INTRODUCTION

“I’ve been shot, and I’ve been stabbed; nothing compares to gout pain.”

This is how Jim, a 77 year old man, describes his pain as he hobbles into the pharmacy to refill his prescription for colchicine. Jim complains that colchicine is not controlling his gout. He is wearing slippers that show his red swollen joint around his right big toe that is warm and painful to touch. Jim says his physician explained that these symptoms are due to podagra, uric acid crystallization and settling in the joint between his foot and big toe.¹ As Jim speaks, his breath projects a strong alcohol smell.

Gout is the most common form of inflammatory arthritis affecting about 9.2 million adults in the United States (US) and is the result of hyperuricemia.^2,3 Men are at higher risk of developing gout than women.⁴ Other risk factors include post-menopause, genetics, end-stage renal disease, and major organ transplant.

Uric acid overproduction, under-excretion, or both, elevate serum uric acid levels.⁵ Underexcretion of uric acid accounts for about 90% of gout cases.⁶ Human bodies produce uric acid as they break down dying tissues.⁴ Other sources of uric acid are foods high in purines, such as meats, seafood, and alcoholic beverages.^{7, 8} Ancient Greek history states that only rich people, who could afford these expensive foods, experience gout.⁹ Therefore, in the 5^th century before Christmas (B.C.), people referred to gout as “the disease of kings.”¹⁰

PATHOGENESIS

Uric acid circulates in the blood as monosodium urate.¹¹ In the kidneys, uric acid and urate undergo filtration and secretion into the filtrate followed by about 90% reabsorption into the blood.¹² The American College of Rheumatology (ACR) guideline defines hyperuricemia as serum uric acid of 6.8 mg/dL or greater, the level above which urate becomes insoluble in the blood.⁴

Gout results from the chronic deposition and crystallization of urate in the joints and tissues.^4,13 Insoluble monosodium urate crystals form stone-like deposits, known as tophi, in soft tissues, synovial tissues, or bones.^14,15 Tophi trigger an inflammatory response, which presents as an acute gout attack.^15,16 However, hyperuricemia does not always result in gout.⁴

Although gout can affect any joint, initial attacks usually involve the big toe joint. Gout attacks are sudden and very painful.¹⁷ Acute gout attacks reach maximum pain level in 12 to 24 hours and may last 3 to 14 days if patients do not seek therapy.¹⁸ For this reason, all healthcare providers including those on pharmacy teams need to educate patients to seek medical care. Effective gout management reduces the risk of long-term complications like degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement.¹⁹

 

DIAGNOSIS OF GOUT

Clinicians diagnose gout by collecting patient history, examining the patient, laboratory workup, and imaging.¹⁹ Uric acid crystals in the synovial fluid or tophi in tissues and/or bones confirm gout diagnosis regardless of the uric acid level.⁴

TREATMENT OF GOUT

The ACR guideline describes 3 treatment goals for patients with gout²⁰:

1. Terminating the acute gout attack
2. Preventing future attacks
3. Lowering the serum uric acid level

Terminating the Acute Gout Attack

The ACR published the most recent guideline for the management of gout in 2020. The ACR guideline recommends colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids (oral, intraarticular, intramuscular) as first-line agents for the treatment of gout flares.²⁰  Patient-specific factors guide the drug choice among the first-line agents. Interleukin-1 (IL-1) inhibitors or adrenocorticotropic hormone (ACTH) are alternative agents.²⁰  If a first-line agent is ineffective, intolerable, or contraindicated, the ACR guideline recommends switching to another first-line agent before trying alternative agents. Topical ice is an adjunct to pharmacologic therapy. The severity of the gout flare guides the treatment duration.

 

Colchicine

Colchicine exerts its anti-inflammatory effects by binding to free tubulin dimers leading to microtubule polymerization inhibition, which affects cellular function.^{21, 22} Colchine has had an interesting history, as the SIDEBAR explains. Common side effects of colchicine are dose-dependent and include diarrhea, nausea, and vomiting.  Because of its mechanism of action, toxic levels of colchicine inhibit cellular division leading to failure of multiple organs .²² Colchicine doses of 0.8 mg/kg are lethal.²³ Colchicine undergoes extensive tissue distribution and therefore, a lower dose can be toxic in patients with liver or renal failure. Some unchanged colchicine undergoes renal excretion through glomerular filtration and therefore, requires dosage adjustment for renal dysfunction.^{21, 24}  Cytochrome P450 3A4 hepatic enzymes metabolize colchicine.^{21, 25} P-glycoprotein facilitates colchicine removal from the body.²⁶ Co-administration of medications that inhibit CYP3A4 enzyme activity (example: grapefruit juice, azole antifungals, erythromycin, verapamil) increase the risk of colchicine toxicity.^{21, 25} In addition, co-administration of colchicine with P-glycoprotein inhibitors (example: digoxin) increases the risk of colchicine toxicity.²⁶ Toxic symptoms are dose-dependent with increasing severity.²⁷ Patients with toxicity may present with gastrointestinal symptoms (nausea, vomiting, diarrhea), hypotension, lactic acidosis, or acute kidney injury.^{22, 27} To decrease the risk of toxicity, colchicine’s prescribing information recommends avoiding its co-administration with P-glycoprotein inhibitors or CYP3A4 inhibitors in patients with renal or hepatic impairment.²⁸ For other patients, the prescribing information recommends weighing risks versus benefits before co-administering colchicine with medications that pose a significant drug interaction.

 

SIDEBAR: HISTORY OF COLCHICINE

Colchicine is derived from a plant, Colchicum automnale.²⁹ Other names for this plant include Autumn Crocus, meadow saffron, naked lady, and colchicum.³⁰ Ebers Papyrus, an Egyptian medical document on herbs dating back to 1500 BC, indicates the use of C. automnale for joint pain.³¹ In 1833, a German pharmacist analyzed the substance and gave it the name colchicine.²⁹ In France, in 1819, a chemist and a pharmacist isolated colchicine from the plant. In 1884, a French pharmacist produced and sold colchicine as 1 mg granules, which is still available in some countries.^29,32 Colchicine accounts for about 0.1-0.6% of the plant content.³³ Non-surprisingly, the C. automnale plant is poisonous. Humans should not ingest the plant. Symptoms of C. automnale toxicity resemble the side effects or toxicity of colchicine.³⁴ These symptoms range from diarrhea, nausea, and vomiting to organ failure and death.

Colchicine was available for decades in the US without a U.S. Food and Drug Administration (FDA) approved labeling.³⁵ Despite the Food, Drug, and Cosmetics Act requiring the FDA to approve medications based on efficacy and safety data, colchicine was grandfathered in. Grandfathered drugs were medications available on market before the Food, Drug, and Cosmetics Act of 1938 or its amendments in 1962.

In 2006, the FDA initiated the unapproved drug initiative (UDI).³⁶ The goal of the UDI program was to decrease the number of medications in the United States that do not carry FDA approval. Under the UDI program, the FDA allowed exclusive marketing to manufacturers who obtain FDA approval. Some pharmacists and pharmacy technicians may recall colchicine shortage as manufacturers of colchicine received warning letters from the FDA to stop selling colchicine.³⁷ Mutual Pharmaceutical Company submitted a new drug application (NDA) for colchicine in November 2008.³⁸ The UDI did not require manufacturers to conduct new clinical trials to obtain FDA approval. Mutual Pharmaceutical Company’s NDA included data from randomized controlled trials in 1974 and 2004 that proved the safety and efficacy of colchicine. As a result, in July 2009 the FDA approved colchicine for the treatment of gout and familial Mediterranean fever. Colchicine came back to the US market under brand name Colcrys.³⁹

 

Colchicine is light sensitive. Pharmacies should protect colchicine from light and dispense it in a light-resistant container.²⁸ The FDA requires pharmacies to distribute a medication guide to patients when dispensing colchicine.⁴⁰ Medication guides inform patients of potential serious adverse reactions and harm mitigation strategies. The Institute for Safe Medical Practices (ISMP) lists colchicine on the look-alike sound-alike (LASA) list due to potential for confusion with Cortrosyn, which is the brand name for cosyntropin.⁴¹  Of note, cosyntropin is a synthetic adrenocorticotropin hormone that has anti-inflammatory properties and is an alternative agent for gout attacks.⁴² In patients with a history of gout, the ACR guideline recommends a “medication-in-pocket” (discussed below) approach to allow early initiation of an anti-inflammatory drug at the onset of a gout flare.²⁰ Since colchicine has anti-inflammatory properties, it is an option for the “medication-in-pocket” approach.

The pharmacist takes a close look at Jim’s prescription refill history to figure out why colchicine is not working for Jim. The pharmacist explores several possibilities:

• Is Jim adhering to his urate-lowering therapy (ULT)?
• Is Jim refilling his colchicine as part of a gout flare prophylactic therapy upon initiating ULT?
• Is Jim asking for colchicine as a “medication-in-pocket” approach?
• Is Jim consuming excessive alcohol?
• Is Jim eating foods rich in purines?
• Is Jim taking any prescription or over-the-counter medications that may increase his uric acid level?

NSAIDs

The FDA has approved indomethacin, naproxen, and sulindac for the treatment of acute gout flare.^{43,44, 45} However, the guideline does not recommend a specific NSAID.²⁰ Choice of agent depends on patient-specific factors including cardiovascular (CV) risk, gastrointestinal (GI) risk, cost, and availability without a prescription.⁴⁶ Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor and therefore carries a low GI risk but is associated with a dose-dependent increase in CV risk.^{47, 48} Ibuprofen carries a low GI risk. Indomethacin, naproxen, diclofenac, and sulindac carry a moderate GI risk.^{49, 50} Among the nonselective NSAIDs, CV risk is highest with diclofenac and lowest with naproxen.⁵¹ Despite differences in CV risk among nonselective NSAIDs, the FDA mandates a boxed warning for all NSAIDs about increased  risk of thrombosis, myocardial infarction (MI), and stroke.^{52, 53} In addition, the FDA requires pharmacies to distribute a medication guide to patients when dispensing a prescription for NSAIDs.⁵⁴ Any NSAID is an option for the “medication-in-pocket” approach.²⁰

Glucocorticoids

The ACR guideline does not recommend a specific oral glucocorticoid.²⁰ Parenteral glucocorticoids (intramuscular, intravenous, or intraarticular) are alternative options for patients who cannot tolerate oral therapy. Glucocorticoids (example: prednisone, methylprednisolone) are an attractive option for patients with chronic kidney disease (CKD) or those who cannot tolerate colchicine or NSAIDs.^1,55 Short-term glucocorticoids do not cause significant side effects.^{56, 57} Glucocorticoids are an additional option for the “medication-in-pocket” approach, including injectable formulations for patients who cannot take oral medications.²⁰ Methylprednisolone is available in different dosage forms such as oral, intramuscular (as acetate or succinate), intravenous (as acetate), and intraarticular (as acetate).⁵⁸

Anakinra

Anakinra is an IL-1 receptor antagonist.⁵⁹ It blocks the activity of the inflammatory mediatory IL-1. Anakinra has an off-label indication for gout attacks at a dose of 100 mg subcutaneously daily for 3 to 5 days.^{60, 61} The ACR guideline classifies anakinra as an alternative agent, particularly due to cost.²⁰ The manufacturer recommends storing anakinra in the refrigerator and protecting from light until ready for administration.⁶² Patients can self-administer anakinra after demonstrating proper administration technique.⁵⁹

ACTH

Adrenocorticotropic hormone (ACTH) binds to melanocortin receptors, which triggers the release of endogenous steroids, thus decreasing inflammation.⁶³ The ACR guideline recommends ACTH as an alternative agent.^20,63 ACTH is available as an intramuscular or subcutaneous injection.⁶⁴ The purified cortrophin formulation carries an indication for acute gouty arthritis.⁶⁵ The manufacturer does not provide a dosing recommendation specific for gout and recommends caution in patients with renal insufficiency.^64-66 The manufacturer recommends storing ACTH in the refrigerator until ready for administration and warming to room temperature before injecting.⁶⁷

Table 1 summarizes the first-line agents for the treatment of gout flares.

Table 1. First-line Agents for the Treatment of Gout Flares20, 24, 44-46, 56, 68-71
Therapy	Dose	Comment	Monitoring parameters
Colchicine	·        Day 1 of therapy: Use treatment dose of 1.2 mg by mouth (PO) as soon as possible then 0.6 mg after one hour. Maximum dose 1.8 mg/day. ·        Day 2 and until flare resolves, use prophylactic dose of 0.6 mg PO once or twice daily.	If creatinine clearance (CrCl) < 30 mL/min:   ·        Use 1.2 mg PO as soon as possible then single dose of 0.6 mg after one hour. Avoid repeating therapy within a 14-day period. ·        Alternatively, use 0.3 mg PO as soon as possible as a single dose. Avoid repeating therapy within 3-7 days.   If patient is on dialysis: ·        Use 0.6 mg PO as a single dose. Avoid repeating therapy within a 14-day period.	Monitor patients with CrCl ≤ 80 mL/min closely for adverse effects.
NSAIDs	·        Indomethacin: 50 mg three time daily until pain is tolerable (usually, 3 to 5 days). ·        Sulindac: 200 mg twice daily until attack resolves (usually, 7 days). ·        Naproxen: 750 mg x 1 dose then 250 mg every 8 hours until attack resolves (usually, 2 days).	·        The manufacturer does not provide recommendations for renal dosage adjustment. ·        The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommends avoiding use of NSAIDs If CrCl < 30 mL/minute.	Monitor GI, renal, and CV toxicity in elderly patients. Prescribe lowest effective dose for the shortest duration possible.
Glucocorticoids	·        Follow specific glucocorticoid dosing recommendation.	Safest option in patients with CKD.	Monitor serum glucose, blood pressure, electrolytes, mood changes, and recurrent infections.

 

Interestingly, a panel consisting of eight patients with gout participated in the development of the 2020 ACR guidelines.²⁰ The patient panel provided valuable input from a patient perspective regarding therapy preference for patients with an established gout diagnosis. The patient panel strongly favored a medication-in-pocket approach for the treatment of acute gout flares. With this approach, the clinician prescribes an anti-inflammatory medication that the patient keeps on hand for use as needed.⁷² Moreover, the patient panel favored an injectable dosage form for the medication-in-pocket to control the pain faster in patients who can take nothing by mouth. The medication-in-pocket approach ensures that patients have quick access to an anti-inflammatory medication at the first onset of gout attack symptoms.²⁰

Jim’s colchicine regimen is consistent with the “medication-in-pocket” to treat an acute gout flare.

MANAGEMENT OF CHRONIC GOUT

The goal of chronic gout management is to lower the serum uric acid level with ULT, if indicated, and to prevent future attacks.²⁰ ULT includes medications that decrease uric acid production or promote uric acid excretion.⁷³ The ACR 2020 guideline recommends a “treat-to-target” approach that guides ULT dose titration and maintenance to achieve serum uric acid of less than 6 mg/dL.²⁰ Lower ULT initial dosing with subsequent titration decreases the risk of gout flare associated with ULT initiation.²⁰

Pause and Ponder: What patient factors determine eligibility for urate lowering therapy (ULT)?

Table 2 provides recommendation on initiation of ULT based on patient-specific factors.

Table 2 - Indication for ULT 20
Patient factors	2020 ACR guideline recommendation	Comment
≥1 subcutaneous tophi	ACR guideline strongly recommends initiating ULT	Moderate or high certainty of evidence that benefits of ULT consistently outweigh the risks
Gout-attributable radiographic damage
≥2 gout flares per year
> 1 flare but < 2 flares per year	ACR guideline conditionally recommends initiating ULT	Low certainty of evidence or no data available and/or benefits and risks closely balanced
First flare and any of the following: ·        Chronic kidney disease (CKD) stage ≥ 3 ·        Serum uric acid > 9 mg/dL ·        Urolithiasis
First gout flare	ACR guideline conditionally recommends against initiating ULT
Asymptomatic hyperuricemia*

*Serum uric acid > 6.8 mg/dL

Pause and Ponder: Which urate-lowering agent is first-line therapy?

Table 3 summarizes urate-lowering medications.

Table 3 - Urate Lowering Medications 20,74-76
Pharmacological class	Mechanism of action	Medication	Comments
Xanthine Oxidase Inhibitors	Inhibition of xanthine oxidase resulting in decreased conversion of hypoxanthine to xanthine and xanthine to uric acid.	Allopurinol Febuxostat	·        Allopurinol is first-line agent. ·        Start allopurinol at ≤ 100 mg/day in normal kidney function and ≤ 50 mg/day in CKD stage ≥ 3 then titrate. ·        Start febuxostat at ≤ 40 mg/day then titrate.
Uricosuric Agents	Inhibition of urate reabsorption in the renal tubules resulting in increased excretion of uric acid in the urine.	Probenecid	·        ACR guideline strongly recommends XOI over probenecid for patients with CKD stage ≥ 3 ·        Start probenecid at 500 mg PO once or twice daily then titrate.
Urate Oxidase Enzyme	Catalysis of uric acid oxidation to water-soluble allantoin resulting in increased excretion of the allantoin in the urine.	Pegloticase	·        ACR guideline strongly recommends against use of pegloticase as a first-line agent ·        Administer pegloticase 8 mg IV infusion every 2 weeks along with methotrexate 15 mg PO once a week with a folic acid supplement. ·        Start weekly methotrexate and folic acid supplementation 4 weeks before initiating pegloticase and continue while on pegloticase.

 

Clinicians usually determine eligibility for ULT when patients present with an acute gout attack.²⁰ Some experts favor initiating ULT two to four weeks after the resolution of a gout attack.⁷⁷ One reason for this practice stems from the fear of gout attack worsening with ULT initiation. The other reason is the perception that during a gout attack, patients are in too much pain to process information regarding chronic therapy. However, the ACR guideline favors initiating ULT during a gout flare as patients may not return for a follow-up visit to initiate ULT after the flare resolves.²⁰

XANTHINE OXIDASE INHIBITORS (XOIs)

XOI include allopurinol and febuxostat.²⁰ XOI are first-line among urate-lowering agents, and the guideline recommends allopurinol as a first-line agent for all patients with gout, unless contraindicated.

Allopurinol

Allopurinol is associated with an increased risk of allopurinol hypersensitivity syndrome (AHS), a rare but severe, and potentially life-threatening adverse reaction.⁷⁸ AHS presents as fever, severe rash, eosinophilia, hepatitis, and acute kidney injury.⁷⁹ AHS is more common in patients who are African Americans or of Southeast Asian descent.⁷⁸ Pharmacogenetic studies show that these patients have a gene on their human leukocyte antigen (HLA) system that increases the risk of developing AHS. This gene is the HLA-B*5801 allele.⁸⁰ The interaction of allopurinol with the HLA-B*5801 allele triggers an immune reaction characterized by T-cell activation.⁸¹ Not all patients who are positive for HLA-B*5801 allele develop AHS.⁸² Risk of AHS increases in HLA-B*5801 allele positive patients who have elevated allopurinol serum level due to dose increase or renal dysfunction.⁸¹

In the US, testing for HLA-B*5801 in Caucasians or Hispanics is not cost-effective.⁸³ The 2020 ACR guideline recommends genetic testing for the HLA-B*5801 allele before starting allopurinol for patients who are African Americans or of Southeast Asian descent.²⁰ The guideline recommends starting allopurinol at a low dose of 100 mg daily for normal renal function and a lower dose in case of renal dysfunction.

The prescribing information recommends protecting allopurinol from light.⁷⁴ ISMP lists the brand name of allopurinol, Zyloprim, on the look-alike sound-alike (LASA) list due to potential for confusion with zolpidem.⁴²

 

SIDEBAR: DID YOU KNOW THAT THE DISCOVERY OF ALLOPURINOL LED TO A NOBEL PRIZE AWARD?

Gertrude Elion, who earned a master’s degree in chemistry from New York University in 1941, worked as a lab assistant for George Hitchings. Up until the 1950s, scientists produced medications by screening and modifying naturally existing substances.⁸⁴ However, Elion and Hitchings’ contribution to medicine was groundbreaking to drug development as they introduced drug therapy that was targeted to specific cells. In 1963, Elion and Hutchings discovered that allopurinol blocked the synthesis of uric acid. In 1988, the Nobel Prize Committee awarded Gertrude Elion and George Hitchings the Nobel Prize in Physiology or Medicine for the discovery of allopurinol and other medications.⁸⁵

 

Febuxostat

Febuxostat carries a boxed warning for increased risk of CV death in patients with cardiovascular disease (CVD), when compared to allopurinol.⁸⁶ Therefore, the 2020 ACR guideline recommends selecting another ULT medication in patients with established CVD.²⁰ For patients who experience a CV event while on febuxostat, the ACR guideline recommends switching to a different ULT medication.²⁰ The FDA requires pharmacies to distribute a medication guide when dispensing febuxostat to patients.⁸⁶

URICOSURICS

Probenecid

Probenecid is the only uricosuric drug approved in the United States.^87,88 Probenecid may cause nephrolithiasis (uric acid stones in the kidneys).⁸⁹ These uric acid stones form as the uric acid crystallizes in an acidic urine. The prescribing information for probenecid recommends adequate hydration and adjunct urine alkalinizing agents (example: sodium bicarbonate or potassium citrate).⁸⁹ However, the 2020 ACR guideline determined insufficient evidence to recommend the routine use of alkalinizing agents with probenecid.²⁰ Probenecid is usually an add-on therapy in patients with partial response to an XOI. Remember to counsel patients on adequate hydration to decrease the risk of nephrolithiasis.

ISMP lists probenecid on the LASA list due to potential for confusion with Procanbid, the brand name for procainamide, an antiarrhythmic drug.⁴² Probenecid also has some interesting abuse potential (see the SIDEBAR).

 

SIDEBAR: CAN PROBENECID HELP ATHLETES IMPROVE PERFORMANCE?

Random drug testing in sports led athletes to misuse probenecid to mask the unlawful use of performance-enhancing drugs such as anabolic-androgenic steroids.⁹⁰ Probenecid inhibits the tubular secretion of anabolic-androgenic steroids in the kidneys, thus inhibiting their excretion in the urine. As a result, urine drug testing will not detect the use of these illegal substance, and athletes can pass the random drug testing successfully. In 1986, a doping control officer traveled from Norway and collected 6 urine samples from 6 Norwegian athletes who were training in the US. The athletes showed up at least 1.5 hours late probably to allow time for onset of action of the masking agent. Five of the samples showed an unusually dilute urine with low specific gravity. In addition, the concentration of endogenous androgenic-anabolic steroids in the urine samples was at least 100 times below normal.⁹⁰ These unusual findings along with suspicious behaviors projected by the athletes during the testing process, triggered further analysis of the urine samples. The lab identified a “new masking agent”, probenecid and its metabolite, in these urine samples. Today, probenecid appears on the World Anti Doping Agency (WADA) prohibited list.⁹¹ The WADA list serves as a standard for identifying substances that athletes may illegally use to enhance performance in sports.⁹¹

 

URATE OXIDASE ENZYME

Pegloticase

The FDA approved pegloticase for adults with chronic gout refractory to conventional therapy.⁹² The 2020 ACR guidelines recommends switching to pegloticase when XOIs, probenecid, and other interventions fail.²⁰ In clinical trials, administering methotrexate with pegloticase increased the chance of tophi resolution by 22.8% compared to pegloticase monotherapy.⁷⁶ Therefore, pegloticase’s prescribing information recommends co-administration with methotrexate, unless contraindicated. Folic acid supplementation decreases the risk of hepatotoxicity and GI side effects associated with methotrexate.⁹³ Pharmacists should counsel patients about the importance of adherence to folic acid while on methotrexate.

The manufacturer recommends storing pegloticase in the refrigerator and protecting it from light before dispensing.⁷⁶ After diluting pegloticase for IV infusion in an institutional setting, healthcare workers should protect the solution from light.

 

Pause and Ponder: When does the guideline recommend switching urate-lowering agents?

The 2020 ACR guideline recommends using the maximum tolerated or recommended dose of a ULT.²⁰  Figure 1 outlines the management of patients taking a XOI requiring adjustment to therapy:

Figure 1. Switching ULT

Jim’s medication profile reveals that he has been taking allopurinol for little over a year now.

 

DURATION OF THERAPY

For patients tolerating ULT, the 2020 ACR guideline recommends indefinite therapy to avoid worsening gout and its associated complications.²⁰ Patients may not adhere to therapy due to cost, pill burden, and low health literacy.⁹⁴ Remember to counsel patient on adherence and goals of ULT as patients may think they do not need to take ULT if they have no symptoms.

PREVENTING GOUT FLARE UPON INITIATION OF ULT

Initiation of ULT may trigger a gout flare due to activation of crystals precipitated in joints.^{95, 96} The risk of gout flare increases with higher reduction in serum uric acid levels. Studies suggest that gout attacks associated with ULT may decrease patient adherence to ULT.⁹⁷ Prophylaxis with anti-inflammatory medications decreases the risk of gout flare upon ULT initiation. The 2020 ACR guideline recommends prophylactic therapy upon initiating ULT and for at least three to six months. Patients who continue to experience flares may require a longer duration of prophylactic therapy.²⁰ Experts recommend colchicine or NSAIDs as first-line prophylactic therapy.⁹⁸ Table 4 summarizes prophylactic medications and recommendations.

Table 4 – Medications that Prevent Gout Attack with ULT Initiation
Medication	Recommendation
Low-dose colchicine	Use 0.6 mg once or twice daily
Low-dose NSAIDs	Use naproxen 250 mg or equivalent dose of different NSAID Add proton pump inhibitor if indicated
Low-dose prednisone or prednisolone	Use less than or equal to 10 mg per day Reserve corticosteroids for patients who cannot tolerate colchicine and NSAIDs

 

NONPHARMACOLOGIC THERAPY AND LIFESTYLE MODIFICATIONS

Serum uric acid levels decrease only slightly with dietary modifications.²⁰ In addition, certain diets may trigger a gout flare. To decrease the risk of flares, the 2020 ACR guideline conditionally recommends the following approaches:

• Limiting alcohol intake
• Limiting purine intake. Some examples of high-purine foods include seafood like sardines, tuna, haddock, and meats like bacon, turkey, veal, and liver.^{99, 100}
• Limiting high-fructose corn syrup intake
• Following a weight loss program if the patient is overweight or obese

Jim projected an alcohol breath when speaking. Jim may be consuming excessive amounts of alcohol. He may be consuming a non-gout friendly diet.

DIGITAL HEALTH AND GOUT MANAGEMENT

Digitalization of health care is rapidly evolving and involves the use of technology to manage health conditions, ameliorate modifiable risk factors, and promote health and wellness.¹⁰¹ Wearable devices such as fitness trackers, patient portals, and mobile apps are only few examples of digital health tools. Investigators suggest that gout mobile health apps may improve patient perception of the disease, clarify beliefs, and benefit self-care.¹⁰² However, further studies are essential to prove these mobile applications beneficial. As of this writing, several gout-related mobile health applications are available. Target users for these applications can be clinicians or patients. For example, a physician developed a mobile application called Gout Diagnosis. The application includes an evidence-based algorithm to facilitate an accurate diagnosis of gout.¹⁰³ On the other hand, patients can download from a variety of existing gout mobile applications at little or no cost.¹⁰⁴ The National Kidney Foundation developed a mobile application called Gout Central. This application comes from a reputable foundation and provides patient education on symptoms and risk factors for gout, nonpharmacologic recommendations such as diet and lifestyle modifications, and medications to treat gout and prevent flares.¹⁰⁴ The FDA does not regulate mobile medical applications.¹⁰⁵ Therefore, the choice of mobile health application depends on patient preference such as cost, ease of use, compatibility, security, and type of content.¹⁰⁶

A mobile application may help Jim learn about foods and drinks that may trigger gout attacks.

PHARMACY TEAM IMPACT ON GOUT MANAGEMENT

Pharmacists are the most accessible healthcare professionals. Patients with a gout flare may seek pharmacists for recommendations on pain management. When patients without a previous gout diagnosis present to the pharmacy, pharmacists may recognize signs of gout and refer them to their primary care clinician. Pharmacists can educate patients who have a diagnosis for gout about the phases and goals of gout therapy, including the likelihood that ULT will be a lifelong therapy.

Pharmacists are well-positioned to assess adherence to ULT and educate patients about the importance of ULT.¹⁰⁷ Pharmacists can assess patient understanding of various therapies and remind them that anti-inflammatory medications treat acute gout attack or prevent gout flare upon initiating ULT. Pharmacists should empower patients to request from their clinician a medication-in-pocket prescription. Pharmacists should counsel patients on the proper use of medication-in-pocket by reminding them to take the anti-inflammatory medication as soon as possible, ideally within 12 hours of onset of a gout attack.¹⁰⁸ In addition, patients may need a reminder about continuing their ULT while taking the medication-in-pocket for acute flares.¹⁰⁹

Pharmacy technicians can ensure that patients have refills on their medication-in-pocket prescription to facilitate early initiation. Updating the patient’s records in the pharmacy software with the gout diagnosis can facilitate this continuity of care. The pharmacy team should encourage patients to fill all their prescriptions at the same pharmacy. Through access to all the patient’s medications, pharmacists and pharmacy technicians can play a crucial role in optimizing gout management by identifying medications that increase serum uric acid levels.¹¹⁰

In addition, the pharmacy team can identify potential drug-drug interactions. This is particularly important with colchicine as it is a substrate for CYP3A4 and P-gp and has a narrow therapeutic window.¹¹¹ In addition, some medications are known to increase serum uric acid levels.²⁰ Advising patients to check with the pharmacy team before purchasing an over-the-counter (OTC) medication can decrease the use of inappropriate medications. When completing transactions at the register, pharmacy technicians are well positioned to identify OTC products that can worsen gout, such as vitamin A or niacin.¹¹² On the other hand, frequent purchase of OTC anti-inflammatory medications like naproxen or ibuprofen may imply uncontrolled gout.

Patients can find educational videos on YouTube to learn more about gout therapy and appropriate diet.¹¹³ Additional resources are available to patients on goutalliance.org. These include videos, podcasts, guides, and awareness events.¹¹⁴ Some patients may like to learn about their condition using gout-related mobile applications.

Pharmacy interns may benefit in hearing from patients about their experience with gout, especially the debilitating pain. This may help future pharmacists empathize and develop better relationships with patients, which can improve patient outcomes.¹¹⁵

The entire pharmacy team could engage in alleviating misconceptions about gout. Some patients with gout have reported stigma regarding their condition from friends, family members, and healthcare workers.¹¹⁶ Some patients with gout have even reported an internalized stigma. Stigmatization may be due to the misbelief that gout is benign, preventable, or self-inflicted.

Did you know that May 22 is National Gout Awareness Day?

Jim states that he feels embarrassed about wearing slippers that expose his swollen toe. The pain is so intense that he is unable to tolerate a close-toe shoe.

Table 5 summarizes some medications that may increase serum uric acid level.

Table 5 – Managing Medications that Increase Serum Uric Acid Level and Risk of Gout Attack20,110,117-119
Medication	Mechanism	Recommendation
Loop and thiazide diuretics Use: hypertension, edema	Decrease urate excretion	The guideline recommends switching to a different antihypertensive and suggests losartan when feasible.
Aspirin (low-dose, 81 mg) Use: prevention of CVD	Increases uric acid renal reabsorption and decreases secretion	The guideline conditionally recommends against discontinuing low-dose aspirin with appropriate indication.
Niacin Use: dietary supplement	Inhibits the enzyme uricase, thus inhibiting the oxidation of uric acid, or decreases uric acid excretion	The guideline does not provide a specific recommendation for niacin-induced hyperuricemia. Experts recommend adequate hydration.

 

After looking into Jim’s medication profile and inquiring about his OTC products, the pharmacist does not identify any medication that may be increasing his serum uric acid level.

CONCLUSION

Gout is the most common type of inflammatory arthritis. Untreated gout can lead to complications such as degenerative arthritis, urate nephropathy, infections, renal stones, joint fractures, and nerve or spinal cord impingement. ULT is indicated for chronic gout management. Allopurinol is the first-line urate-lowering agent. Colchicine, NSAIDs, and corticosteroids are indicated for acute flares, and, in lower doses, for gout flare prophylaxis upon initiating ULT. Diet and lifestyle modifications complement the pharmacologic therapy. The pharmacy team plays a crucial role in identifying drug-induced hyperuricemia and educating patients about the importance of adherence to ULT. Gout flares are painful and debilitating. Pharmacists can recommend initiation of anti-inflammatory therapy for acute gout flares. Pharmacy technicians can ensure patients have refills for their anti-inflammatory medication to facilitate the medication-in-pocket approach.

Jim’s uncontrolled gout may be due to various reasons that pharmacy team can investigate. Inquiring about Jim’s drinking habits and educating him about the negative impact of alcohol on gout management is a necessary first step in his therapy. If an adequate trial of dietary changes does not control his symptoms, then switching to a different XOI or adding probenecid, depending on what he has tried so far, would be appropriate.

 

 

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INTRODUCTION

A drug information (DI) request is a medication-related question posed by any interested party, but usually a healthcare professional or a patient. As the healthcare team’s drug expert, one of a pharmacist’s main duties is answering these queries effectively and providing an answer that is appropriate for the inquirer’s level of expertise. Pharmacy technicians and pharmacy interns also answer some drug information questions (see TECH TALK SIDEBAR). This continuing education activity outlines various drug information questions that pharmacy staff field most often and describes a methodical approach to ensure pharmacy staff answer requests effectively and accurately.¹

 

 

TECH TALK SIDEBAR: Questions within the Pharmacy Technician’s Scope of Practice?^2,3

Pharmacy technicians and interns can answer general questions that are within the bounds of their education and training. That vague statement requires some interpretation. If the answer is common knowledge (not specialized pharmaceutical knowledge), technicians can answer. In addition to working with supervising pharmacists to interpret the statement, pharmacy technicians and interns need to know state law governing their scope of practice.

 

Pharmacy technicians and interns are often the first point of contact for customers who want over-the-counter (OTC) medications. Technicians can answer general questions about ingredients if the information is on the label. Some examples include

• Does this product contain acetaminophen? What brands of acetaminophen do you stock?
• Where are the medicines for pain?
• Is there a less expensive generic or store brand for this product?
• Do you have any [insert name of prescription medication] in stock?
• Do I need to refrigerate this liquid antibiotic?
• What does “analgesic” mean?
• What does “sustained release” mean?
• Is this prescription for a controlled substance?
• Why can’t I refill this prescription today?

 

Pharmacy technicians and interns can also convey information from the pharmacist but should be careful. A PRO TIP is that if technicians or interns don’t understand what the pharmacist says, they should ask the pharmacist to make the information clearer. And if the answer is long or complicated, they should write it down and recite it back to the pharmacist before transmitting it to the person with the question.

 

Helping customers find specific medications or classes of medications is within the technician’s scope of practice. When patients have questions about their medications, doses, and how best to administer them, technicians may hesitate to answer. If the information is clearly printed on the prescription label, on the auxiliary labels, or contained in an FDA-approved Medication Guide, the technician or intern can answer.

 

Technicians and interns need to work with the supervising pharmacist to determine if they can answer other questions. When in doubt, technicians should consult with or refer the question to the pharmacist. Technicians and interns must refer questions about potential adverse effects, administration problems, possible alternative medications, and clinical issues to the pharmacist. Before referring the patient, they can collect some baseline information. They cannot counsel or give advice, even if the medication is OTC.

 

 

Depending on the practice setting, the nature and complexity of DI requests can vary. Being able to answer DI requests is every pharmacy employee’s responsibility (although the type of information varies and at a certain level, the response is the pharmacist’s primary responsibility). Having an organized approach to answering DI questions is highly relevant when working within the community and hospital settings.⁴

 

Pharmacy employees who work primarily within a community setting can expect to receive DI requests from patients and from practitioners. These requests can range from asking about drug storage requirements (which a technician can usually answer) to consequences of taking an OTC medication in combination with prescription drugs, to requests regarding the safety of a medication for an uncommon or off-label indication. Pharmacists who work in hospital settings can expect to receive most DI requests from colleagues within the care team. For instance, a DI request could come from a prescriber asking about medication absorption and distribution in a patient with comorbid conditions, or from a nurse asking if a medication can be crushed. Pharmacists who work in industry settings, however, may receive medication information requests that vary greatly from those received in clinical settings.⁴

 

All DI requests require referencing reliable materials and sometimes, various internal policy or research documents. While DI requests are diverse, they all require similar analysis of sources and communication to provide a quality answer. Because pharmacy employees at different levels of responsibility can answer DI questions, this continuing education activity will call the person asking the question the requestor and the person finding the answer the respondent.

 

SCREENING THE REQUEST

One of the most confounding situations in the pharmacy occurs when someone asks a question, the respondent spends times finding an answer, and then the requestor says, “Oh, that’s not what I needed to know!” Sometimes, requestors don’t really know how to ask questions effectively. This is a problem that all customer service fields encounter, and answering DI requests is both a clinical function and a customer service. It’s why when you call many customer service lines, the customer service representative will say, “OK, what I hear you asking is….” and then rephrase the question.⁵

 

To answer DI requests effectively, the respondent must thoroughly understand the question.⁵ Very specific questions tend to be easily answerable, while others are more general or vague. In both instances, respondents need to ensure they understand the question. They can rephrase the question in their own words and say, “Let me make sure I understand. Do you mean….”, or they can use open ended questions (questions that cannot be answered with a yes or a no) to ask the requestor to provide more information. This avoids answering a question that wasn’t asked or intended or was poorly formulated.

 

Often, requestors don’t know how to ask a question that will provide the information they need. The hallmark of this type of question is that the requestor may use jargon inappropriately or words that don’t seem to make sense. Respondents can say, “Excuse me, I’m not sure I understood entirely. Can you rephrase the question?” or “Pardon me, but I didn’t quite understand the question. Can you tell me a little more about what you want to know and why?” That final word—WHY—provides the impetus for the requestor to provide necessary information.

 

Once the question has coalesced and both parties agree on its intent, the respondent can solicit important details from the requester and, if applicable, the patient, before delving into a search. At this point, the respondent needs to spend time actively listening to the requestor’s explanations.

 

This can be difficult if the requestor is long-winded, difficult to understand, or cognitively impaired, so it requires patience. Here’s a PRO TIP for listening: it’s called the traffic-light-rule.⁶ During the first 30 seconds (which seems like a short period of time, but is actually relatively long), the requestor’s “talking light” is green. Pharmacy staff should let them talk. In the next 30 seconds, the requestor’s light is yellow: pharmacy staff probably have enough information and should make note of comments or questions. After one minute, the requestor’s talking light is red: pharmacy staff should be comfortable stopping the requestor politely or asking questions.⁶

 

Before continuing, review the following DI requests. How would you proceed? Later  in this activity, we’ll provide a description of the ideal process.

 

Pharmacist DI request #1: TN, 35-year-old obese female (BMI = 32.4 kg/m²) with uncontrolled type 2 diabetes will start on an atypical antipsychotic today to manage schizophrenia. TN’s psychiatric nurse practitioner (NP) calls with questions about drug selection. The NP mentions that TN’s drug formulary lists aripiprazole, haloperidol, olanzapine, and quetiapine as tier 1 preferred options. The NP wants your opinion as to which atypical antipsychotic may be most appropriate to prescribe for TN. What do you suggest?

 

Pharmacist DI Request #2: You work at a tertiary care internal medicine center. MS, an 80-year-old female, was recently admitted to the medicine floor. She had fallen when she was trying to use the restroom at her nursing home and presented to the emergency department with a wrist fracture. She suffers from insomnia and other comorbidities. Her medication list includes lisinopril 20 mg daily, metformin 500 mg twice daily, rosuvastatin 20 mg daily, and lorazepam 0.5 mg PRN anxiety and sleep. The nursing home staff states that MS received more doses of lorazepam in recent weeks. The medical resident believes that the increased lorazepam use could have contributed to the fall and wants to know if trazodone would be a safer replacement for MS’s insomnia. How do you respond?

 

Technician DI Request #1: I left this medication in my bathroom for four days, and then I noticed it says, “Keep in the refrigerator.” My house is cold, and the bottle didn’t feel warm. Is this still good, and if it isn’t, what should I do?

 

Technician DI Request #2: My child is having trouble swallowing her medication and refuses to take it. Are there any easier ways I could give it to her?

 

Identify Critical Information

Although it may seem counterintuitive, beginning with the end in mind is critical and the person gathering information must determine the requestor’s preferred response format. This means asking how the requester wants to receive the response. The respondent will need to adjust the answer according to the requestor’s preferences. Some requestors will want to wait for an answer. If the information is to be communicated through email or an electronic medical record, respondents may use their organization’s required format (a SOAP note or similar formats; see Table 1), but formats used in medical records may not be the most efficient approach in person or over phone. In person or on the phone, respondents need to use a more conversational tone. Furthermore, the respondent will need to determine the requestor’s level of medical competency and tailor the response accordingly. If the requestor is a patient, it is more appropriate to use simple language than if a provider asked the same or  similar question. Respondents will have to evaluate these factors critically to provide a sound and comprehensive answer.⁷

Table 1. Formats for Communicating Critical Information^8,9

Communication Format	Parts of the format	Uses
SOAP	S: Subjective information This section includes descriptive information about a patient’s symptoms, feelings and experiences.   O: Objective information This section includes pertinent lab values, imaging, or diagnostic tests.   A: Assessment In this section the subjective and objective information are taken into consideration to make an assessment regarding the patient's disease states.   P: Plan/ Follow Up This section outlines a detailed plan regarding the patient's treatment and the follow-up and monitoring required.	This format is a widely-used written format in healthcare. It helps organize pertinent patient information and efficiently present an answer. This format is especially useful when the respondent must consider multiple pieces of information.
ISBAR	I: Introduction Introduction of the pharmacist and the respondent, and the pharmacist’s role and location.   S: Situation What are the current events regarding the patient?   B: Background What has happened in the past with the patient?   A: Assessment Identify the problem at hand and make assessments regarding the patient's disease state.   R: Recommendation Outline the next steps and your plan.	This format is beneficial for verbal communication. It helps the presenter explain the problem at hand and the solution in a time efficient way.
TITRS	T: Title Introduction of who you are and your purpose in helping the patient.   I: Introduction Present the patient and the problems that the patient needs help with.   T: Text State subjective and objective information that is necessary to support any recommendations.   R: Recommendation Outline the treatment plan in a clear, complete, and concise manner.   S: Signature Include name, title, and phone number.	This format is beneficial when a brief and concise formal consult is needed to communicate a progress note towards a medical team.

 

Assess the Urgency of the Response

While it is critical to provide an appropriate response for the question, doing so in a timely manner is just as critical. Asking the requestor is the simplest way to determine the expected response time. However, many times the requestor isn’t present or cannot be reached, and it is up to the respondent to determine which questions require immediate responses and which may not. Clinically critical topics include

• Medication safety: does the DI request ask if a certain therapy could cause or have caused harm to the patient?
• Time sensitivity of the treatment: how important is timeliness to the treatment and disease progression?
• How much of a concern is the problem to the requestor: does it seem that the requestor needs an immediate response?

 

Sometimes, respondents don’t know the answer to the question immediately.^10,11 Pharmacy staff will never be able to answer every question, but they can handle every question gracefully and provide a complete, accurate answer within a reasonable time. When they don’t know the whole answer, they should answer what they can immediately and tell the respondent that they need to do a little more research to answer the remainder. A PRO TIP is to tell the requestor when to expect an answer (and to be sure to follow through).^10-12

 

Obtain Sufficient Background Information

In simple words, this step is about getting to know the patient or problem or establishing a strong understanding of the patient’s relevant characteristics by obtaining background information. Since some patients have low health literacy, obtaining this information can be a challenge. However, narrowing the search to only include relevant information and filtering unnecessary information can make the process more efficient. This could be achieved by⁷

• Asking targeted questions to patients. For example, instead of asking patients if they take their medication regularly (a closed-ended question that can be answered with yes or no), asking when they last took their medications provides a more precise answer.
• Identifying avenues that can provide accurate information. For example, instead of asking patients what other medications they take, checking the local profile and/or contacting their community or specialty pharmacist to receive a medication list can be more accurate.
• Reviewing any available records like medical charts or dispensing records.

 

Identify Extraneous Information

Obtaining complete information is important but ensuring that the information is pertinent to the question being asked is just as important.

 

Many times, DI requests are in-depth and require researching two or more sources before arriving at an answer. While conducting this search, ensure that the sources are relevant to the problem at hand. For example, if a study suggests that a medication is contraindicated in a patient, determine if the patient’s characteristics are similar to the study’s population. Furthermore, extraneous information could come from data gathering as well. For example, a patient may have multiple diseases, but they may not all impact the problem at hand. Making this distinction is important to provide a thorough and accurate answer.⁷

 

Answers to Pause and Ponder

Pharmacist DI request #1: Haloperidol is not an atypical antipsychotic; therefore, it would be eliminated immediately and the remaining atypical antipsychotics would be reviewed as outlined below:

Screen Request	Pertinent patient information: past medical conditions (uncontrolled diabetes, schizophrenia). Medications on tier 1 of patient's formulary: quetiapine, olanzapine, haloperidol, aripiprazole.
Reformulate Request	This is a therapeutics drug information request because the provider is looking for the best medication to treat the patient's schizophrenia without adding any contraindications to the patient's current medication list or concomitant medical conditions.
Formulate Response	The provider made the request in writing, so a written response is most appropriate. The SBAR format would succinctly and effectively convey the message. First, we conducted a Google search and a tertiary source search (PubMed) including the pertinent patient information and request. Our search read "effects of antipsychotics on obesity and diabetes." Through this, we determined that some antipsychotics lead to changes in metabolic activity. Because the patient has diabetes that is exacerbated by weight gain, the best choice is an antipsychotic that does not have a significant effect on the metabolism. After conducting a more thorough primary source search on the metabolic effects of antipsychotics, we found that the best drug would be aripiprazole. Additionally, monitoring the BMI and efficacy would be appropriate.
Assess Understanding	Provide the response in a professional and timely manner. Document the request to display accountability and in case there is a similar question in the future. Follow up with the requestor to access the outcomes and ensure that there are no lingering questions or concerns.

 

Pharmacist DI request #2:  Off-label use of low-dose (25 to 100 mg) trazodone, a decades-old antidepressant with drowsiness as a side effect, is common.¹³ In fact, off-label usage for insomnia has surpassed its use for depression.¹⁴ The American Academy of Sleep Medicine does not recommend trazodone because of limited supporting data. A 2018 Cochrane review found equivocal evidence supporting its short-term use for insomnia, but little data on long‐term safety and efficacy exists.¹⁵ The Beers Criteria doesn’t highlight trazodone as a potentially inappropriate medication in older adults, not because of evidence demonstrating safety, but because of lack of studies demonstrating harm. However, a retrospective cohort study found low-dose trazodone was no safer with respect to fall-related injury risk than benzodiazepines among 15,582 nursing home residents aged 66 years and older. Future studies need to confirm trazodone’s safety with respect to other risks such as dependence, withdrawal, and cognitive impairment.¹⁶

 

Technician DI request #1:

It would depend on the medication. Some medications, like amoxicillin, are refrigerated to preserve the taste while most others, such as insulin, are refrigerated to preserve the compound. The technician should ask what medication the patient is referring to and then look up the specific storage requirements for that medication. Some places where this information is available include Drugs.com (https://www.drugs.com/medical-answers/drugs-that-require-cold-storage-166784/) and (https://www.iehp.org/en/members/helpful-information-and-resources?target=emergency-safety). If the medication is not listed in these resources or the medication’s stability has possibly been compromised (such as exposure to extreme heat), the technician should consult the pharmacist.

 

Technician DI request #2:

It would vary depending on the medication. Some medications have specific coating that needs to stay intact to ensure proper drug delivery, and such medications should not be crushed. Other medications do not have such restrictions and can be crushed, split in half, sprinkled in foods like applesauce, or have a liquid formulation that can be considered as an alternative with a doctor’s approval. The technicians should ask, “What medication is your child taking so that I can look it up?” Information regarding which medications can be crushed can be found in the following website https://pharmacist.therapeuticresearch.com/Content/Segments/PRL/2014/Aug/Meds-That-Should-Not-Be-Crushed-7309. If the medication or the specific dosage form is not available on the list, the technician should ask the pharmacist to review the medication.

 

Recognize when to ask for additional support or information. While drug information requests can be challenging, involving other healthcare professionals to hear about their experiences with similar clinical situations can offer a new perspective. Some benefits of consulting with experts include formulating a patient-specific answer to the question whereas a study may be irrelevant. When the request requires analysis beyond the scope of a drug information search, it is appropriate to reach out to a professional. While this may take additional time, arriving at the correct answer is more important than to harm the patient unknowingly. And a PRO TIP is that if reaching out will mean you cannot answer the question in the time frame promised, contact the requestor and say you need more time and why.

 

REFORMULATING THE REQUEST 

To ensure the core request is clear, the respondent will need to ask many questions, especially if requesters don’t know what question they need to ask. Before starting to research the answer, respondents need to gather information needed from the requestor. In addition, it’s prudent to identify resources the requestor has already consulted (and their reliability in case information needs to be corrected).

 

Categorize the Request

Requests can be based on complex patient specific cases, for educational purposes, or geared towards a decision-making process in medication therapy for a specific patient demographic. To fully optimize patient care and provide evidence-based recommendations, it is helpful to ask specific questions and consider all factors pertinent to the specific DI request. Categorizing the request can help stay on track, address all concerns, and point the respondent to the appropriate resources. Table 2 lists common categories and the questions that can clarify the request.

 

Table 2. Common DI Categories and Related Questions¹

DI Category	Related Questions
Allergy/Cross-reactivity	Does the patient have any documented allergies? What caused or is suspected to have caused the allergic reaction? When did the patient take the medication, and when did the reaction occur? What type of allergic reaction occurred? Is this a class or drug specific effect?
Alternative, or Complementary Medicine	Where did the patient obtain the medication? Why is the requestor taking or interested in taking the medication? What other medications or treatments are available?
ADR/Safety	What are the possible side effects? What monitoring parameters need to be considered?
Compatibility (Y-site, syringe, IV)	What solution will medication be used in? If applicable, how will the medications be administered?
Dosage/Route/Administration	What is the route of administration? What is the recommended therapeutic dose for pediatrics, adults, and geriatrics? How should the medication be taken (with/without food, with water, etc)
Drug Identification	What was the source of the medication (e.g., domestic or foreign)? What is the generic and brand name? Where did the medication come from?
Ingredients/Stability	What physical conditions exist? (Temperature, light protectant, storage duration, diluents) Are there IV admixture compatibility/non-admixture stability data available?
Interactions	What are the possible interactions between: ●      Drug-drug ●      Drug-food ●      Drug-lab ●      Drug allergy
Kinetics	What is the onset/half-life/duration? What are the serum levels? Is dialysis a consideration? What is the medication’s bioavailability?
Pharmacoeconomics	Are there other competitors on the market? Are there cheaper alternatives with the same therapeutic effects? What is the AWP pricing?
Pharmaceutics	What is the drug route of administration and drug dosage? What patient factors will affect the drug? Age, weight, gender, organ function, current medications
Pharmacology	What factors will affect drug metabolism and bioavailability?
Pregnancy/Lactation	What health conditions does the mother have? What medications is the mother currently taking? What is the current trimester? How long has the mother been taking the medication or expected to take this medication? Will the drug be present in breast milk? How will the drug affect the infant? What is the infant's age? What health conditions do the mother and infant have? Was the infant a full term or premature delivery?
Vaccinations	Is the vaccination appropriate for the patient? What are some side effects to monitor? When should the patient get the vaccination?
Therapeutics	What is the desired effect? Is the goal cure or prophylaxis? What previous medications and doses has the patient used? Is this medication being used for an FDA approved or off-label use?
Toxicity	What are possible sequelae? What management strategies are available?

Abbreviations: ADR = adverse drug reaction; AWP = Average Wholesale Price; FDA = Food Drug Administration; IV = Intravenous

 

Finding Reliable Sources

Being able to locate sources efficiently and correctly for a DI request is very important. Three main types of sources are available: primary, secondary, and tertiary.

• A primary source is any original research found in journals. Examples of primary sources are trial results found in the New England Journal of Medicine (NEJM) or similar journals in which researchers use a trial design to answer a specific question. (Note that NEJM and similar journals also publish secondary source materials, too.) This is the strongest Limitations of using this evidence include lack of access to journals that require paid subscriptions and lack of good search skills to find relevant papers.
• Secondary sources analyze, interpret, present, or restate information from primary sources. Textbooks, books and review articles, commentaries, guidelines, and Medline are examples of secondary sources.
• Tertiary sources compile information from other sources and organize it. Lexicomp , Micromedex, and DynaMed are common tertiary sources for DI requests as they use information from Food and Drug Administration-approved complete prescribing information (package inserts) and clinical studies. One limitation to be aware of is these sources are not updated rapidly therefore the information could be old and outdated.

 

Determine the Best Source

When evaluating DI requests, in most cases the best course of action is to start with tertiary sources, such as textbooks or DI databases, when possible.¹ These platforms provide a starting point and often suggest a basic idea for the answer. For many DI requests such as dosage, half-life, or adverse effects, the tertiary resource may provide a sound answer. Requests asking to compare two medications’ efficacy or assess the appropriateness of an uncommon or off-label medication use may require further research. Databases that identify off-label use include Micromedex.  In such cases, a primary source is the best resource. References sections of databases like DynaMed and Micromedex can be a great start for finding appropriate primary sources. Using search engines such as MEDLINE, PubMed or Google Scholar (scholargoogle.com) can provide access to relevant primary literature as well.¹ Reviewing two to three sources is good practice for most drug information requests. Respondents must determine the relevance of the studies by evaluating if the trial size was large enough to be statistically reliable, if its findings were clinically significant, and if the patient population is similar to the patient.

 

Use General Search Engines Appropriately

Using general search engines like Google, and Microsoft Edge can be an acceptable starting point for a search. A metasearch engine is usually better. A metasearch engine is a platform that aggregates the results from multiple search engines and organizes them based on their relevance. Examples of metasearch engines include Dogpile, ixquick, and Metacrawler which aggregate information from sources like Google and Yahoo as well as videos posted on various platforms.

Researchers must consider the following factors when determining a source’s credibility¹⁷:

• Is the information’s original source listed and reliable?
• Does the funding for the site come from a sound source such as a university (.edu), an established patient advocacy organization or a professional society (.org), or a government-funded organization (.gov)?
• How is the information presented and how is it supported?
• Who wrote the article on the webpage? Is the author a credible healthcare provider or a journalist writing about a medical topic?
• Is the information updated and verifiable with other sources?

 

Table 3 matches types of information and reliable sources to find information.

 

Table 3. Finding Reliable Sources for Drug Information Requests

Type of Request		Source
Alternative or Complementary medicine		Natural Medicine Comprehensive Database
ADR/Safety		Lexicomp*, UpToDate*, Micromedex*, Package Inserts
Compatibility		FDA-approved prescribing information, Trissel’s Stability of Compounded Formulations*
Dosage/Route/Administration		Complete prescribing information, Lexicomp*, Micromedex*, etc.
Drug Identification		Lexicomp* (Drug I.D) Drugs.com, WebMD Pill identifier, RxResouce.org (pill identification tool)
Ingredients/Stability		Complete prescribing information, Lexicomp*
Interactions	CYP	Complete prescribing information, Lexicomp*
	HIV	HIV Drug Interactions Clinicalinfo Drug Database
Kinetics		Complete prescribing information, Lexicomp*
Pharmacoeconomics		Studies published in pharmacoeconomics journals
Pharmaceutics		PubMed* and primary sources
Pharmacology		Lexicomp*, Micromedex* and could require further research with primary sources
Pregnancy/Lactation		LactMed
Regulatory		The Pharmacy Practice Act, Pharmacist's Manual
Therapeutics		Dynamed*, UpToDate*, DiPiro’s textbook
Toxicity		MSDS, PubChem, Micromedex*
Vaccinations		CDC vaccine and immunization schedule, Lexicomp
Veterinary Information		Plumb’s Veterinary Drug Handbook

*=sources requiring a subscription or payment

Abbreviations: ADR = Adverse Drug Reactions; CDC = Center for Disease Control and Prevention; CYP = Cytochrome P450; FDA = Food and Drug Administration; MSDS = Material Safety Data Sheet;  HIV = Human immunodeficiency virus

 

Another relevant option that many healthcare professionals are considering for answering drug information requests is artificial intelligence (AI) platforms such as ChatGPT. While these seem to be able to provide responses that are based on data and research, the issue that users run into is the AI is not able to approach/appraise situations critically. While AI can provide information that may be or seem accurate, it is cannot assess the data that it uses to ensure that it is relevant to the situation or specific patient. Additionally, AI doesn’t cite its sources, meaning that it can be difficult to assess the appropriateness of the source. Last, it is important to realize that AI has sometimes provided wrong answers that could lead to patient harm and therefore need to be checked against reliable sources.

 

Figure 2 summarizes a typical drug information process.

Figure 2. The Drug Information Process

FORMULATE THE RESPONSE 

Verbal responses tend to be easier for most people than written responses, but respondents should document every request. One simple rule should guide the response: Use principles of clear communication. Clear communication reduces risks of misinterpretation and increases the requestor’s understanding. It optimizes patient care. Clear, concise sentences that are short (fewer than 25 to 32 words) and straightforward create an ideal response.¹⁸ It is best to be comprehensive with adequate information and complete sentences that leave no confusion. Each statement should have a clear purpose with no extraneous information or unnecessary words. Respondents must paraphrase important information from accumulated data taken from reliable sources, while avoiding copying and pasting from other outside sources. The response must focus on the audience (the requestor) and the requestor’s background, remembering that different types of professionals have different education and focus.¹⁸

 

Organize and Evaluate Information 

Organizing information makes research and presentation straightforward and simple for the audience to understand quickly. Templates are available to help keep information organized and formulated, but they have advantages and disadvantages.

 

• Pros: Templates provide consistency that makes it easier for requesters to follow. (Saving your responses to DI requests is a PRO TIP, discussed in the SIDEBAR) Templates also provide an idea about how the completed presentation will look and reduce the time associated with creating the response. Some organizations provide templates for their employees. Lacking an approved template, respondents can find customizable templates from their workplace or university. Example templates found in the appendices show how useful templates can be. Templates can act as checklists to remember what should be included in a drug information response.
• Cons: Many templates limit the amount of allowable customization or text, and respondents must be knowledgeable about editing templates. Templates may also limit the approach to the topic and limit the information to standard or predictable fields; this is a problem when the question is unique or unusual. It is important to understand that templates are guides in answering requests and are not restrictions.

 

Templates that can be used while answering drug information questions have different strengths and limitations. The choice of template can be dependent on the pharmacist’s preference as well as the type of drug information request. We reviewed the templates in the addendum and assessed their utility. Take a minute to look at them. How do your assessments compare to ours?

 

Template 1 located in Appendix 1:

Pros: Extensive prompts for what should be included in a drug information response. This format is very detailed which could be useful for less experienced users.

Cons: Could be too detailed to be used for a wide range of requests. It lacks space, so users will have to use it against a document that they have already created.

 

Template 2 located in Appendix 2:

Pros: This format displays the drug information request topic quickly, organizes patient information and the response, and includes references to use for evidence-based literature support. It is broad enough to be used for multiple types of requests. It could be especially helpful for pharmacists who receive a wide variety of requests as it allows them to focus and tailor responses appropriately.

Cons: Insufficient prompts or guidance responders, making it more suitable for experienced pharmacy staff. This would too broad for beginners or pharmacy students because it does not outline various aspects of drug information responses.

 

SIDEBAR: Saving FAQs for Future Use: The FAQ File^19,20

Pharmacy staff often notice that they receive the same or similar questions repeatedly. Each time a requestor asks the question, the respondent must answer again. When employees in the pharmacy discuss questions they receive, they may find that although each of them has only answered a specific question once or twice, collectively they are answering the same question often. A frequently asked question (FAQ) file has numerous advantages. It can

• Save time for everyone including the requestor
• Standardize the answer so that it is consistent each time staff answer the specific question
• Provide the answer in clear language
• Create an answer that technicians and students can give to requestors without asking the pharmacist to intervene
• Refer requestors to web sites or documents for additional information

 

To develop a reliable FAQ file, pharmacy staff should take several steps:

• Identify the questions that are asked frequently.
• Develop a simple format for all FAQs. Usually, the actual question appears at the top of the documents, with the answer below.
• Start small and ask one employee to draft the FAQ.
• Have two or three people review the FAQ, including a pharmacist and at least one or two support personnel. Encourage reviewers to provide constructive criticism. If the FAQ usually comes from a colleague or patient, involve colleagues and patients in the review.
• A good process for reviewing FAQs is to ask a reviewer to read to a certain point and then stop. The project coordinator should ask, “Can you tell me in your own words what you just read?” If the reviewer explains and the information is incorrect, the project coordinator should not correct the reviewer; rather, the project coordinator should make a note that the section needs work and why.
• The project reviewer should ask additional, open-ended questions including
  • What’s your general reaction to this draft FAQ?
  • What did you like about this draft FAQ?
  • What did you dislike about this draft FAQ?
  • Is anything in this draft FAQ confusing?
  • What would you do if you got this document?
  • What do you think the writer was trying to do with this document?
  • And here’s a PRO TIP: Often, people will not answer directly because they do not want to appear uneducated or picky. A way to circumvent this issue is to ask, “Thinking of other people you know who might get this document…”
    • What about the document might work well for them?
    • What about the document might cause them problems?
  • Once the FAQ completes the process and is ready for “prime time,” save it in a format that cannot be edited (i.e. a PDF that is locked for editing) and upload it to a shared file or drive where all employees can access the document and print or clip it to an email when needed.

 

Finally, drugs and drug information change over time. Organizations that use FAQ files must schedule routine review (at least annually and more often if necessary) to ensure that the content in FAQ files remains current and correct.

 

Proofing and Editing Drafts 

Proofing and editing written drafts entails first fact-checking the narrative and the sources used, and then reviewing the text to ensure it is clear and professional. The respondent must re-assess and re-evaluate each source and the information gathered. Asking other healthcare professionals who have expertise to contribute to or proofread the draft is smart. Collaborating with colleagues can be beneficial, especially in healthcare. The recent emphasis on interdisciplinary approaches reminds us that healthcare professionals from multiple backgrounds need to collaborate and exchange information more often than not. Colleagues can also help confirm or modify any information, while also giving feedback to learn how to better future drug information requests.

Once the data is confirmed as accurate, the last step is to double check for spelling and grammar errors and ensure the response is clear and concise. A skilled pharmacy technician is often an exceptional collaborator in this step.

 

Document, Document, Document

Documentation is helpful when pharmacy employees have to refer back to that specific topic on a similar drug information question or when colleagues have a similar request in the future. Documenting the response will aid as a reference point and could help clinicians in the future make decisions regarding patient care.²¹ Documentation will also display accountability and the respondent’s value to the organization and the interdisciplinary team. Many healthcare organizations have policies and procedures for documenting DI requests, and all staff should follow them if they exist.

 

ASSESS REQUESTOR’S UNDERSTANDING AND SATISFACTION 

Following up after responding to a DI request is a professional action. The respondent should follow up with the requestor in a timely manner and assess the outcomes. If the requestor is not completely satisfied, the respondent can adjust the answer and recommendations appropriately.⁷ Follow-up will also reveal if the requestor has implemented the recommendation (and if it worked), provide feedback for potential modifications in future DI requests, and show professionalism and dedication to patient care. A PRO TIP is to document the follow-up and outcomes.

 

CONCLUSION

Pharmacy teams have serious responsibilities related to DI requests, which can cover a broad spectrum of topics and specialties. Pharmacists, pharmacy technicians, and pharmacy students should use a methodical approach, followed by documentation. As the ever-changing landscape of healthcare, medicine, and technology continues to advance, the providing drug information will remain an integral part of the pharmacist’s responsibilities.

 

Table 4 provides additional resources.

 

Table 4. Additional Resources

Systematic Approach to Answering Drug Information Requests   This resource helps characterize the various types of drug information requests	https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/preceptor-toolkit/sicp-busy-day-systematic-approach-answering-drug-info-requests.ashx?la=en&hash=7C8B36648FAB999DE761D3AE37BFE48A847B8551
7 Tips on Improving Communication in Your Pharmacy   This resource provides guidance on how best to speak with patients	https://www.pbahealth.com/elements/7-tips-on-improving-communication-in-your-pharmacy/
Formulating an Effective Response: A Structured Approach   This resource provides strategies to answer formulated drug information requests.	https://accesspharmacy.mhmedical.com/content.aspx?bookid=2275&sectionid=177197497 :
ASHP Guidelines on the Pharmacist’s Role in Providing Drug Information   This resource provides suggestions on how to answer a formulated drug information request.	https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacists-role-providing-drug-information.pdf
How To Evaluate Health Information on the Internet: Questions and Answers   This resource provides approaches on how to find credible sources to answer drug information requests.	https://ods.od.nih.gov/HealthInformation/How_To_Evaluate_Health_Information_on_the_Internet_Questions_and_Answers.aspx

 

 

Templates:

Requirements checklist for drug information Response1 - UBC Blogs. Accessed July 3, 2023. https://blogs.ubc.ca/oeetoolbox/files/2019/01/Requirements-Checklist-for-Drug-Information-Response.pdf.

Drug Information Request and Response Form.; 2017. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/DIR-Example.pdf

PHRM Handbook. Accessed July 3, 2023.

https://blogs.ubc.ca/oeetoolbox/files/2019/01/Drug-Information-Request-and-Response-Fillable-Form-.pdf

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