Insomnia in palliative care

INTRODUCTION — 

Insomnia is a condition of impaired sleep, with difficulties in initiating or maintaining sleep and/or experiencing sleep as nonrestorative and unrefreshing, despite having the appropriate opportunity for sleep to occur, which causes impairment in daytime functioning or other consequences for the patient during the day.

Patients receiving palliative care vary in terms of their functional status and where they are in their personal trajectory in a serious illness. As a result, the approach and treatment to insomnia in these patients should be individualized with careful attention to the patient's goals and current health status. The approach to insomnia will need to be updated as the patient progresses through their disease. An overview and the general treatment approach to insomnia in other patient populations, is discussed separately. (See "Overview of the treatment of insomnia in adults".)

PREVALENCE AND IMPACT — 

Insomnia is common in palliative care patients, with a reported prevalence of approximately 60 percent [1-5]. Insomnia has a negative impact on quality of life and the ability to perform normal functions. In addition, it is considered a risk factor for the development of physical and psychiatric disorders. (See "Risk factors, comorbidities, and consequences of insomnia in adults", section on 'Adverse outcomes'.)

DIAGNOSIS — 

The diagnosis of insomnia in palliative care populations is the same as in other adults. Insomnia is usually classified as either short-term (duration of less than three months), or chronic (symptoms occurring at least three times per week for more than three months) (table 1) [6]. Diagnostic criteria are presented separately. (See "Evaluation and diagnosis of insomnia in adults", section on 'Diagnostic criteria'.)

INITIAL ASSESSMENT

History — In formulating a treatment plan, patients should be asked about any history of insomnia prior to the development of serious illness; family history of insomnia; and correlations with any treatments, procedures, or medications (eg, opioids, steroids, anticholinergic medications). A preexisting history of impaired sleep can help inform the approach to the current insomnia and the likelihood of finding successful treatment. Acute stressors are common in patients with serious illness. Assessing for these and their impact on sleep can help formulate an effective treatment plan. Normalizing sleep difficulties for patients during the interview can allow patients that are hesitant to share that they are burdened by insomnia.

Questions that may be helpful in understanding insomnia in the palliative care population include:

●"Many people I see with serious illness struggle to get good restful sleep. How have you been sleeping?"

●"Try imagining, if I could remove your pain (nausea, etc) with a magic wand, how would your sleep be?"

●"What did your bedtime routine used to look like? Do you have a nighttime routine now?"

●"Have you been unable to consistently take any of your usual medications lately?"

●"Do you drink alcohol regularly, or have you reduced your use of alcohol recently?"

●"Where does your mind go when you are awake at night?"

Addressing predisposing factors — Assessing for factors that may be contributing to insomnia, especially those that may be modifiable, is critical in the development of a treatment plan [7]. Patients should be evaluated for coexisting psychiatric or medical disorders (table 2). Ongoing use of alcohol can contribute to sleep disorders, as can efforts to reduce consumption too quickly. In the context of palliative care, insomnia often coexists with other symptoms, and the presence of one often exacerbates the other [2,8]. Quickly and effectively treating these contributors to poor sleep often significantly improves the complaints of insomnia. However, targeting both these predisposing factors and primary insomnia at the same time is often appropriate and necessary for complete symptom palliation. Predisposing and precipitating factors are discussed in more detail separately. (See "Overview of the treatment of insomnia in adults", section on 'Predisposing and precipitating factors'.)

Physical symptoms — Pain, and other physical symptoms (eg, nausea, frequent stooling and voiding, incontinence, night sweats, shortness of breath, orthopnea, cough, hiccups), and other sleep disorders (eg, sleep apnea, sleep-related movement disorders, and circadian rhythm disorders) can cause or exacerbate sleep disturbances [8,9]. Pain symptoms may increase at night, perhaps because when patients are less distracted by the events of the day, they have more attention available to experience the pain. In turn, insufficient sleep lowers the pain threshold.

Psychological symptoms — Palliative care patients experience acute stressors on a routine basis and often experience heightened psychological distress due to fear, anger, or concern over their illness and approaching end of life, which can prevent initiation or maintenance of sleep. An anxiety or depressive disorder can also contribute to sleep disturbance [10,11]. Palliative care patients often describe anxious and negative ruminations, which tend to focus on the various aspects of their disease, the uncertainty of what lies ahead, what else they could have done, who will take care of them or their children, whether physical suffering will be unbearable, or whether they will wake in the morning. Inquiring about these types of thoughts can help the patient share the true burden of their insomnia, and in our experience is therapeutic. Inquiring about "racing thoughts," "what if" statements, and the making of mental "to-do lists" often elicits some of the psychological underpinnings of insomnia that can underpin and contribute to the patient's treatment plan. (See "Overview of anxiety in palliative care" and "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis" and "Approach to the adult patient with suspected depression".)

Patients who have spiritual concerns and distress that contribute to insomnia may benefit from referral to chaplaincy, if available. (See "Overview of spirituality in palliative care", section on 'Treating and attending to spiritual distress'.)

Progression of illness — As patients progress in their illness, insomnia may be exacerbated by increasing worry, spending more time in bed, daytime somnolence, new medications, worsening symptoms, and more sedentary behavior. These changes can lead to the patient losing the normal cues for when sleep should occur, thus worsening insomnia.

Further, as illness advances, patients may experience a loss of the ability to swallow medications. When this includes chronic medications, it can lead to withdrawal syndromes that may include sleep disturbance. For example, benzodiazepine and opioid withdrawal may negatively impact sleep, as can sudden discontinuation of many antidepressants and hypnotics. Intermittent ability to successfully take oral medications can also be a challenge as this can lead to recurrent withdrawal experiences and thus ongoing sleep disruption.

Medication side effects — Assess the patient's current medication list for drugs that may be worsening insomnia as well as any recently discontinued medications that may have an associated withdrawal syndrome. Medications such as opioids, glucocorticoids, beta-receptor agonists, many antidepressants, and psychostimulants may have arousal or stimulant properties that can exacerbate sleep disturbances [12] (table 2). Whenever possible, stimulating agents should be stopped. If they are required, they should be administered as early in the day as possible, ideally in the morning.

Some medications induce somnolence (eg, mirtazapine), and these agents can be used preferentially when treating other conditions. It is important to frequently review a patient's medication list as disease progresses to ensure that each drug continues to be indicated and safe. A medication that had been tolerated well when the patient was healthy may now be negatively impacting their sleep. For example, a patient's nightly over-the-counter sleep aid that contains diphenhydramine may have been well tolerated for years but now is instead contributing to cognitive impairment or urinary retention that is negatively impacting their ability to sleep. (See "Overview of the treatment of insomnia in adults", section on 'Medication side effects'.)

NONPHARMACOLOGIC INTERVENTIONS AS FIRST-LINE THERAPY — 

Several nonpharmacologic interventions improve sleep among adults with advanced serious illness [13]. Patients will likely benefit from a combined approach to these interventions [14-19]. A 2021 clinical practice guideline for treatment of insomnia in the general adult population supports a multicomponent approach, which can be extended to palliative care patients [20].

Addressing the environment — Sleep may benefit from environmental interventions such as keeping rooms cool, well-ventilated, and with low light at night. In addition, patients should be provided with a comfortable bed (the use of foam "egg crate" or memory foam mattress toppers may be helpful). Distracting noise can be a factor for some patients who may find benefit from the use of white noise machines [21].

For patients in an inpatient setting, clinicians and staff should minimize disruptions to a patient's sleep. This includes reducing exposure to loud or active stimuli. Dimming lights in the vicinity of the patient's room may provide a simple cue to others to maintain a calm, quiet, sleep-promoting environment. Further efforts include:

●Reducing or eliminating clinical activities (eg, blood pressure checks)

●Avoiding administration of medication, fluids, and/or nutrition during the night

●Limiting visitors during times when the patient should not be disturbed

Improving sleep in an inpatient setting is discussed further separately. (See "Poor sleep and insomnia in hospitalized adults".)

Lifestyle modifications

Encourage healthy sleep-wake cycles — A number of lifestyle modifications may promote a more regular sleep pattern and can be instituted in a palliative care setting. These are described in the table (table 3). Key components include:

●Spending time out of bed each day, especially during the hours leading up to bedtime

●Avoiding daytime naps, especially late in the day

●Limiting large meals or excessive fluids at bedtime

●Avoiding stimulants (eg, caffeine), particularly late in the day

●Minimizing alcohol use

●Limiting patient use of computers, smartphones, and iPads at night

Clinicians should encourage the maintenance of familiar and predictable routines as long as the patient is able. For example, if a patient routinely showers and has a snack prior to bed, then this routine should be continued when feasible. As disease progresses, alternate bedtime routines may be created to allow for the types of activities that are tolerated by the patient.

Maintaining or restoring the circadian rhythm can improve sleep. For example, increased exercise and regular exposure to daylight for at least an hour every morning have been shown to restore sleep cycles among patients with Alzheimer disease [14]. Light exposure can be accomplished using artificial full-spectrum or blue lights (with no UV) when natural daylight exposure is not possible [22]. A helpful concept to discuss with patients is that, "a good night's sleep starts first thing in the morning." Using this as a reminder that getting up and out of bed each day is an important component of the insomnia treatment plan. When a patient is bedbound, especially later in illness, consider having the bed position changed during the day. For example, moving the bed to face a window can help to reinforce that it is daytime. Then when the bed is moved back to its "sleep time" a ritual is begun to prepare the body and mind for sleep.

Exercise — Exercise may provide benefit for patients well enough to engage in it in some form. In a 2020 meta-analysis of 27 trials conducted among patients with cancer and sleep disturbance, both aerobic exercise and mind-body exercise (eg, yoga, qigong, tai chi) improved sleep outcomes compared with a variety of active and inactive control interventions [23].

Cognitive behavioral therapy for insomnia as preferred treatment — For patients with persistent insomnia despite environmental-associated modifications, behavioral therapy is the first line of treatment. Cognitive behavioral therapy for insomnia (CBT-I) is the preferred form of treatment for chronic insomnia in the general adult population [24]. The efficacy of CBT-I for treatment of chronic insomnia is supported by multiple randomized trials involving patients with and without medical comorbidities. These data are discussed separately. (See "Cognitive behavioral therapy for insomnia in adults".).

While patients receiving palliative care were largely excluded from clinical trials of CBT-I, it is reasonable to expect that the benefits of CBT-I would apply to this population. Moreover, behavioral therapy is often preferred over pharmacotherapy initially in the palliative care population because it avoids the potential risks associated with multiple sedating medications.

CBT-I has been difficult for many patients to access, in part due to a lack of available trained therapists. A noninferiority study of cancer patients with insomnia used a step-based approach to CBT-I, first starting with a web-based intervention and then only moving patients who failed to have an adequate response to that intervention to face-to-face CBT-I. They found that this more widely accessible stepwise intervention strategy was not inferior to the standard face-to-face CBT-I treatment of insomnia that has previously been proven to treat insomnia in cancer patients. Unfortunately, they had an exclusion criterion of needing to have a prognosis of greater than one year. Thus, the applicability of this approach to many patients receiving palliative care is unclear [25].

Other behavioral approaches include mindfulness-based interventions and relaxation techniques. However, while mindfulness-based interventions have been found to be beneficial for a variety of indications in hospice and palliative care settings, there are no studies evaluating mindfulness-based techniques for treating insomnia in palliative care. In a meta-analysis of studies in the general population, mindfulness meditation was found to "mildly improve" sleep in patients with insomnia without significant adverse effects, suggesting it may be safe in other populations such as those with medical illness [26].

Even though these approaches clearly offer benefit to many patients, those with advanced disease and those on opioids may not have the attentional capacity to participate in behavioral approaches to insomnia; others may not want them.

PHARMACOLOGIC INTERVENTIONS — 

There are limited data on the effectiveness of sleep aid medication in palliative care patients. The approach to the selection of a sleep aid should be individualized, and the lowest effective dose of medication should be administered. Finding an effective dose is important. Thus, while it is important to assess for side effects, it is also important to titrate agents prior to calling a trial a failure. As with most drugs, patients with serious illness must be carefully and continually monitored for both positive and adverse effects, particularly as the patient's disease progresses. For example, it is important to ensure that as a patient's medication list grows, or they become more susceptible to delirium, their sleep aids continue to provide more benefit than harm. One should not hesitate to change course to find an effective means of improving sleep. Pharmacologic treatment for insomnia in the general adult population is discussed further separately. (See "Pharmacotherapy for insomnia in adults".)

Palliative care considerations — Palliative care patients may have particular considerations regarding pharmacologic treatment for insomnia:

●Evolving stage of illness – Palliative care patients may have changing sensitivity and risk associated with the use of the common pharmacologic treatments as their disease progresses. Patients early in their disease trajectory may tolerate and respond to typical sleep aids as well as a medically healthy patient. However, patients at an advanced stage of illness are more likely to suffer adverse effects from sleep aids due to drug-drug interactions or the presence of end-organ impairment [7,27,28]. However, the risk/benefit analysis may also shift as the disease status changes. Concerns about dependence and addiction may be more salient earlier in the illness trajectory than at the end. For this reason, it will be important to revisit the decision to use medications and the overall treatment strategy for insomnia over time.

●End-of-life considerations – For patients at the end of life, the clinician should fully consider the experiences described by the patient during the assessment of their insomnia. Patients may experience insomnia as extremely burdensome, a time of profound worry with severe anxious and negative ruminations, contributing to daytime somnolence, loss of function, and poor quality of life. Focusing on the patient's goals, the likelihood of symptom improvement, and what matters most to them will be helpful in designing an effective treatment strategy. At the same time, it is necessary to have a heightened awareness of the potential adverse effects of treatment. The risks of medication (eg, delirium, daytime somnolence, falls), should be discussed with the patient or surrogate, and evaluated in light of the patient's goals. Sleeplessness should be addressed quickly and effectively because of the frequent high levels of distress that occur with insomnia at this phase of life.

●Synergistic beneficial effects – Since, for many palliative care patients, insomnia is one of multiple symptoms, considering insomnia medication within the context of the other symptoms may allow for synergies and simplicity. Medications used in this setting commonly have multiple effects, including some that may be therapeutic for symptoms besides insomnia. Some benzodiazepines have benefits for dyspnea and thus might be preferentially used in patients with both insomnia and dyspnea, with appropriate cautions. Similarly, mirtazapine, lorazepam, and quetiapine all have antiemetic properties, as well as being potential treatments for insomnia. Patients with insomnia accompanying depression or anxiety may receive "double benefits" from use of a sedating antidepressant.

●Drug-drug interactions – As illness progresses and a patient begins to take a larger number of medications, the risk of interactions grows as well. Not only should a prescriber check for interactions, but also the potential for additive effects.

●Greater likelihood of side effects – Palliative care patients are at higher risk of adverse side effects due to the greater prevalence of polypharmacy, frailty, end-organ damage, and other coexisting conditions. Many of the drugs used for insomnia have the potential to cause delirium, a particularly concerning consequence for patients and their families. Side effect profiles should be assessed for the risk of unintended consequences. As examples:

•If a patient has insomnia due to delirium (eg, accompanied by restlessness, agitation, or psychosis), prescribing zolpidem or benzodiazepines or using the over-the-counter agent diphenhydramine to treat insomnia may worsen the delirium.

•Patients with end-stage chronic obstructive pulmonary disease (COPD) may experience worsened respiratory function when prescribed benzodiazepines, although benzodiazepines can also be a good treatment for dyspnea in other cases.

●Older adults – Older adult patients often have multiple comorbid medical conditions that can contribute to sleep disturbances and make them more susceptible to the adverse effects of sleep aids. In addition, there are known changes in sleep structure and quality that occur with aging, including increased and prolonged nighttime awakenings, reduced sleep efficiency, reduced rapid eye movement (REM) sleep, reduced time spent in deep sleep, and disruption of circadian rhythms [28]. Pharmacologic options for older patients are discussed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations' and "Overview of the treatment of insomnia in adults", section on 'Older adults'.)

●Patients with cognitive impairment – Patients with cognitive impairment are at an increased risk for experiencing insomnia as a potential symptom of their underlying dementia illness or from associated conditions (eg, sundowning, agitation, or delirium). Nonpharmacologic interventions are the preferred initial means of treatment of insomnia in this patient population, and use of medications requires close monitoring for side effects, particularly delirium. (See 'Addressing the environment' above and "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Management' and "Overview of the treatment of insomnia in adults", section on 'Dementia and other neurodegenerative disorders'.)

Sedating antidepressants — These agents are reasonable choices for some palliative care patients, especially when the insomnia is felt to be due, at least in part, to a mood or anxiety disorder (See "Pharmacotherapy for insomnia in adults", section on 'Antidepressants'.)

Doxepin — Low dose doxepin is approved for the treatment of insomnia. Its mechanism of action is due to its antagonism of the histamine H1 receptor.

●Dosing – We start with a dose of 3 to 6 mg, and increase to 10 mg if needed while monitoring for adverse effects [29]. This medication is also available as a liquid solution, which can be helpful in dosing small amounts when insurance does not cover brand-name drugs. Administration should not occur within three hours of a meal because high-fat meals can reduce its bioavailability and delay peak effects by up to three hours.

When finances dictate, we have also found it safe to use the lowest dose generic tablet version (10mg). However, escalating doses of doxepin expose the patient to a greater anticholinergic load, so it is important to use the lowest effective dose and avoid doses above 6 mg for patients at particular risk of adverse effects of anticholinergic medications. Doxepin is also available in liquid form. (See "Drug prescribing for older adults", section on 'Anticholinergic activity'.)

●Side effects and risks

•The primary side effects of doxepin are related to its antagonism of the muscarinic cholinergic receptors and include dizziness, dry mouth, blurred vision, constipation, and urinary retention. These side effects appear to be especially common in older patients and become more prominent at higher doses [29-33]. At the ultralow doses used for insomnia, 3 to 6 mg, it is highly selective for the histamine receptor and is not felt to have anticholinergic properties.

•Delirium can occur.

●Contraindications

•Due to the risk of delirium, doxepin is less well suited for older patients or those with dementia due to anticholinergic effects, although low doses (eg, 3 and 6 mg) are usually well tolerated [34].

•Doxepin should not be used in patients with narrow-angle glaucoma or urinary retention.

●Potential indications – For patients with insomnia related to pruritus, doxepin may help treat the pruritus as well, especially if the patient can tolerate higher doses [33].

Trazodone — Trazodone is often prescribed off-label for insomnia. There is limited prospective data in palliative care populations [35,36] but it has been found to be an effective antidepressant in patients with Alzheimer disease [37]. We typically find trazodone reasonably safe and well tolerated. (See "Pharmacotherapy for insomnia in adults", section on 'Trazodone'.)

●Dosing – For frail or older patients, we use a starting dose of 12.5 mg given about 30 to 60 minutes before bedtime (more typical starting doses are 25 to 50 mg). The dose may be titrated up by 25 or 50 mg increments, to 100 mg while observing for adequate positive effect or the emergence of unwanted side effects. In cases where there is benefit but not complete efficacy, and lack of adverse effects, it may be reasonable to go up to as high as 200 mg. At doses beyond 100 mg, there are greater risks of anticholinergic side effects, although at these higher doses, the patient may have a positive impact on mood. In our experience, doses beyond this have not provided additional benefit.

●Side effects and risks

•Side effects include risk of syncope, edema, blurred vision, diarrhea, nasal congestion, priapism, and weight loss.

•It has the potential to cause cognitive and motor impairment, which can be life threatening as part of serotonergic syndrome, although this is rare.

•The primary concerns in this patient population are corrected QT (QTc) prolongation, impaired platelet aggregation, hypotension, and increasing the serotonergic load, thereby increasing the risk of serotonin syndrome, especially in patients who are already on other medications with serotonergic action (table 4). (See "Serotonin syndrome (serotonin toxicity)".)

●Contraindications

•Caution should be used in patients with impaired liver function, with use of the lowest effective dosing.

●Potential indications – Similar to other sedating antidepressants, mood or anxiety disorder may be synergistically targeted, especially at higher dose ranges.

Mirtazapine — Although indicated for major depression, generalized anxiety disorder, and tension-type headaches, mirtazapine is associated with sedative side effects that may be useful for the treatment of patients with mood or anxiety disorders who are also experiencing insomnia [38,39]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine' and "Pharmacotherapy for insomnia in adults", section on 'Mirtazapine'.)

●Dosing – When using mirtazapine for insomnia, we often start at either 7.5 or 15 mg at bedtime. We may increase to 22.5 or 30 mg, although at these doses some patients begin to experience more stimulating qualities of the drug.

●Side effects and risks

•The most common side effects are somnolence, increased appetite, weight gain (not usually seen in patients with cancer-related cachexia), and dizziness [40].

•Additional side effects and cautions are discussed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Mirtazapine'.)

●Potential indications

•Similar to other sedating antidepressants, mood or anxiety disorder may be synergistically targeted, especially when combined with a serotonin reuptake inhibitor.

•Mirtazapine has antiemetic properties, which may be useful in some palliative care patients. It may also be helpful for individuals with poor appetite.

•Mirtazapine comes as an oral disintegrating tablet, which may be of benefit to some patients who have difficulty swallowing pills.

Benzodiazepine receptor agonists — Benzodiazepine receptor agonists (BZRAs) for insomnia include older benzodiazepines and nonbenzodiazepine BZRAs, which have alternate structures but similar mechanisms of action. Caution should be used in patient, drug, and dose selection. Use of these medications should be individualized based on the patient's current status, prognosis, goals, and underlying medical condition. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine receptor agonists'.)

Caution in patients using opioids — BZRAs should be used with caution in patients who are already on opioids; however, this is not meant to be a complete contraindication. Note that in our practice it is quite common that a patient requires both of these classes of medications for various indications. For example, anxiety disorders, dyspnea, nausea, and insomnia often warrant use of benzodiazepines while the patient is also on an opioid for another indication. Being aware of the pharmacokinetics, the risk of decreased tidal volumes with benzodiazepines, decreased respiratory drive with opioids, and sedation is needed to ensure patients benefit from the combination without experiencing adverse effects.

Certainly, in situations of abuse and substance misuse, this combination is well publicized as potentially deadly, but in the hospice and palliative care population, it has been found that using these agents together can be done safely and with good outcomes [41,42]. However, caution is particularly important to consider in patients with substance use disorders due to concerns of impulse control and accidental overdose. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine receptor agonists' and "Insomnia in patients with a substance use disorder", section on 'Pharmacologic treatments'.)

Benzodiazepines

●Dosing – Dosing for several agents is provided in the table. For most patients, we start at the lowest doses (table 5).

●Side effects and risks – Benzodiazepines are associated with adverse effects, including the following [7,43,44]:

•The rapid development of tolerance in some patients, which may cause the return of insomnia symptoms.

•Symptoms of withdrawal if they are discontinued.

•Potential for cognitive impairment and falls.

●Contraindications

•Benzodiazepines are less well tolerated in older patients and those with comorbidities, including dementia or other central nervous system disease.

•Caution should be used in finding the lowest effective dose in patients with COPD, as this class of drug has been associated with increased mortality in this patient population.

●Potential indications

•A benzodiazepine may be the preferred agent in patients with dyspnea (not caused by COPD) or nausea.

•These agents may be helpful for patients with anxiety due to severe dyspnea.

Nonbenzodiazepine BZRAs — Several nonbenzodiazepine BZRAs are approved for the treatment of insomnia in the general population including eszopiclone, zaleplon, and zolpidem. However, there are side effects that may be problematic for some palliative care patients and older adults.

●Dosing – While there are no evidence-based guidelines for specific dosing in palliative care populations, we choose the lowest possible dose and titrate carefully, assessing for positive and negative effects. Alternatively, if a patient has a personal history with one of these agents, we may allow their experience to guide initial dosing while being mindful of their current state of frailty or possible additive effects of other medications. Further dosing information is provided separately (table 6). (See "Pharmacotherapy for insomnia in adults", section on 'Nonbenzodiazepine BZRAs'.)

●Side effects and risks

•The most common side effects are somnolence, drowsiness, dizziness, delirium, and a risk of rare but serious complex sleep-related behaviors.

•There may be an increased risk for ataxia and falls [45].

•While previous studies have suggested BZRAs do not predispose patients to tolerance with longer-term use (ie, six months), subsequent data show that dependence may develop [46,47].

•Additional side effects and cautions are discussed separately. (See "Pharmacotherapy for insomnia in adults", section on 'Nonbenzodiazepine BZRAs'.)

●Contraindications

•All BZRAs are listed as potentially inappropriate medications in older adults by the Beers Criteria based on risk of adverse effects, but they may be used safely in patients with good cognitive reserve after a careful assessment of risk for adverse effects [48]. In these situations, we use a time-limited trial at the lowest effective dose, titrating as needed and tolerated, and then reevaluating over time whether the risk/benefit ratio is still in alignment with the patient's treatment goals and if the medication is improving the patient's quality of life. (See "Overview of the treatment of insomnia in adults", section on 'Older adults'.)

•Patients at high risk of delirium (eg, frail older patients, those with neurocognitive disorders) are less favorable candidates for these agents.

Desprescribing — When working with palliative care patients, especially older individuals, who have been prescribed BZRAs, it is important to discuss the risks and benefits of continuing to use these agents with them, or their surrogate if appropriate. Deprescribing these medications is sometimes advisable as the risk of adverse events increases as a patient ages or becomes more frail. With education and open discussion, a shared decision about whether to continue or taper off should be made. Many factors will go into this risk-benefit analysis, including the patient's current physical and cognitive states, current experience of benefit or harm to quality of life, duration of use, and their prognosis. (See "Deprescribing", section on 'Benzodiazepines and benzodiazepine receptor agonists' and "Drug prescribing for older adults", section on 'Potentially inappropriate medications'.)

Ramelteon — Ramelteon, a selective melatonin receptor agonist, is approved for the treatment of insomnia in the United States and Japan. It can potentially be helpful in patients with sleep onset problems or sleep phase disruption. In contrast to BZRAs, it is nonhabit forming and does not appear to have the side effects associated with other hypnotics. There are no data on the efficacy or safety of ramelteon in palliative care populations. However, at least some data support safety in medically complex patients [49].

●Dosing – Ramelteon is available in a single 8 mg dose, to be taken within 30 minutes of going to bed. It should not be taken with or soon after a high-fat meal.

●Side effects and risks – The most common side effects are somnolence, dizziness, fatigue, nausea, and exacerbation of insomnia. (See "Pharmacotherapy for insomnia in adults", section on 'Ramelteon'.)

●Contraindications – This agent should be avoided in patients with severe hepatic impairment.

●Potential indications – This drug may be considered in patients with disrupted circadian rhythm, especially those in an intensive care unit (ICU) setting where it has been studied to help reduce episodes of delirium.

●Drug-drug interactions – Ramelteon has important drug-drug interactions that should be carefully considered, especially in palliative care patients who may be on a number of different agents. It is metabolized primarily through the CYP450 1A2 pathway; thus, it should not be coadministered with other potent inhibitors of this pathway, such as ciprofloxacin and fluvoxamine. Detailed information on drug interactions can be found in the drug interaction program within UpToDate.

Sedating antipsychotics

Quetiapine — Although evidence for its effectiveness for insomnia is inconclusive, low-dose quetiapine can be used, with proper monitoring, off-label for insomnia [50]. At doses typically used for this indication, (25 to 50 mg), quetiapine is primarily sedating through its antihistamine properties. We do not typically use quetiapine for the sole purpose of treating insomnia but do use it when there are other target symptoms to treat (eg, psychosis, mood disorders, impulsive agitation in delirium), or other indications (eg, augmentation of an antidepressant, assisting with affective instability).

●Dosing – Because of quetiapine's tendency to contribute to orthostatic hypotension, we start a relatively low doses (ie, 25 to 50 mg) and increase in increments of 25 to 50 mg per week, depending on how frail the patient is while frequently evaluating for side effects. Titration may be faster in a monitored setting.

●Side effects and risks

•Orthostatic hypotension

•Prolongation of the QTc interval

•Akathisia, while relatively uncommon, may occur

•Metabolic effects including weight gain

●Contraindications

•Quetiapine should be used with greater caution in older adults because of reduced drug clearance and more frequent adverse effects [51].

•We avoid this agent in patients with prolonged QTc intervals and monitor the QTc interval in patients with risk factors for QTc prolongation such as use of other potentially QTc-prolonging agents. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Drugs that prolong the QT interval'.)

●Potential indications – We generally only use this agent to assist with insomnia when it may also be used to target other symptoms such as augmenting an antidepressant for a major depressive disorder, reducing affective instability in a bipolar spectrum illness, and reducing distressing symptoms of psychosis and impulsive agitation in delirium.

Melatonin — Melatonin is a neurohormone secreted by the pineal gland that can assist with maintaining sleep-wake cycle. It has been well characterized as a substance that promotes sleep or prepares the body for sleep rather than inducing sedation [52]. It is a widely available over-the-counter agent that is often used to alleviate insomnia, despite the lack of prospective data, as well as other conditions. In our clinical practice, many patients present to care having used melatonin without professional guidance. This can include using higher than recommended doses, inconsistent dosing, and administering it too late in the sleep cycle. Taking a thorough history should help to elucidate these issues. While most patients tolerate melatonin well, some do experience side effects. (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

●Dosing – Most experts believe that, at doses ranging from 0.3 to 20 mg, melatonin is well tolerated without adverse effects. In our clinical practice, when using melatonin, we recommend 1 to 3 mg two to three hours before bedtime.

●Side effects and risks – In our clinical practice, the most common and notable adverse effects have been vivid dreams, nightmares, next-day sedation, and headaches.

Patients have often already had experience with melatonin. If this is the case, it is important to determine how they have used it, and what their response was. This information can help to guide a decision to use melatonin and how to dose it. Patients who have used high doses or have used it inconsistently can retry it at a low dose, in a consistent manner, two to three hours before desired sleep, and in combination with other sleep-promoting changes.

Dual orexin receptor antagonists — Dual orexin receptor antagonists (DORAs) are indicated for insomnia characterized by difficulty with sleep onset and/or sleep maintenance. Available agents include suvorexant, lemborexant, and daridorexant. These agents have not yet entered into our routine practice of caring for hospice and palliative care patients but are used in adults with insomnia characterized by difficulty with sleep onset and/or sleep maintenance. Interactions with medications commonly prescribed in palliative care patients (eg, opioids, antipsychotic medications, antidepressants, chemotherapy agents) may limit use. (See "Pharmacotherapy for insomnia in adults", section on 'Dual orexin receptor antagonists'.)

●Dosing – Clinicians should be aware of dose modifications related to use of CYP3A inhibitors and/or inducers. This is discussed in detail separately. (See "Pharmacotherapy for insomnia in adults", section on 'Dual orexin receptor antagonists'.)

Over-the-counter agents — A variety of other over-the-counter agents are available to treat insomnia. This subject is addressed in detail separately. (See "Pharmacotherapy for insomnia in adults", section on 'Over-the-counter sleep aids'.)

IMPACT ON CAREGIVERS — 

Although the data are more limited, the patient's insomnia can significantly impact their caregiver's sleep quality and overall quality of life [53]. Impaired sleep in caregivers increases irritability, depression, anger, and guilt and decreases overall ability to provide care [54]. Disrupted sleep is common among caregivers. In a systematic review of 10 published studies, 72 percent of caregivers reported moderate to severe sleep disturbance, and some experienced up to a 44 percent reduction in total sleep time (from the typical eight hours) [55]. Caregivers describe a negative impact on mood, irritability, anxiety, and finding themselves falling asleep in dangerous situations, such as while driving. A significant factor impacting the caregivers' sleep was the insomnia of the patient. Thus, when considering the risks and benefits of a treatment plan for the patient's insomnia, the impact of successful treatment on the caregivers should also be taken into account.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

●Prevalence and diagnosis – Insomnia is a condition of impaired sleep, with difficulties in initiating or maintaining sleep, and/or experiencing sleep as nonrestorative and unrefreshing, despite having the appropriate opportunity for sleep to occur. It is estimated that insomnia affects over 60 percent of palliative care patients. (See 'Prevalence and impact' above and 'Diagnosis' above.)

●Initial assessment – The initial assessment should address predisposing factors that may impair sleep, including physical symptoms (eg, pain, shortness of breath), psychological symptoms, progression of illness, and medication side effects. (See 'Addressing predisposing factors' above.)

●Addressing the environment – Addressing environmental issues may improve sleep. These include keeping rooms cool, well ventilated, and with low light at night, limiting the use of computers and other stimuli (eg, television, loud music). (See 'Addressing the environment' above.)

●Lifestyle modifications – A number of lifestyle modifications may promote a more regular sleep pattern and can be instituted in a palliative care setting. These include reducing or avoiding daytime naps, eliminating large meals or fluid consumption before bedtime, and avoiding stimulants, including caffeine. Daytime light exposure and activity levels should be increased when possible. (See 'Lifestyle modifications' above.)

●Cognitive behavioral therapy for insomnia – For patients with persistent insomnia despite environmental-associated modifications, CBT-I is the preferred first-line therapy (when practical and available), as it is in the general adult population. The evidence supporting CBT-I for treatment of chronic insomnia is discussed separately. (See 'Cognitive behavioral therapy for insomnia as preferred treatment' above.)

●Pharmacologic options – Pharmacologic therapy is appropriate for patients who decline, cannot access, or do not have an adequate response to CBT-I. The approach to selecting a sleep aid should be individualized, considering the patient's evolving stage of illness, end-of-life considerations, and drug-drug interactions. The lowest effective dose should be used. As with most drugs, patients in palliative care must be carefully and continually monitored for both positive and adverse effects, particularly as the patient's disease progresses (See 'Pharmacologic interventions' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Scott Irwin, MD, PhD, who contributed to earlier versions of this topic review.