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Focus on Anxiety, Agitation, and Terminal Restlessness in the Hospice Patient

January 17, 2022

This document is for informational and educational purposes only and is not a substitute for medical advice, diagnosis, or treatment provided by a qualified health care provider.  All information contained in this document is protected by copyright and remains the property of ProCare HospiceCare.  All rights reserved.


Anxiety is one of the most common symptoms for hospice patients. It has been reported within 20% to 50% of patients with advanced cancer. While the impact of anxiety is recognized, anxiety management in palliative care is a major challenge due to a variety of contributing factors. Timely identification, support, and treatment of anxiety are essential in patients with limited life expectancy. Anxiety management benefits from a multi-dimensional team approach. From physicians to nurses to social workers and spiritual care – all disciplines can play a role in helping alleviate anxiety. There are several etiologies behind anxiety in hospice patients – including metabolic causes, drug withdrawal, and adverse drug effects. Anxiety has cognitive, emotional, behavioral, and physical manifestations ranging from mild/occasional to a severe/constant state of anxiousness.


Non-pharmacological management of anxiety may include:

  • Deep breathing
  • Spiritual care
  • Supportive care (previously referred to as palliative care)
  • Complementary therapy (including mind-body techniques, music therapy, visual imagery, aromatherapy)

 

Benzodiazepines (including lorazepam or alprazolam) are considered the mainstay of therapy in the management of anxiety. Choice of benzodiazepines depends on the following patient-specific factors:

  • Duration of action
  • Desired onset of action
  • Route of administration available
  • Dosing schedules

 

Antidepressants are another frequently used class of medications to treat anxiety. Selective Serotonin Reuptake Inhibitors (SSRIs including escitalopram or sertraline) are a frequently used class. Even though they fall under the pharmacologic category "antidepressants", these medications can have a powerful effect on chronic anxiety. By regulating brain chemistry, these agents help further prevent episodes of anxiety and might help patients rely on benzodiazepines less. Since excessive use of benzodiazepines can cause sedation and affect valuable moments with a loved one nearing end of life, taking a preventative medication may be a better option. The limitation to the use of antidepressants for chronic anxiety at the end of life is that they need time to work, taking up to six weeks for full clinical effect. Some patients reaching the end of their lives might not have this much time and should rely solely on as- needed medications, such as benzodiazepines.


Agitation is a term that describes anxious, restless and unsettled behavior. It can be linked to emotional, physical, or spiritual distress. Terminal agitation refers to agitation that occurs in the last few days of life. Terminal agitation may also be described as terminal restlessness, terminal anguish, confusion at the end of life, or terminal delirium. These terms all have different meanings, but do overlap. Agitation can come on suddenly or gradually and often comes and goes. Signs and symptoms of terminal agitation can include any of the following: confusion, moaning, hallucinations, and sometimes angry and aggressive behavior. There can be many possible causes for agitation, including uncontrolled pain or discomfort, urinary retention, infection, sepsis, or organ failure.


Neuroleptics, also known as antipsychotic medications, are used to treat and manage symptoms of many psychiatric disorders. They fall into two classes: first-generation or "typical" antipsychotics, and second-generation or "atypical" antipsychotics. Haloperidol and Chlorpromazine are two first-generation antipsychotics used to treat agitation.


Second Generation (Atypical) Antipsychotics

Olanzapine (Zyprexa®)

  • Tablet, ODT (oral disintegrating tab)
  • 2.5-5 mg daily
  • Max/day: 20mg
  • May cause hyperglycemia
  • Anticholinergic effects

Quetiapine (Seroquel®)

  • Tablet, Tablet, XR
  • 25-50 mg Q8-12h
  • Max/day: 800mg
  • Preferred in Parkinson’s disease over other antipsychotics
  • Anticholinergic effects

Risperidone (Risperdal®)

  • Tablet, Solution, oral, ODT
  • 1-3 mg BID
  • Max/day: 16mg
  • Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression

When an individual is in the final days of life, terminal restlessness is often a common symptom. Definitions of terminal restlessness include the following: the thrashing or agitation that may occur in the last days of life. Frequently, it is associated with impaired consciousness, anxiety, and often, involuntary muscle twitching or jerks. Agitation and terminal restlessness often present together in hospice patients. It is estimated that 42% of all dying patients experience restlessness and agitation in the last 48 hours of life.


 The pharmacological involvement of terminal restlessness involves options such as: haloperidol, atypical antipsychotics like olanzapine, risperidone, and quetiapine, or benzodiazepines like lorazepam or midazolam may be appropriate. 


 For assistance in determining the best course of treatment for your patient’s specific symptoms, please contact a ProCare HospiceCare pharmacist for a symptom management consultation. We would be happy to assist.

 


Written by Jennifer Procaccino, PharmD



References

  1. Zweers D, de Graeff A, Duijn J, de Graaf E, Witteveen PO, Teunissen SCCM. Patients’ Needs Regarding Anxiety Management in Palliative Cancer Care: A Qualitative Study in a Hospice Setting. American Journal of Hospice and Palliative Medicine®. 2019;36(11):947-954. doi:10.1177/1049909119846844.
  2. Anxiety. Palliative Care Guideline Plus. Available from: https://book.pallcare.info/index.php?tid=47&searchstring=anxiety. Accessed on September 16, 2021.
  3. Stoklosa J, Patterson K, et al. Anxiety in Palliative Care- Causes and Diagnosis. Available from: https://www.mypcnow.org/fast-fact/anxiety-in-palliative-care-causes-and-diagnosis/
  4. National Cancer Institute. Adjustment to Cancer: Anxiety and Distress. Available from: https://www.cancer.gov/about-cancer/coping/feelings/anxiety-distress-hp-pdq. Accessed on September 16, 2021.
  5. Morrow A. Symptoms and Management of End-of-Life Anxiety. Very well health. Available from: https://www.verywellhealth.com/managing-anxiety-1132473Accessed on September 16, 2021.
  6. Buckley L. Case-based learning: anxiety disorders. The Pharmaceutical Journal. Available from: https://pharmaceutical-journal.com/article/ld/case-based-learning-anxiety-disordersAccessed on September 6, 2021.
  7. Terminal agitation at end-of-life. Marie Curie. Available from: https://www.mariecurie.org.uk/professionals/palliative-care-knowledge-zone/symptom-control/agitationAccessed on September 16, 2021.
  8. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2021; September 16, 2021.
  9. Head B, Faul A. Terminal restlessness as perceived by hospice professionals. Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):277-82. doi: 10.1177/104990910502200408. PMID: 16082913
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Renal impairment is relatively common in both the elderly and hospice patients, and it can affect the way medications act in the body in several ways. Most commonly, it results in decreased clearance of renally-excreted medications, leading to accumulation of the drug and/or its metabolites and subsequent adverse or toxic effects. The absorption of oral medications may be reduced in patients with renal impairment due to increased gastric pH and gut wall edema. Uremia caused by renal impairment can increase sensitivity to medications that act on the central nervous system (CNS), as well as increase the risk of hyperkalemia due to potassium-sparing drugs. In addition, uremia can enhance the potential for NSAID-induced edema or GI bleeding. Renal impairment can also lead to edema or ascites, cachexia, dehydration, decreased albumin levels and binding capacity, and decreased tissue binding, all of which can impact the effects of medications. To compensate for these renal impairment-induced changes in drug disposition, the typical actions taken regarding medication administration are to decrease the dose, increase the dosing interval, or a combination of the two. The action that would be recommended depends on the drug and its specific characteristics. There are many medications that require dose adjustment in renal impairment, but here we’ll be discussing just those that are most often seen in hospice. The goal is to make you aware of these common medications (and categories) that often need dose adjustment so they trigger a mental alert for possible follow-up if they are ordered for your patients with decreased renal function. Opioids: Many opioids can accumulate in renal impairment as the parent drug and/or metabolites. Tramadol has a maximum daily dose in all patients, but in patients with a creatinine clearance (CrCL) less than 30 mL/minute, this maximum dose is reduced to 200 mg per day and the dosing interval should be extended to every 12 hours. Morphine renal dose reductions start with a CrCL less than 60 mL/minute, with possible extension of the dosing interval at this point as well. It is typically recommended to start considering alternatives to morphine in patients with a CrCL less than 30 mL/minute, and to avoid it altogether in patients with a CrCL less than 15 mL/minute. At end of life, the benefits of morphine can sometimes outweigh the risks. Because the presentation of renal accumulation-based adverse effects may be delayed, morphine can be used even in severe renal impairment or renal failure when the prognosis is hours to days, or in dialysis patients when death is imminent. Typically, oxycodone and hydromorphone are considered preferred alternatives to morphine in patients with significant renal impairment, although they both have metabolites that can accumulate in renal failure. As a result, the dose of oxycodone should be reduced and the dosing interval increased in patients with a CrCL less than 60 mL/minute, and oxycodone extended-release products should usually be avoided in patients with a CrCL less than 30 mL/minute. Hydromorphone dose reduction is also recommended when CrCL is less than 60 mL/minute; further dose reduction and extension of the dosing interval is recommended for hydromorphone when CrCL is less than 30 mL/minute. Although hydrocodone and its active metabolites may accumulate in renal impairment, there are no dose reductions for hydrocodone/acetaminophen according to the manufacturer’s labeling. Hydrocodone extended-release products (Hysingla ER®, Zohydro ER®) are rarely used in hospice, but dose reductions are recommended in patients with moderate to severe renal impairment. Methadone and fentanyl patch are considered among the safest opioids in renal impairment because they do not have active metabolites. However, renal impairment can still alter how fentanyl moves in the body, so dose reduction is recommended in patients with a CrCL of 50 mL/minute or less. For methadone, dose reduction is not recommended until very severe renal impairment (CrCL less than 10 mL/minute). No dose reductions are recommended for buprenorphine at any degree of renal impairment, and it is generally considered safe in this population. NSAIDs: Examples of NSAIDs that are commonly used in hospice include ibuprofen (Advil®, Motrin®), naproxen (Aleve®), and meloxicam (Mobic®), and as mentioned previously, there are some concerns regarding the use of NSAIDs in renal impairment. According to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline, prolonged therapy with NSAIDs is not recommended if GFR is less than 60 mL/minute/1.73m² , and NSAIDs should typically be avoided in patients with a GFR less than 30 mL/minute/1.73m². As a general rule, NSAIDs should be used at the lowest effective dose for the shortest time possible in patients with renal impairment. In addition, NSAIDs should be avoided in patients with a high risk for developing acute kidney injury (e.g. volume depleted, elderly, and/or taking other nephrotoxic medications), and should be discontinued if acute kidney injury occurs during use. Antimicrobials: Many antimicrobials require dose reduction and/or extension of the dosing interval in renal impairment. Specific dosing recommendations depend on the antimicrobial in question and the type of infection being treated. When used for multiple doses, the dose of the antifungal fluconazole (Diflucan®) should be reduced in patients with a CrCL of 50 mL/minute or less. Examples of antibiotics commonly used in hospice that need dose adjustment include: sulfamethoxazole/trimethoprim (Bactrim®); fluoroquinolone antibiotics, including ciprofloxacin (Cipro®) and levofloxacin (Levaquin®); certain penicillin antibiotics, such as amoxicillin and amoxicillin/clavulanate (Augmentin®); and some cephalosporins, including cephalexin (Keflex®) and cefdinir (Omnicef®). Nitrofurantoin (Macrobid®, Macrodantin®) also has significant concerns in renal impairment. According to the manufacturer’s prescribing information, it is contraindicated in anuria, oliguria, or significant renal impairment (defined as a CrCL less than 60 mL/minute or clinically significant elevated serum creatinine). However, limited data suggest it is safe and effective for short-term use in patients with a CrCL of 30 to 60 mL/minute, although there appears to be an increased risk of pulmonary adverse events when eGFR is less than 50 mL/minute. In any case, nitrofurantoin should be avoided altogether in patients with a CrCL less than 30 mL/minute, due to the risk of pulmonary toxicity, hepatotoxicity, and peripheral neuropathy. Renal impairment can affect drug disposition in several ways, often increasing the risk of adverse and toxic effects. Whenever you have a patient with renal impairment, evaluate whether they are taking medications that may be cause for concern and require dose adjustment, and remember that hospice clinicians, pharmacists, and drug information resources can help by providing specific renal dosing recommendations. By Joelle K. Potts RPh, PharmD, BCGP REFERENCES: Aging and Kidney Disease. National Kidney Foundation. Available at: https://www.kidney.org/news/monthly/wkd_aging [accessed 8/8/2022] Aronoff GR, Bennett WM, Berns JS, Brier ME, Kasbekar N, Mueller BA, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th American College of Physicians, Philadelphia, PA; 2007. Renal Impairment. Chapter in: Palliative Care Formulary, 7th Edition (PCF7). Wilcock A, Howard P, Charlesworth S, Eds. Pharmaceutical Press, London, UK. Chapter 17, added April 2017; 715-35. Drug monographs. Lexcomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc. https://online.lexi.com. O’Connor NR, Corcoran AM. End-stage renal disease: symptom management and advance care planning. Am Fam Physician. 2012; 85(7): 705-10. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. Jan 2013; 3(1). Available at: www.kidney-international.org Macrobid® Prescribing Information. Proctor and Gamble Pharmaceuticals, Inc. Cincinnati, OH. Revised Jan 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf [accessed 6/13/2022] Macrodantin® Prescribing Information. Almatica Pharma Inc. Pine Brook, NJ. Revised Mar 2013. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016620s072lbl.pdf [accessed 6/13/2022] 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated Beers Criteria® for potentially inappropriate medication use in older adults. JAGS. 2019; 00: 1-21
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