PharmSmart: Two thousand and two, two thousand and three . . . Why can’t I sleep?

By Seasons | June 18, 2021

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Sleep disorders are very common in society today - including patients receiving hospice care.

Pain, anxiety, and depression are frequently present along with constraints on movement, lack of signals regulating the circadian rhythm (zeitgebers), noisy monitors, round the clock checks or medication administrations, and many other disruptions which can all cause trouble sleeping. Finding the underlying cause of the sleep disorder is helpful in establishing a treatment plan. Just to make sure we’re all on the same page, insomnia includes difficult falling asleep, staying asleep, and waking up too early (and not by choice!). The approach to insomnia management in hospice and palliative care patients should be individualized based on the patient’s functional status and illness trajectory.

Let’s consider a case . . . Meet AL

AL is a 72 year old female who is a resident in a residential hospice facility. When the advance practice nurse asks about her sleep, she reveals that she has a hard time falling asleep at night. She says she lays in bed awake for up to 2 hours every night before she can actually fall asleep. The lack of sleep makes her so tired during the day that she falls asleep while her family is visiting her. Her daughter asks you if there’s a good sedative that you can order for AL. How would you respond? Well, let’s read on a bit further before we reach for that prescription pad!

Insomnia occurs in about half of all patients receiving palliative care, ranging from 2.1% to 100% of patients. Treatment options are both non-pharmacologic, and pharmacologic.

Before jumping in with a medication to treat insomnia, it is important to assess for the presence of a physical complaint that could impact sleep such as physical discomfort, shortness of breath, or cough that may be keeping the patient awake. Often we find that a patient who cannot get comfortable tosses and turns all night, and then they nod off frequently during the day. This makes it very difficult for the family and informal caregivers. It’s important to try and correct this reversal of the sleep/wake cycle so the patient sleeps better at night, and is more alert during the day. Perhaps the patient is taking a medication that keeps them awake at night, or minimally makes it harder to fall asleep (such as a corticosteroid [dexamethasone] or stimulant [methylphenidate]).

The next non-pharmacologic strategy is assuring the patient’s environment is conducive to a good night’s rest. The temperature should be comfortable (cool, well ventilated), perhaps using a white noise machine, and eliminating distracting sights (such as lights in the room or outside the room, devices in the room, or covering up the clock) and sounds (e.g., turn the television off).

Lifestyle modifications such as trying to eliminate daytime naps, avoiding large meals, snacks or drinks at bedtime, and avoiding caffeine close to bedtime (or after dinner) may be helpful.

Some patient may benefit from light exercise, as their physical status allows. Patients and families should be educated about good sleep hygiene (try to keep the bed for sleeping only within reason) and a good bedtime routine.

Non-pharmacologic behavioral therapy interventions may be beneficial such as mindfulness medication, use of an app like Calm (which can even read you a bedtime story!), or other relaxation techniques. Sleep restriction therapy, which involves minimizing interruptions of the sleep period by limiting how much time patients spend in bed at night, can also be helpful. For example, if the patient reports getting 5 hours of sleep each night, they are only allowed to spend that long in bed. The patient is then allowed to slowly increase time spent in bed as they consolidate their sleep.

Back to poor AL, who we left hanging. Suppose in further conversation we find that AL does tell you that she’s uncomfortable when she lays down. She has not been taking any analgesics regularly, and you suspect the source of her discomfort (generalized aches and pains) is due to osteoarthritis in several joints. One option would be to start the 8-hour oral formulation of acetaminophen (e.g., two, 650-mg capsules every 8 hours) so she can rest more comfortably during the night.

Wow – that was amazing, AL actually started falling asleep more quickly and staying asleep for a longer period of time.

Now several months have passed, and despite adding additional analgesics, AL is once again experiencing insomnia. She does complain of anxiety, specifically she is worried about what awaits her in the afterlife. The chaplain has started making weekly visits to AL with good success. At some point however, it becomes clear that AL may benefit from a pharmacologic agent to assist with falling and staying asleep. What sedative-hypnotics are available and how do we choose which medication to start? Let’s take a look at a comparison of the available agents.

Generic (Trade) Name

Starting Dose

Maximum Dose

Comments

Antidepressants

May be helpful in concurrent insomnia and depression.

Trazodone (Desyrel, Oleptro)

12.5-25 mg

200 mg

Administer 1 hour prior to bedtime. Primary adverse effects include sedation, dizziness, headache, dry mouth, blurred vision, orthostatic hypotension, priapism. Off-label use.

Mirtazapine (Remeron)

7.5 mg

Sedating effects diminish above 15 mg

Administer prior to bedtime. May be helpful to help fall asleep and stay asleep. Primary adverse effects include sedation, dry mouth, increased appetite/weight gain, constipation. Off-label use.

Doxepin (Silenor)

Age < 65: 6 mg

Age > 65: 3 mg

6 mg

Administer 30 minutes prior to bedtime. Strong anticholinergic adverse effects (dry mouth, blurred vision, constipation, urinary retention).

Benzodiazpines

May cause cognitive impairment, falls, CNS depression (esp. with opioids), tolerance/withdrawal when DC’ed. May worsen respiratory function, esp. in patients with COPD.

Lorazepam (Ativan)

0.5-1 mg

4 mg

May be more beneficial for patients with difficulty falling asleep. Off-label use.

Temazepam (Restoril)

7.5 mg

30 mg

May be better choice for patients with difficulty staying asleep

Nonbenzodiazepine GABAa agonists

May cause cognitive impairment, falls, CNS depression (esp. with opioids), tolerance/withdrawal when DC’ed.

Zolpidem (Ambien)

IR, women: 5 mg

IR, men: 5 mg

CR, women: 6.25 mg

CR, men: 6.25 mg

SL, women: 1.75 mg

SL, men: 3.5 mg

IR, women: 5 mg

IR, men: 10 mg

CR, women: 6.25 mg

CR, men: 12.5 mg

SL, women: 1.75 mg

SL, men: 3.5 mg

Administer immediately before bedtime with at least 7-8 hours before needing to be awake

Zaleplon (Sonata)

5 mg

20 mg

Administer at bedtime

Eszopiclone (Lunesta)

1 mg

3 mg

Administer immediately before bedtime

Melatonin receptor agonists

Melatonin

0.5 mg

5 mg

Administer one hour prior to bedtime. Generally well tolerated, may cause headache, dizziness, drowsiness, nausea.

Ramelteon (Rozerem)

8 mg

8 mg

Administer within 30 minutes of bedtime

Antipsychotics

Quetiapine (Seroquel)

12.5-25 mg

800 mg (in research; use in clinical practice usually restricted to starting/low dose)

Helps with falling and staying asleep. Adverse effects include headache, agitation, dry mouth, and periodic leg movements. Off-label use.

Miscellaneous agents

Gabapentin (Neurontin)

100-300 mg

Doses as high as 900-1800 mg/day have been reported

Adverse effects include drowsiness, dizziness and weakness, especially with dose titration. Off-label use.

Nonprescription agents

Diphenhydramine (Benadryl)

25 mg

50 mg

Administer at bedtime. Strong anticholinergic; may cause sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention. Nonprescription.

Doxylamine (Unisom)

25 mg

50 mg

30 minutes before bedtime. Strong anticholinergic; may cause sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention. Nonprescription.

So what’s our plan for AL, who has been patiently waiting for us to make our move? Of course we will continue to explore any psychosocial/spiritual issues that may be keeping her awake at night, and rule out any other reversible causes of insomnia (comorbid condition or symptom, a medication that causes sleeplessness). We will discourage daytime napping and encourage a good sleep hygiene practice.

If the patient has a comorbid condition that would benefit from selecting a specific sedative-hypnotic (e.g., AL has anxiety so perhaps a benzodiazepine may be a good choice) that’s a good place to start.

Otherwise, perhaps a more benign agents such as melatonin, low-dose mirtazapine or trazodone may be useful. Important points to remember include:

  • All sedative-hypnotics can cause a “hang-over” fuzzy-headed feeling; advise patients to be careful when arising in the morning (fall risk) and not to drive until the effect of the sedative-hypnotic is fully appreciated. If this effect is bothersome, consider reducing the dose administered the night before.
  • Be mindful of the adverse effects of the sedative-hypnotics. For example, antihistamines have very strong anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention, confusion). Most sedative-hypnotics are CNS depressants, and may suppress respiration as well, particularly when combined with an opioid. It’s always prudent to use the lowest dose possible. Try to order the sedative-hypnotic “as needed” unless it’s truly necessary to administer routinely.
  • Consider attempting a dosage reduction occasionally. Monitor the patient’s response very carefully both in terms of therapeutic success and potential toxicity.

Insomnia is an understandable complication of advanced illness. With careful assessment, implementation of non-pharmacologic strategies, and the safe use of sedative-hypnotics, we can generally achieve therapeutic success!

 

Recommended Readings:

  • Clark CP, Moore PJ, Gillin J. Sleep Disorders. In: Ebert MH, Leckman JF, Petrakis IL. eds. Current Diagnosis & Treatment: Psychiatry, 3e. McGraw-Hill; Accessed January 28, 2021. https://accessmedicine-mhmedical-com.proxy-hs.researchport.umd.edu/content.aspx?bookid=2509&sectionid=200806088
  • Good P, Pinkerton R, Bowler S, Craig J, Hardy J. Impact of Opioid Therapy on Sleep and Respiratory Patterns in Adults With Advanced Cancer Receiving Palliative Care. J Pain Symptom Manage. 2018 Mar;55(3):962-967. doi: 10.1016/j.jpainsymman.2017.11.026. Epub 2017 Dec 5. PMID: 29208477.
  • Hirst JM, Irwin SA. Overview of insomnia in palliative care. UpToDate, Accessed February 15, 2021. https://www.uptodate.com/contents/overview-of-insomnia-in-palliative-care#H519785601
  • Krystal AD, Prather AA, Ashbrook LH. The assessment and management of insomnia: an update. World Psychiatry. 2019;18(3):337-352. doi:10.1002/wps.20674
  • A Good Night’s Sleep. NIH National Institute on Aging (NIA). Accessed February 16, 2021. https://www.nia.nih.gov/health/good-nights-sleep
  • Nzwalo I, Aboim MA, Joaquim N, Marreiros A, Nzwalo H. Systematic Review of the Prevalence, Predictors, and Treatment of Insomnia in Palliative Care. Am J Hosp Palliat Care. 2020 Nov;37(11):957-969. doi: 10.1177/1049909120907021. Epub 2020 Feb 26. PMID: 32101021.

 

Let’s see how smart you are!

1.Which of the following factors may contribute to a hospice or palliative care patient developing insomnia?

  1. Anxiety or general worrying
  2. Physical discomfort/pain
  3. Distracting noises or lights at night
  4. A and B
  5. A, B and C

2.Mr. Johnson is a 68 year old man with stage 4 lung cancer with metastasis to the bone. His medications include:

  1. MS Contin 30 mg po q12h
  2. Oral morphine solution 10 mg po q2h prn
  3. Dexamethasone 4 mg po q12h
  4. Lisinopril 10 mg po qam
  5. Multi-vitamin po qam

Which of his medications may be contributing to the insomnia he’s developed?

  1. MS Contin
  2. Dexamethasone
  3. Lisinopril
  4. Multi-vitamin

3. Which of the following sedative-hypnotic agents may cause a “hang-over” effect, leaving the patient groggy the following morning?

  1. a. zolpidem
  2. b. Gabapentin
  3. c. Both zolpidem and gabapentin
  4. d. Neither zolpidem nor gabapentin

Answers: 1. E; 2. B; 3

 
This edition of PharmSmart was written with the assistance of Katie Zimmerman, student pharmacist

PharmSmart is a monthly article dedicated to best practices in drug management for patients nearing the end of life, with a little cheer and lightheartedness woven throughout. It is edited by Dr. Mary Lynn McPherson, PharmD. Dr. McPherson is the Executive Director of Advanced Post-Graduate Education in Palliative Care at University of Maryland. Dr. McPherson is a consultant pharmacist to Seasons, and answers complex medication questions for our clinical teams at all hours of the day or night. She is a nationally-recognized expert in medication management for hospice and palliative care patients.

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