Ten Tips Palliative Care Pharmacists Want the Palliative Care Team to Know When Caring for Patients

Abstract

As palliative care (PC) moves upstream in the course of serious illness and the development of drugs and their indications rapidly expand, PC providers must understand common drug indications and adverse effects to ensure safe and effective prescribing. Pharmacists, experts in the nuances of medication management, are valuable resources and colleagues for PC providers. This article will offer PC providers 10 useful clinical pharmacy tips that PC pharmacists think all PC providers should know for safe and effective symptom management. Close collaboration with or addition of a trained pharmacist to your PC team can improve clinical care for all PC patients.

Introduction

Pharmacists possess a wealth of knowledge about pharmacology and the clinical application of pharmacotherapy and can share that knowledge with care teams and the patients they care for across clinical settings. Pharmacists have unique training in the pharmacology and nuances of medications, helping guide therapeutic decision making and ensuring safe and effective use of pharmaceuticals. The American Society of Health Systems Pharmacy Guideline on the Pharmacist's Role in Palliative and Hospice Care¹ outlines the essential and desired roles for the pharmacist in the palliative care (PC) and hospice setting. One of the key roles includes optimizing symptom management for PC patients through the expert provision of evidence-based, patient-centered medication therapy and serving as an authoritative resource on the optimal use of medications in symptom management and PC.¹ While more pharmacists are receiving specialized training in PC, this highly specialized level of medication review and team support is not a resource that all teams can access.

As the number of drugs and indications for their use expands rapidly and as many drugs are used effectively off-label as well, it is difficult for practicing clinicians to keep up. As PC is moving upstream in serious illness, PC providers need to understand a wider array of drug indications and side effects. We present here a list of 10 tips that will help PC clinicians to manage commonly encountered symptoms. These tips were chosen by specialty-trained and experienced PC pharmacists from different practice sites across the United States. This information is applicable to patients receiving PC in any setting, and general pharmacologic principles can be applied to any patient being treated with the medications being discussed. We hope these tips will provide clarity around commonly asked pharmacy questions and provide some insight into the clinical expertise of your pharmacy colleagues.

Tip 1: Fentanyl is a tricky medication to use due to the variable pharmacokinetics of each of its different formulations and the many available methods and charts for conversion.

Fentanyl is often used inappropriately.^2–6 All fentanyl formulations except injectable fentanyl require patients to be opioid tolerant.⁷ Transmucosal immediate-release fentanyl (TIRF) formulations have a quick onset of action and are indicated only for breakthrough cancer pain via the TIRF Risk Evaluation and Mitigation Strategy (REMS, www.TIRFREMSaccess.com). TIRF formulations are not interchangeable on a microgram to microgram basis.

Transdermal fentanyl is FDA-approved for opioid-tolerant patients with severe pain requiring daily, around-the-clock chronic opioids. However, patients with cachexia display impaired absorption of transdermal fentanyl, and recent studies indicate patients with albumin levels <2.5 g/dL may experience decreased analgesic effectiveness when converted to transdermal fentanyl.^7,8 Heat may increase absorption of transdermal fentanyl, making it a risky choice for patients with fevers. Opioid conversion to transdermal fentanyl can be challenging due to multiple conversion charts and formulas. The FDA-approved label for transdermal fentanyl provides a conservative dose conversion chart, which may result in uncontrolled pain and/or withdrawal symptoms. Alternatively, postmarketing studies in patients with cancer suggest 2 to 2.5 mg of oral morphine per day is approximately equianalgesic to 1 mcg/h of transdermal fentanyl.^9,10 Of note, the 12 mcg/hour transdermal fentanyl patch was approved by the FDA in an effort to provide flexibility when titrating doses, not as a starting dose.

Transdermal and continuous infusion fentanyl conversions require consideration of timing to design effective and safe analgesic regimens. The onset of effect for transdermal fentanyl is 12–24 hours with peak plasma concentrations between 24 and 36 hours. Fentanyl is highly lipophilic, and equilibrium must be achieved between plasma and tissues, including fat and skeletal muscle, whether it is given as a continuous infusion or via the transdermal route. Steady-state levels with transdermal fentanyl are not reached until three to six days after patch initiation. Therefore, transdermal fentanyl is not a safe or effective therapeutic choice for a patient with unstable, changing pain. When stopping transdermal fentanyl, the average elimination half-life is 20 to 27 hours due to ongoing absorption from a subcutaneous depot in addition to the tissue reservoir of fentanyl. In contrast, the half-life when stopping a continuous infusion is 9 to 16 hours.¹¹

Tip 2: Drug-induced QT interval prolongation is dose and route related and uncommon at doses typically used in PC; QT interval prolongation is associated with an increased risk of Torsade de Pointes (TdP) and can progress to ventricular fibrillation and sudden cardiac death.

It has been shown that many PC patients, at baseline, have a prolonged QTc (interval between the start of the Q wave and end of the T wave on electrocardiogram, corrected for heart rate), but that severe prolongation is rare.¹² There is a two- to threefold increased risk of TdP when QTc >500 milliseconds (ms) or with a change of greater than 60 ms, although there is no threshold where TdP is likely to occur. Predictors of QT prolongation include use of QTc-prolonging medications, hypokalemia, elevated serum creatinine, female gender, structural heart disease, advanced age, prolonged baseline QTc, bradycardia, and drug interactions.¹³ Always consider interactions with supplements and herbals such as grapefruit juice, which may increase risk due to inhibition of the cytochrome P450 system.

When considering a potentially QTc-prolonging medication, implement the lowest effective dose and administer orally whenever possible. Dose-dependent risk is associated with tricyclic antidepressants, chlorpromazine at doses >100 mg, and ondansetron at one to two hours after intravenous administration.¹⁴ Intravenous administration of haloperidol has as much as a twofold greater risk of QTc prolongation than does PO administration and higher risk is associated with daily doses of greater than 15 mg.¹⁴ QTc prolongation is rare with atypical antipsychotics, with virtually no QTc prolongation from aripiprazole.¹⁴ One open-label randomized study found a fourfold increased risk with PO haloperidol versus olanzapine.¹⁵ Commonly used doses of metoclopramide for motility are not associated with QTc prolongation nor are sertraline, paroxetine, and duloxetine.¹⁴ Mirtazapine and trazodone have a low-risk profile at therapeutic dosing. Methadone has been associated with QTc prolongation and TdP in very high doses (>100 mg/day), with interacting medications, or when other risk factors are present.¹⁶ Exercise caution and assess risk factors as described above, based on the clinical situation.

Tip 3: There are many corticosteroids and choice of agent should be based on the pharmacology of the individual agent, with dexamethasone, the preferred drug in the management of many PC patients for its relative potency and lack of mineralocorticoid activity.

Corticosteroids (also referred to as glucocorticoids or steroids) are among the most commonly used medications in hospice and PC. Indications include pain (including metastatic bone pain), anorexia, cachexia, fatigue, nausea and vomiting, depression, brain metastases, hypercalcemia, malignant bowel obstruction, spinal cord compression, superior vena cava syndrome, and more. Steroids modulate proinflammatory mediators, reduce peritumor edema, and alter adrenergic activity in the dorsal horn (lessening fatigue).¹⁷

There is no clear evidence to support selecting one steroid over another, aside from differences in duration of action and glucocorticoid (anti-inflammatory) and mineralocorticoid activity (sodium and fluid retention). See Table 1 for characteristics of individual steroids.¹⁸ Given its high glucocorticoid potency and low mineralocorticoid propensity, dexamethasone is commonly selected in PC. Doses vary according to data, expert opinion, and patient tolerability, but a typical dexamethasone dose is 8 mg per day. This may be given as a single dose, but is more commonly administered as 4 mg twice daily (with breakfast and lunch, to avoid causing insomnia). Conveniently, dexamethasone is available as a 1 mg/mL oral solution for patients who have difficulty swallowing tablets or capsules.

Table 1.

Comparable Steroid Dosing and Relative Mineralocorticoid Activity

Steroid	Comparable dose (mg)	Relative mineralocorticoid activity
Cortisol	20	1
Prednisone	5	0.8
Methylprednisolone	4	0.5
Dexamethasone	0.75	0

Adapted from Becker.¹⁸

Acute adverse effects associated with corticosteroids include increased risk of infection (including thrush), edema, dyspepsia and gastrointestinal (GI) ulceration, glucose intolerance, insomnia, delirium, and anxiety. Longer courses of therapy may cause steroid facies (moon-like), fat redistribution (buffalo hump), adrenal suppression, skin fragility, impaired wound healing, proximal muscle weakness, and osteoporosis. Short-term use of corticosteroids does not warrant GI prophylaxis with proton pump inhibitors unless steroids are coprescribed with nonsteroidal anti-inflammatory drugs (NSAIDs).¹⁹ If therapy persists longer than two weeks, it is advised that the steroid dose be tapered down when discontinuing therapy.

Tip 4: Opioid selection should be based on the pharmacokinetics of the individual drug, with attention paid to onset, formulation, half-life, and time to reach steady state levels, particularly for drugs such as methadone and fentanyl.

Immediate release morphine, oxycodone, hydromorphone, and fentanyl formulations have similar oral and, except oxycodone, intravenous (IV) pharmacokinetic properties. IV time to peak concentration is ∼10 minutes and oral peaks at one hour; the average half-life is four hours (accounting for active metabolites). Based on five half-lives, these drugs ultimately reach steady state concentrations in about 20 hours.

Steady state concentration is important for clinicians as it indicates a safe time to reassess therapy and titrate the dose if needed, and are particularly important with longer-acting formulations.²⁰ In the case of sustained release morphine, generally, steady state is reached in two to three days.^21,22 Controlled release oxycodone achieves steady state concentrations in one to two days.²³ Serum concentrations for transdermal fentanyl gradually increase following initial patch application generally leveling off between 12 and 24 hours and remain relatively constant with some fluctuation for the remainder of the 72-hour application period, reaching steady state serum concentrations by the end of the second 72-hour period.²⁴ Pharmacokinetic studies of transdermal fentanyl reveal peak levels between 36 and 48 hours.²⁴ Accordingly, the clinician may choose to start with a more conservative dose than what was determined by the equianalgesic calculation. If warranted by the continued “as needed” opioid use, fentanyl may be titrated up to the intended transdermal fentanyl dose after 48 hours.

Methadone's unique plasma distribution phase is about 3 to 4 hours with a long and variable elimination half-life of 15 to 60 hours, with reports as long as 150 hours.²⁵ For analgesia, methadone should be dosed between every 6 to 12 hours to account for the plasma distribution phase and methadone should not be titrated any sooner than four to seven days. Furthermore, methadone should be initiated and monitored by clinicians who are familiar with and appreciate its unique pharmacology beyond just its half-life.

Tip 5: When patients report adverse effects to a medication that seem unexpected, it is important to remember uncommon but potential side effects of palliative drugs, such as headaches and constipation with ondansetron, lower extremity swelling with gabapentin, and long-term side effects of opioids, including immune system compromise and hormonal shifts.

Rarely do medications exist without side effects. In all healthcare settings, including PC, medications are utilized if the “efficacy to adverse effects” ratio is high. More common in PC is the off-label use of medications, often at doses lower than the FDA approved indications. PC providers use medications often thought of as benign although side effects can occur. Table 2 relates medications commonly used in PC and their nonclassic, potential side effects.²⁶ Understanding these side effects should be considered before selecting therapy and while monitoring patients on these agents.

Table 2.

Some Commonly Used Medications with “Secret Side Effects” ²⁵

Medication	Secret side effect (incidence if known)
Ondansetron	Headache (9–27%), constipation (6–11%)
Metoclopramide	Restlessness (10%), increased incidence of diarrhea
Tramadol	Hypoglycemia
Gabapentin	Peripheral edema (8%)
Scopolamine patch	Anticholinergic, notably sedation, dizziness, constipation delirium
Promethazine	Anticholinergic notably sedation, dizziness, constipation
TCAs	Anticholinergic (dry mouth, constipation)
Fleet's enema	Hyperphosphatemia (93–96%)
Lactulose	Flatulence (20%), abdominal pain (20%), eructation (20%)
Olanzapine	Orthostatic hypotension (3– ≥20%)
Clonidine	Hypotension, bradycardia, drowsiness (2–38%), headache (1–29%), dizziness, 4–16%; skin rash (15–50%), xerostomia (≤40%)
Opioids	Long-term side effects: immunosuppression, hormonal/endocrine dysfunction

Tip 6: Since refractory constipation is very challenging to manage, it is essential to understand the onset and efficacy of commonly used agents; nontraditional alternative options, such as “Vaseline balls,” can be considered as well.

Constipation is defined as a reduction in the frequency of bowel movements and/or the need to strain due to hard stools.²⁷ Patients with advanced illness frequently experience constipation due to their disease process, altered dietary habits, reduced physical activity, and as a side effect of medications. Management of opioid-induced constipation is commonly achieved with a stimulant laxative (senna or bisacodyl) or an osmotic laxative (saline laxatives, sugars, sugar alcohols, or polyethylene glycols). The onset of traditional laxatives at standard dosing can range from 30 minutes to 6 hours with magnesium hydroxide, 6 to 12 hours with senna, and as long as 24–48 hours with lactulose or polyethylene glycol. Importantly, recent research has shown that senna plus docusate is inferior to senna alone in patients with cancer or advanced illness.²⁸ New agents introduced to the market include lubiprostone (a chloride channel activator), linaclotide (guanylate cyclase C agonist), and several peripherally active mu-opioid receptor antagonists (e.g., naloxegol and methylnaltrexone).²⁹ With a number needed to treat to achieve the FDA-determined therapeutic endpoint of 3–13 and a monthly cost of $300–$1,500, newer agents are generally not considered first-line options.

Administration of laxatives by mouth as well as enemas or suppositories per rectum may be necessary to provide effective relief. If fecal impaction develops, manual disimpaction followed by an enema is a commonly used approach. This can be generally uncomfortable, and the FDA has issued a warning about overuse of sodium phosphate products due to dehydration and electrolyte imbalance.³⁰ One home remedy commonly used to prevent constipation is “frozen Vaseline balls.” A Vaseline ball is a solid formulation of mineral oil making it less likely to be aspirated. Vaseline balls are home-prepared pea-sized balls of chilled Vaseline, rolled in confectioner's sugar. The patient swallows two to three balls several times a day. A survey of 353 hospice professionals showed that over 2/3 of respondents were familiar with the use of Vaseline balls, and 87% thought they were effective or very effective in producing laxation.³¹

Tip 7: Immunotherapy drugs (often ending in -mab) and oral oncology agents (often ending in -nib), while not chemotherapy, can cause generally manageable adverse effects such as rashes, diarrhea, or pain flare, but may also interact with medications such as H2-receptor blockers and proton pump inhibitors that patients use for chronic or other medication-induced symptoms.

Adverse effects from immunotherapy may occur at any point but are most common during the first 8 to 12 weeks of therapy. Skin-related toxicities (rash, pruritus) are the most common side effects of immune checkpoint inhibitors (e.g., ipilimumab, pembrolizumab). Grade 1–3 (mild to moderately severe) skin adverse effects can be managed with emollients, antihistamines, and topical steroids. GI toxicity, including diarrhea and colitis, is common with ipilimumab. Grade 1–2 (mild to moderate) diarrhea can be managed with loperamide and electrolytes, but persistent grade 2, 3, or 4 diarrhea usually requires an immunotherapy break and treatment with high-dose corticosteroids. Refractory cases can be treated with infliximab.

Nivolumab and pembrolizumab most commonly cause immune-related arthritis that can be palliated with NSAIDs (cyclooxygenase [COX]-2 selective if thrombocytopenic) or nonacetylated salicylates like choline magnesium trisalicylate or salsalate. Moderate symptoms may require 10–20 mg/day of prednisolone and higher doses may be required for severe symptoms.³² Use of systemic corticosteroids is not absolutely contraindicated with immunotherapy, although may theoretically decrease its effectiveness. Due to unclear data on the impact of short term corticosteroid use on clinical outcomes during immunotherapy treatment, concomitant corticosteroid use should always be first discussed with the treating oncologist.^33–35

Oral tyrosine kinase inhibitors (TKIs—drugs often ending in–nib) can cause skin-related toxicities, diarrhea, changes in hair pigmentation, and neuropathy.³⁶ Importantly, many oral TKIs require an acidic environment for absorption. While data on clinical outcomes from this drug interaction are limited, proton pump inhibitor use may decrease progression-free and overall survival when used concomitantly with sunitinib or erlotinib.^37–39 If using an H2 receptor antagonist or oral antacid solution with oral TKIs, patients should take the H2 receptor antagonist at least two hours after oral chemotherapy to minimize the risk for interaction.

Tip 8: Data around the benefits of olanzapine (Zyprexa) to treat nausea, appetite, and insomnia are growing, but a broad adverse effect profile and relatively high cost limit widespread use.

Olanzapine is an atypical antipsychotic with a complex receptor-binding profile. It has an established role in the management of delirium and severe mental health disorders with growing data supporting its use in nausea and vomiting. Nausea and vomiting can lead to appetite and weight loss, decreased mood, and overall poorer outcomes. Although these disparate symptom clusters sometimes require management with several agents, one multimodal agent may be preferable. Olanzapine's affinity for the dopamine, histamine, muscarinic, and 5HT-3 (serotonin) receptors is largely responsible for its efficacy in the management of nausea/vomiting.⁴⁰ The data supporting use of olanzapine for nausea and vomiting in oncology have led the American Society of Clinical Oncology to add olanzapine to its antiemetic regimen for treatments involving highly emetogenic chemotherapy and for breakthrough nausea and vomiting.⁴¹ Retrospective and case report data also demonstrate that olanzapine is effective in treating nausea in PC patients.⁴² Clinical experience supports that olanzapine is effective for the relief of refractory nausea and vomiting.

The same complex receptor-binding profile is responsible for its many potential side effects, some of which can help treat concomitant symptoms. With strong affinity for the muscarinic and histaminergic receptor, olanzapine tends to be sedating, and as a result can help patients suffering with insomnia. Its broad effects on the serotonin, dopamine, adrenergic, histamine, and cholinergic receptors are thought to be the underlying mechanism for associated weight gain as well.⁴³ Finally, its effects on depression and anxiety likely stem from its affinity for the dopamine and serotonin receptors and potentially its gamma amino butyric acid (GABA) and benzodiazepine-like activity as well. Other common immediate side effects include dry mouth, constipation, orthostasis, and dose-dependent extrapyramidal symptoms. Longer term effects include glucose changes, hyperprolactinemia, and alterations in liver enzymes.⁴⁴ Oral olanzapine is more expensive than oral haloperidol or prochlorperazine, and its orally disintegrating formulation costs even more. Discontinuation of other antiemetics in favor of one medication may help justify the cost.

Tip 9: NSAIDs have the potential to improve somatic pain; through optimal patient selection, duration, dosage, consideration of COX-1 or COX-2-selectivity, and consideration of the overall risk-benefit profile, risks for cardiac events, and GI bleeding can be minimized.

NSAIDs are commonly used in palliative and end-of-life care as adjuvant analgesics and are often first-line therapy for cancer-related bone pain.^45,46 Recent data call this practice into question.⁴⁷ The National Comprehensive Cancer Network (NCCN) Adult Cancer Pain Guidelines caution against routine NSAID use given the potential for additive toxicities when NSAIDs and many chemotherapy agents are used together (e.g., thrombocytopenia, renal impairment, hepatotoxicity, and cardiovascular risk).⁴⁸ COX-type selectivity may alter relative bleeding risk or cardiovascular toxicity of the respective agent. COX-I isoenzyme selectivity, seen most strongly in ketorolac and indomethacin,⁴⁹ is generally associated with less cardiac risk, but an increased risk of GI bleeding. NSAIDs possessing higher selectivity for the COX-II isoenzyme (celecoxib, meloxicam, etodolac, and diclofenac) are associated with a lower risk of GI effects, but may still predispose patients, especially those with underlying risk (i.e., hypovolemia, diabetes, interstitial nephritis, or papillary necrosis) to the same nephrotoxicity as do traditional NSAIDs. Nonselective COX-I/COX-II inhibitors, including naproxen, ibuprofen, and nabumetone, among others, can confer both GI and cardiac risks.⁴⁹

Nonacetylated salicylates such as diflunisal and choline magnesium trisalicylate have minimal to no effect on platelet aggregation due to their thromboxane and prostaglandin sparing effects.^50,51 Analgesic and anti-inflammatory effects of these agents have been called into question, but efficacy has been exhibited in head to head studies with traditional NSAIDs.⁵² The exact pharmacologic mechanism of these agents in the inflammatory cascade remains unclear, but may be attributed to the antagonism of nuclear factor (NF)-κB and microglial nitrite secretion.⁵³

Recently, topical application of NSAIDs, such as ketoprofen gel, has become more commonplace in the treatment of small-joint osteoarthritis. The tolerability and adverse effect profile of this treatment modality mirrors placebo, potentially improving utility in the palliative or end-of-life patient.⁵⁴ All NSAIDs require judicious monitoring and careful consideration of additive drug-related adverse effects, especially renal and bleeding risk.

Tip 10: Benzodiazepines, both high risk and high benefit at the end of life, are utilized for the short-term treatment of anxiety and can be a helpful adjunct for dyspnea and insomnia.

Lorazepam is the most commonly used benzodiazepine in PC given its numerous administration options and lack of active metabolites. Alprazolam is frequently avoided due to its risk of abuse, accumulation, and confusion in frail patients and older adults. While benzodiazepines have many uses in PC, safer treatment alternatives, such as selective serotonin reuptake inhibitors, may be preferred when there is a longer prognosis. Concomitant evidence-based, nonpharmacologic strategies such as cognitive behavioral therapy^55,56 and music therapy⁵⁷ should be considered as first-line interventions. Provision of psychological support, attention to a patient's spiritual needs, and complementary treatments such as Reiki are also important tools when managing anxiety.

Since anxiety frequently co-occurs with acute dyspnea, it can be difficult to tease out the response to treatment. A systematic review calls into question the routine practice of treating dyspnea in the absence of anxiety with benzodiazepines.⁵⁸ Typical first-line therapy for dyspnea is an opioid; therefore, the potential risk for additive central nervous system and respiratory depression should be considered with concurrent administration.⁵⁹

Benzodiazepines, especially at low to moderate doses, may produce paradoxical agitation. In fact, benzodiazepine exposure represents a common underlying etiology for delirium. There is also the risk of abuse, correlated directly with faster and higher drug concentration peaks. A careful patient and family history of substance use disorder risk factors should be considered and a careful accounting of doses undertaken.

Benzodiazepines are frequently categorized by their length of activity, although elimination half-life (T1/2) may not translate into duration of effect (Table 3). A short-acting agent may result in anxiolytic gaps, while a long-acting agent increases the risk for drug accumulation and adverse effects. An easy to remember mnemonic is the short length of action (LOA) with Lorazepam, Oxazepam, and Alprazolam. In cases of hepatic compromise, the mnemonic LOT (lorazepam, oxazepam, temazepam) helps clinicians recall those benzodiazepines that do not undergo Phase 1 metabolism.

Table 3.

Pharmacodynamic and Pharmacokinetic Properties of Select Benzodiazepines

Drug	Elimination T_1/2 (hours)	Relative potency (mg)	Comments
Alprazolam	12–15	0.5	Risk of rebound anxiety; high abuse potential
Chlordiazepoxide	30–100	10	Active metabolite may accumulate
Clonazepam	30–40	0.25	CYP 3A4 substrate
Clorazepate	36–200	7.5	Prodrug of nordiazepam
Diazepam	20–80	5	Rapid redistribution, duration of action not represented by T_1/2
Lorazepam	10–14	1	Sublingual administration pharmacokinetics similar to oral administration
Oxazepam	5–15	15	Delayed peak serum concentrations
Temazepam	8–15	5	High variability in T_1/2

Table adapted from Dipiro (2014)⁶⁰ and Lexicomp.⁶¹

CYP, cytochrome P450.

Conclusion

There are important general principles that PC practitioners should recall when recommending medications for symptom management. It is not possible to predict exactly how any one patient will react to a medication, but a general understanding of the basic pharmacology and of nuances of the commonly used agents will help to achieve rapid and effective symptom control. The aforementioned tips are those our group of PC pharmacists and practitioners consider to be essential clinical pearls that all PC providers should be aware of to help provide safe and effective symptom management for their patients receiving PC.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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