Treatment of Insomnia at End of Life

Fatigue is defined as a subjective feeling of tiredness, weakness, or lack of energy that can affect one’s physical, emotional, and cognitive state.

Pain is a common and debilitating symptom experienced in our hospice and palliative care patients.

By Meri Madison, PharmD, RP

By 2030, 1 in 5 Americans will be aged 65 and older and we can anticipate 52 million falls and 12 million fall injuries.

The presence of noisy respirations due to excessive secretions (also known as “gurgling” or “rattling”) at end of life predict a prognosis of days to weeks and can be alarming to family members.

When managing symptoms at end of life, it can be a struggle to find the most appropriate medications.

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

Buprenorphine is a unique opioid analgesic. It has several benefits (“pros”) for pain management, but it also has a few significant risks (“cons”) that prevent it from being used more frequently in hospice.  For pain management, buprenorphine is available as a buccal film (Belbuca®), a weekly transdermal patch (Butrans®), and an injection solution (Buprenex®). The forms that are most often seen in hospice patients are the buccal film and transdermal patch, which are used routinely as long-acting opioids for chronic pain, and these are the dosage forms we’ll be discussing here. Buprenorphine injection is indicated for acute pain and is not recommended for long-term use, and it is rarely used in hospice. Other dosage forms (monthly subcutaneous injection, 6-month subcutaneous implant, and daily sublingual tablet) are indicated for opioid use disorder and are not FDA-approved for pain management. What makes buprenorphine unique is the way it binds to various opioid receptors. The most commonly used opioid analgesics (e.g. morphine, oxycodone, fentanyl, and hydrocodone) are full mu-opioid receptor agonists, meaning they bind to and activate the mu-opioid receptor. In contrast, an antagonist blocks a receptor by binding to it without activating it; naloxone (Narcan®) is an excellent example of a mu-opioid receptor antagonist. Buprenorphine is a partial mu-opioid receptor agonist, which means that it binds to the mu-opioid receptor but activates it to a lesser degree than a full agonist. In addition to its effects at the mu-opioid receptor, buprenorphine has activity at three other opioid receptors: it is an antagonist at the delta- and kappa-opioid receptors, and a full agonist at the ORL-1 (opioid receptor-like 1; a.k.a. nociceptin) opioid receptor. The Pros of Buprenorphine: Effective for pain. Buprenorphine’s partial agonism at the mu-opioid receptor refers only to its activity level at the receptor, and not to its effectiveness as an analgesic. In fact, buprenorphine’s analgesic effects are comparable to full mu-opioid receptor agonists in a variety of different pain types, including moderate to severe post-operative and cancer pain, osteoarthritis, and chronic low back pain. Buprenorphine is also effective for neuropathic pain. Lower risk of certain opioid adverse effects. Because of buprenorphine’s unique activity at four opioid receptors, it is less likely to cause several common opioid adverse effects. When compared with most full mu-opioid receptor agonists, buprenorphine has a lower incidence of respiratory depression – although, as with all opioids, this adverse effect is still possible. Because buprenorphine is also less likely to produce euphoria, it has less potential for physical dependence and addiction; as such, it is classified as a Schedule III (C-III) controlled substance. In addition, when compared with the extended-release forms of oxycodone, hydromorphone, and oxymorphone, buprenorphine buccal film causes significantly less nausea, vomiting, constipation, dizziness, and somnolence. When buprenorphine is compared to morphine, the differences in adverse effect frequency are less pronounced, perhaps due to the dosage forms evaluated (or not evaluated). When comparing buprenorphine buccal film to morphine (dosage form not specified), buprenorphine appears to have just slightly lower incidences of constipation, somnolence, anxiety, and dry mouth. In a 2018 systematic review and meta-analysis of buprenorphine vs. morphine in acute pain management, the only significant difference in adverse effects identified was that buprenorphine was associated with less pruritis. The dosage forms considered in this review varied but were typically morphine injection vs. buprenorphine injection or sublingual tablet (not the patch or buccal film forms of buprenorphine that we usually see in our hospice patients). Safe in special populations. In addition, buprenorphine is considered safe in populations that we see often in hospice: those with renal impairment, including dialysis; those with mild to moderate hepatic impairment; and the elderly. The Cons of Buprenorphine: High cost. Unfortunately, buprenorphine patch and buccal film are relatively high-cost medications, which makes them much less attractive for use in hospice. Depending on the strength, the average cost for the generic weekly patch ranges from approximately $10 to $28 per day; the average cost for the brand buccal film, which is dosed once or twice a day, ranges from approximately $8 to $19 per film. Dosing limitations and cautions in severe hepatic impairment. A potential concern, especially in hospice patients, is that buprenorphine patch and buccal film both have maximum recommended doses. Also, the dose of the patch should be titrated no more frequently than every 72 hours, while the dose of the buccal film should be titrated no more frequently than every 4 days. Because buprenorphine has primarily hepatic metabolism, there are cautions regarding its use in severe liver impairment; in these patients, the dose of the buccal film should be reduced, and the transdermal patch form is not recommended. The Verdict: There are a number of reasons why buprenorphine patch and buccal film are excellent long-acting analgesics for many patients, especially those who are not approaching end of life. However, the cons can be significant, and buprenorphine is usually not preferred as a first- or second-line option for the majority of our hospice patients because other long-acting analgesics are effective and available at a much lower cost (e.g. methadone, morphine extended-release, and many strengths of fentanyl patch). In addition, the fact that buprenorphine patch and buccal film have maximum recommended doses may become an issue at end of life in patients whose pain is rapidly escalating. Of course, the pros and cons must always be weighed for each patient and their specific situation; no doubt there will be some hospice patients for whom buprenorphine patch or buccal film is an ideal choice. Written by Joelle Potts, PharmD, CGP REFERENCES: Lexicomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc.; July 23, 2022. https://online.lexi.com. [last accessed 7/23/2022] Buprenorphine Practitioner Resources and Information. 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Available at: https://butrans.com [last accessed 3/15/2022] Belbuca® (buprenorphine buccal film) prescribing information. BioDelivery Sciences International, Inc., Raleigh, NC. Revised March 2021. Available at: https://www.belbuca.com. [last accessed 3/15/2022]