.1016/j.kint.2020.06.024
67. Koliaki C, Tentolouris A, Eleftheriadou I, Melidonis A, Dimitriadis G, Tentolouris N. Clinical management of diabetes mellitus in the era of COVID-19: practical issues, peculiarities and concerns. J Clin Med. 2020;9(7):2288. doi:10.3390/jcm9072288
68. New Data Alert: COVID-19 Brings Crisis of Access for Millions Living with Diabetes. American Diabetes Association (ADA). Published December 23, 2020. Accessed April 15, 2021. https://www.diabetes.org/newsroom/press-releases/COVID-19-brings-crisis-of-access-for-millions-living-with-diabetes
69. Xu Z, Wang Z, Wang S, et al. The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID-19. J Diabetes. 2020;12(12):909-918. doi:10.1111/1753-0407.13084
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71. Hassanein M, Radhakrishnan Y, Sedor J, et al. COVID-19 and the kidney. Cleve Clin J Med. 2020;87(10):619-631. doi:10.3949/ccjm.87a.20072

Arthur E. Schwarting Symposium LIVE Event – Thursday, April 24, 2025

The Arthur E. Schwarting Symposium is an educational conference focused on pharmacy practice for pharmacists in many settings.

Arthur E. Schwarting Symposium 2025

Information Overload: Sorting the Wheat from the Chaff

Five hours of live CE that will include 1 hour of Law, 1 hour of Patient Safety
Thursday, April 24, 2025
10:30 am – 4:20 pm

$25 for the first activity and $15 for each additional hour added.
or
$85 for 5 hours of live CE!

2025 Schwarting Agenda

11:00am-12:00 pm Information overload to action: Decoding academic concepts for pharmacy preceptors
Jennifer Luciano, PharmD, Director Office of Experiential Education, University of Connecticut School of Pharmacy, Storrs, CT

At the end of this presentation the learner will:

Discuss how ACPE standards, the NAPLEX blueprint, and Entrustable Professional Activities (EPAs) guide the development of clinical competence in students, specifically in the context of patient care.
Describe the Pharmacist Patient Care Process (PPCP) and its key components.
Explain how the PPCP framework is applied in experiential education and clinical rotations.

ACPE UAN: 0009-0000-25-026-L04-P Application

12:05-1:05 pm Patient Safety: Anticoagulation Stewardship: Identifying Key Data, Avoiding Errors, and Enhancing Safety
Youssef Bessada, PharmD, BCPS, BCPP, Assistant Clinical Professor,UConn School of Pharmacy, Storrs, CT

At the end of this presentation the learner will:

Differentiate high-priority, practice-changing information from less relevant or conflicting data after reviewing the anticoagulation guidelines, literature and clinical updates.
Recognize common anticoagulation-related errors in pharmacy practice and implement strategies to minimize patient safety risks
Identify red flag situations in anticoagulation management that pose patient safety risks.
Determine the appropriate guidelines or evidence-based resources to guide clinical decision-making and referrals

ACPE UAN: 0009-0000-25-029-L05-P Application

1:10-2:10 pm Information Overload in Chronic Coronary Disease
Michael White, PharmD, FCCP, FCP, BOT Distinguished Professor and Chair of Pharmacy Practice University of Connecticut School of Pharmacy, Storrs, CT

At the end of this presentation the learner will:

Determine if a patient has chronic cardiac disease (CCD).
Identify lifestyle modifications that can reduce the risk of CCD.
Identify therapies that can reduce final health outcomes for specific CCD patient types to design successful drug regimens.
Describe how the steps in the PPCP process can be applied when reviewing a cardiac patient.

ACPE UAN: 0009-0000-25-028-L01-P Application

2:15-3:15 pm Law: Understanding Disabled Pharmacy Patients’ Right to Nondiscrimination
Caroline Wick, JD, MSPH, BA, Practitioner-in-Residence and Acting Director of the Disability Rights Law Clinic, American University Washington College of Law, Washington DC

At the end of this presentation the learner will:

Describe the federal and state laws that protect patients with disabilities
Recognize situations in which accommodations should be provided to disabled patients
Recall examples of common modifications for patients with disabilities

ACPE UAN: 0009-0000-25-027-L03-P Knowledge

3:20-4:20 pm- So Much STI Data: Information to help you stay current and informed
Jennifer Girotto, PharmD, BCPPS, BCIDP, Associate Clinical Professor, UConn School of Pharmacy, Storrs, CT

At the end of this presentation the learner will

Describe updated screening recommendations and epidemiological trends of sexually transmitted infections (STIs).
Review the Centers for Disease Control and Prevention’s STIs recommendations.
Explain latest evidence based STI updates.
Given medication shortages, outline the pharmacist’s role in delivering targeted patient education and implementing strategies for responsible medication stewardship for STIs.

ACPE UAN: 0009-0000-25-030-L01-P Application

Handouts will be posted 72 hours prior to the event in 2 slide/page and 6 slide/page below:

11:00am-12:00 pm 2 slides/page
6 slides/page

12:05-1:05 pm 2 slides/page
6 slides/page

1:10-2:10 pm 2 slides/page
6 slides/page

2:15-3:15 pm 2 slides/page
6 slides/page

3:20-4:20 pm 2 slides/page
6 slides/page

“The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.”

Henry A. Palmer CE Finale LIVE Event Friday, Dec 13, 2024

Photograph of Henry A. Palmer

The School of Pharmacy Henry A. Palmer CE Finale, named for beloved professor and mentor, Dr. Henry A. Palmer, is a continuing education program offered at the end of each calendar year. Held during December, the program helps pharmacists fulfill their last minute CE requirements. The program is typically not a single theme, but an ala carte program offering a variety of presentations covering contemporary issues in pharmacy practice/therapeutics. Pharmacists may enroll in one or more [up to 8] hours of continuing education.

The University of Connecticut

School of Pharmacy

Presents the

Henry A. Palmer C.E. FINALE 2024

Aged to Perfection: Pharmacist Strategies for Elder Care Excellence

A LIVE (both virtual and in-person) application and knowledge-based continuing education activity for practicing pharmacists in all settings

Friday, December 13, 2024

7:30 AM – 5:00 PM Eastern Time
Sheraton Hartford South, Rocky Hill, CT

For a full course description see the Henry A. Palmer CE Finale Brochure 2024

REGISTRATION

Handouts for CE Finale will be available the first week of December

HANDOUTS FOR CE FINALE (these will be uploaded as available)

LAW: Medical-Legal Considerations of Aging Patients for Pharmacists-1 slide per page and clickable links

Law: Seniors Self-Diagnosing and Treating: A Brave (and scary) New World-6 per page
Law: Seniors Self-Diagnosing and Treating: A Brave (and scary) New World-2 per page

Balancing Safety and Efficacy: Addressing Medication Dilemmas in Older Adults -6 per page
Balancing Safety and Efficacy: Addressing Medication Dilemmas in Older Adults -2 per page

Immunization: Our Best Shot – Tips and Tools to Vaccinate Older Adults-6 per page
Immunization: Our Best Shot – Tips and Tools to Vaccinate Older Adults–2 per page

Opioids: Impact of Palliative Care on Total Pain in the Older Adult-6 per page
Opioids: Impact of Palliative Care on Total Pain in the Older Adult–2 per page

Patient Safety: Cheers to the Beers: Unpacking the Latest Updates for Safer Prescribing-6 per page
Patient Safety: Cheers to the Beers: Unpacking the Latest Updates for Safer Prescribing-2 per page

Beyond Memory Loss: Mastering the Management of Behavioral Symptoms in Dementia– 6 per page
Beyond Memory Loss: Mastering the Management of Behavioral Symptoms in Dementia–2 per page

LAW: Call 1-800-Get-Cash Fast: Drug-Related Advertisements about Litigation-6 per page
LAW: Call 1-800-Get-Cash Fast: Drug-Related Advertisements about Litigation-2 per page

CE FINALE SCHEDULE/TOPICS/LEARNING OBJECTIVES

7:30-8:00 a.m. – Registration and Check-In/Sign-In

8:00-8:05 a.m. – Opening Remarks- Philip Hritcko, Dean, School of Pharmacy

8:05-8:10 a.m. – Operational Instructions-Jeannette Y. Wick, Dir. OPPD

8:10-9:10 a.m. – LAW: Medical-Legal Considerations of Aging Patients for Pharmacists
Jennifer A. Osowiecki, RPh, JD, Cox & Osowiecki, LLC, Hartford, CT

At the conclusion of this presentation, pharmacists will be able to:

1. List at least three common medical-legal concerns associated with aging.

2. Identify what constitutes elderly abuse or neglect and describe whether the pharmacist has a reporting obligation.

3. Discuss the likelihood of polypharmacy and measures that pharmacists can employ to facilitate better medication management and compliance for elderly patients and their caregivers.

0009-0000-24-042-L03-P (0.1 CEU or 1 contact hour) (Application-based)

9:15-10:15 a.m. Law: Seniors Self-Diagnosing and Treating: A Brave (and scary) New World

Michael White, PharmD, FCCP, FCP, BOT Distinguished Professor and Chair of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT

At the conclusion of this presentation, pharmacists will be able to:

Describe the reasons seniors are increasingly diagnosing and treating themselves with therapies
Describe the legal and regulatory pathways that provide seniors access to therapies outside the drug supply chain
Describe the ways that pharmacists can recommend dietary supplements that are free of adulterants and contaminants
Describe the risks associated with self-treatment with dietary supplements, “peptides”, and counterfeit drugs

0009-0000-24-044-L03-P (0.1 CEU or 1 contact hour) (Knowledge-based)

10:20-11:20 a.m. – Balancing Safety and Efficacy: Addressing Medication Dilemmas in Older Adults

Christina Polomoff, PharmD, BCACP, BCGP, FASCP, Population Health Clinical Pharmacist, Associate Clinical Professor, University of Connecticut School of Pharmacy, Storrs, CT

At the conclusion of this presentation, pharmacists will be able to:

Analyze pharmacokinetic and pharmacodynamic changes associated with aging
Identify opportunities for deprescribing and medication management
Use evidence-based tools and strategies to optimize medication regimens, applying deprescribing frameworks and decision aids in real-world geriatric care

0009-0000-24-043-L01-P (0.1 CEU or 1 contact hour) (Application-based)

11:25-12:25 p.m. – Immunization: Our Best Shot – Tips and Tools to Vaccinate Older Adults

At the conclusion of this presentation, pharmacists will be able to

1. RECOGNIZE appropriate vaccine recommendations for the older adult population

2. IDENTIFY potential barriers to vaccinations

3. ANALYZE current methods used to improve vaccination rates

4. DISCUSS ways to improve vaccine compliance in your patient population

0009-0000-24-047-L06-P (0.1 CEU or 1 contact hour) (Application-based)

12:25-12:45 p.m. – BREAK-light snacks will be served.

12:45-1:45 p.m. – Opioids: Impact of Palliative Care on Total Pain in the Older Adult

Megan Mitchell, PharmD, MS, Pharmacy Clinical Coordinator Pain Management and Palliative Care, University of Connecticut Healthcare, Farmington, CT

At the conclusion of this presentation, pharmacists will be able to:

Describe Palliative Care and its importance in the healthcare system today
Define the concept of “total pain” and the importance of whole person care in pain and symptom management
Recognize the physiologic changes that occur with aging and how those impact pain and symptom management
Determine the role of the pharmacist in total pain management in the older adult

0009-0000-24-046-L08-P (0.1 CEU or 1 contact hour) (Application-based)

1:50-2:50 p.m. –Patient Safety: Cheers to the Beers: Unpacking the Latest Updates for Safer Prescribing
Kelsey Giara, PharmD, Freelance Medical Writer, Pelham, NH

At the conclusion of this presentation, pharmacists will be able to:

Review the role of the Beers Criteria in reducing potentially inappropriate medication (PIM) use and enhancing patient safety in older adults
Identify recent updates to the Beers Criteria and their implications for medication management in geriatric care
Apply the updated Beers Criteria to real-world scenarios, optimizing medication selection and minimizing risks in older adult

0009-0000-24-045-L05-P (0.1 CEU or 1 contact hour (application-based)

2:55-3:55 p.m. – Beyond Memory Loss: Mastering the Management of Behavioral Symptoms in Dementia

Kristin Waters, PharmD, BCPS, BCPP, Assistant Clinical Professor, UConn School of Pharmacy, Storrs, CT

At the conclusion of this presentation, pharmacists will be able to:

Identify clinical characteristics of the behavioral symptoms of dementia (BSD) including agitation, psychosis, and sleep disturbances
Discuss medications currently used in the management of BSD along with emerging pharmacologic therapy options
Determine the most appropriate pharmacologic treatment option for a patient with behavioral symptoms of dementia based on patient-specific factors

0009-0000-24-048-L01-P (0.1 CEU or 1 contact hour) (Application-based)

4:00-5:00 p.m. –LAW: Call 1-800-Get-Cash Fast: Drug-Related Advertisements about Litigation
Jeannette Y. Wick, RPh, MBA, Director Office of Professional Pharmacy Development, UConn School of Pharmacy, Storrs, CT

At the conclusion of this presentation, pharmacists will be able to:

Explain common terminology associated with commercials targeting older Americans
Describe legal processes associated with lawsuits generated against companies that make products alleged to cause harm
Discuss generalities in potential lawsuits associated with media promotion campaigns
Identify areas where no information is available to provide good, valid answers for patients who ask questions

0009-0000-24-049-L03-P (0.1 CEU or 1 contact hour) (Application-based)

CE FINALE ENCORE WEBINARS AVAILABLE

If you find you cannot make it to our LIVE EVENT on Friday, December 13^th, you can participate in our ENCORE LIVE WEBINARS that will be streamed on the following dates:

Monday, December 16, 12:00 (Noon) – 1:00 pm – Seniors Self-Diagnosing and Treating: A Brave (and scary) New World
Monday, December 16, 7:00 pm – 8:00 pm – Patient Safety: Cheers to the Beers: Unpacking the Latest Updates for Safer Prescribing
Monday, December 16, 8:10 pm – 9:10 pm – Immunization: Our Best Shot – Tips and Tools to Vaccinate Older Adults
Tuesday, December 17, 12:00 (Noon) – 1:00 pm – Opioids: Impact of Palliative Care on Total Pain in the Older Adult
Tuesday, December 17, 7:00 pm-8:00 pm – LAW: Call 1-800-Get-Cash Fast: Drug-Related Advertisements about Litigation
Wednesday, December 18, 12:00 pm-1:00 pm – Beyond Memory Loss: Mastering the Management of Behavioral Symptoms in Dementia

Registration Information

Online: https://ce.pharmacy.uconn.edu/henry-a-palmer-ce-finale/

A continuous class schedule format will be used. This format does not include breaks but does include a 20 minute lunch period.

Refunds and Cancellations: The registration fee, less a $75 processing fee, is refundable for those who cancel their registration three (3) days prior to the program (by December 10) After that time, no refund is available.

Location: The Henry A. Palmer C.E. Finale will be held both virtually or in-person. You must sign in to the Webex link at the designated time using the link in your confirmation email if you decide to participate virtually.

Continuing Education Units

The University of Connecticut, School of Pharmacy, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Statements of Credit will be awarded at CE Finale based on full sessions attended and completed online evaluations. Pharmacists can earn up to 8 contact hours (0.80 CEU) three of which are Law credits, and one is an Immunization credit, one is a Patient Safety credit and one is an Opioid credit.

Please Note: Pharmacists who wish to receive credit for the presentations MUST ACCURATELY complete the registration and online evaluations within 45 days of the live program (January 27, 2025). Participants are accountable for their own continuing education requirements for license renewal and are required to follow up with joanne.nault@uconn.edu to resolve a discrepancy in a timely manner. PLEASE CHECK YOUR CPE MONITOR PROFILE within 3 days of submission to assure that your credits have been properly uploaded. Requests for exceptions will be handled on a case-by-case basis and may result in denial of credit.

Activity Support: There is no funding for this program.

Long-Acting Injectable Medication Products

Pharmacists possess the training and skills necessary to administer certain long-acting injectable (LAI) medications used in the management of mental illnesses and substance use disorders. Through collaborative practice agreements, pharmacists can administer Long Acting Injectables in almost every state. In some states, including the state of Connecticut, this occurs via collaborative agreements, and necessary injection and disease state training. Administration of these medications by pharmacists can increase accessibility of care for patients.

UConn has developed web-based continuing pharmacy education activity to enhance pharmacists’ skills and help them make sound clinical decisions about long acting injectables administration. This course includes eight hours of CPE (or eight hours of credit), required by the State of Connecticut. Successful completion of these eight hours (with four activities consisting of three hours online pre-requisite work and five hours of LIVE CE) will earn the pharmacist a Certificate in Long-Acting Injectables of Psychotropic Medication.

The three activities below are available separately for $17/hour each, or as pre-requisites for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program at $299 which includes both the prerequisites and the full day of LIVE training.

At the end of this application-based continuing education activity, the learner will be able to:

Compare and contrast among different long-acting injectable (LAI) medications currently available for the

treatment of schizophrenia, bipolar disorder and substance use disorders including:

· Dosing

· Generic and brand names

· Adverse effects

· Administration schedule

· Overlap with oral medications

· FDA-approved indications

If desired, pharmacists can register for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program

or for the individual activities. The Certificate consists of three activities in our online selection, and a 5 hour LIVE activity.

You may register for individual topics at $17/CE Credit Hour, or for the Entire LAIA Certificate at $299.00 which includes 5 hours of LIVE CE and the 3 online pre-requisites listed below.

You must register for ALL 4 activities to receive the bundled pricing of $299.00

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Dr. Waters is a consultant with Janssen Pharmaceuticals. She will discuss all drugs without bias. All financial interests with ineligible companies (as noted) have been mitigated.

Guideline-Driven Treatment for Mental Illnesses and Substance Abuse Disorders

At the end of this application-based continuing education activity, the learner will be able to:

Describe first- and second-line treatment options for the following disease states:

· Schizophrenia

· Bipolar disorder

· Alcohol use disorder

· Opioid use disorder

Identify where long-acting injectable medications fit into treatment guidelines for each disorder

Apply clinical treatment guidelines to select optimal pharmacologic treatment for a patient diagnosed with these disorders

If desired, pharmacists can register for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program

or for the individual activities. The Certificate consists of three activities in our online selection, and a 5 hour LIVE activity.

You may register for individual topics at $17/CE Credit Hour, or for the Entire LAIA Certificate at $299.00 which includes 5 hours of LIVE CE and the 3 online pre-requisites listed below.

You must register for ALL 4 activities to receive the bundled pricing of $299.00

Dr. Waters is a consultant with Janssen Pharmaceuticals. She will discuss all drugs without bias. All financial interests with ineligible companies (as noted) have been mitigated.

Learning Objectives

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

An Educational Grant has been provided by:

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

An Educational Grant has been provided by:

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

About this Course

Target Audience

Pharmacist Learning Objectives

Bundle Options

Accreditation Statement

Grant Funding