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. As insomnia can be an associated symptom of many other conditions, a diagnosis of an insomnia disorder is recommended to be considered only when it is separate and distinct enough to require independent attention and treatment. The technical qualities of the definition of insomnia can minimize the distress that often accompanies a patient’s experience of insomnia. Patients rightfully attribute great value to having consistent restful sleep at night. When this becomes impacted, anxiety, impaired daytime function, and worsened quality of life frequently follow.

Unfortunately, insomnia is a very common medical complaint in primary care patients, and the same is true for patients in palliative care, which is illustrated by studies that report that the prevalence of insomnia is over 60 percent [1-4]. Insomnia is associated with multiple consequences that have a negative impact on quality of life and the ability to perform normal functions. In addition, insomnia is a strong predictor of the development of psychiatric disorders. (See "Risk factors, comorbidities, and consequences of insomnia in adults", section on 'Adverse outcomes'.)

Patients receiving palliative care may vary in terms of their functional status and where they are in their personal trajectory in a chronic illness. As a result, the approach and treatment to insomnia in these patients should be individualized with careful attention to the patient’s goals. Interventions for insomnia should be reviewed as a patient’s disease course unfolds and adjusted as needed to ensure the benefits of treatments continue to outweigh the risks that are acceptable to the particular patient. An overview and the general treatment approach to insomnia, as well as an overview of palliative care and the assessment of patients in palliative care, are discussed separately. (See "Benefits, services, and models of subspecialty palliative care" and "Overview of managing common non-pain symptoms in palliative care" and "Overview of comprehensive patient assessment in palliative care" and "Overview of the treatment of insomnia in adults".)

DIAGNOSIS — According to the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), insomnia is present if the patient reports the following (table 1) [5] (see "Evaluation and diagnosis of insomnia in adults", section on 'Diagnostic criteria'):

●Difficulty initiating sleep, difficulty maintaining sleep, or waking up too early, despite adequate opportunity and circumstances for sleep

●Daytime impairment that is attributable to the sleep difficulties

The ICSD-3-TR classifies insomnia in three categories: chronic insomnia disorder (symptoms occurring at least three times per week for more than three months), short-term insomnia disorder (duration of less than three months), and other insomnia disorder [5].

Associated factors — Clinicians should evaluate for factors that may contribute to sleep disturbances, which can potentially be addressed. These include:

●Physical symptoms – The presence of other physical symptoms may exacerbate sleep disturbances and vice versa [6]. Multiple symptoms can predispose to sleep disturbances. In one study of 70 inpatients in a specialized palliative care unit, pain was the most frequently cited reason by patients who did not sleep through the night [7]; others included breathlessness, cough, and hiccups. 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. Insomnia can worsen this phenomenon and therefore lead to increased pain and analgesic use. Further, insufficient sleep may lower the threshold of tolerable pain.

●Emotional distress, psychiatric illness – Palliative care patients may experience heightened distress due to fear, anger, or concern over their illness and approaching end of life, which can prevent initiation or maintenance of sleep. A diagnosis of anxiety or depression can also contribute to sleep disturbance [8,9]. Palliative care patients with insomnia frequently describe anxious and negative ruminations, due to either a diagnosed mental disorder or as part of a sub-syndromal constellation of symptoms. Topics for ruminations or anxious thoughts include 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, will physical suffering 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 is often therapeutic. (See "Overview of anxiety in palliative care" and "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis" and "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Unipolar depression in adults: Assessment and diagnosis".)

●Environmental factors – Exposure to loud or active stimuli (eg, music, other people’s conversation, computer screens, television, beeping alarms, pill crushers) can preclude restorative sleep and exacerbate insomnia. For patients who are in an inpatient facility, this also includes clinician-centered activities, such as rounds during the evening, medication scheduling, waking the patient for assessments during sleep, and increased light exposure during the night. The reported incidence of insomnia among hospitalized patients varies. (See "Poor sleep and insomnia in hospitalized adults".)

●The patient’s physical condition – As patients progress in their illness, insomnia may be exacerbated by symptoms associated with declining performance status, including becoming more bedbound, daytime somnolence, and more sedentary behavior. These changes can lead to the patient losing the normal cues for when sleep should occur thus worsening insomnia. Sleep during the day decreases the homeostatic drive to sleep at night.

●Medication side effects – Medications that are being used for other indications may have arousal or stimulant properties that can exacerbate sleep disturbances. These include opioids, steroids, beta-receptor agonists, many antidepressants, and psychostimulants [10]. (See "Overview of the treatment of insomnia in adults", section on 'Medication side effects'.)

●Medical issues – Certain populations have an increased incidence of insomnia. These include:

•Nearly 70 percent of patients with cancer [11,12]

•Between 30 and 70 percent of patients with chronic obstructive pulmonary disease (COPD) [13]

•Between 74 and 98 percent of patients with Parkinson disease [14]

•At least one-third of patients with chronic heart failure [15]

TREATMENT APPROACH

General principles — Insomnia is common and can be highly distressing to patients and their caregivers. Taking an active approach in determining the patient’s overall goals can help inform how to approach the treatment of their insomnia.

Patients facing serious illness often report that night is a time of great worry, due to ruminations on their mortality, the uncertainty of their disease trajectory and what they may expect going forward for their lives, as well as fears of whether they may even wake up the next day. When discussing insomnia, inquiring about these types of symptoms and thoughts can elucidate the burdens of their insomnia. Allowing the patient to share these common experiences can be a therapeutic intervention that also contributes to the clinician’s understanding of the impact of the insomnia.

In the context of palliative care, insomnia often coexists with other symptoms, such as pain, depression, and anxiety, and the presence of one often exacerbates the other, contributing to a decrease in quality of life [4,7]. Assessing for factors that may be contributing to insomnia is critical in the palliative care patient population prior to treatment [1]. Whenever possible, clinicians should attempt to treat potentially reversible contributors to insomnia (eg, pain control, suppression of cough, treatment for depression). In addition, patients who experience symptoms in addition to insomnia may be best managed by the administration of agents that list somnolence as a side effect (eg, mirtazapine for depression, nausea, or appetite stimulation). At the same time, however, agents used to treat insomnia should have as little risk as possible of causing or exacerbating other conditions (eg, delirium).

The approach to insomnia should take into account the patient’s overall clinical status. Patients who are receiving palliative care but maintain a relatively better prognosis and have minimal comorbid conditions will likely tolerate typical pharmacologic treatments for insomnia similarly to medically healthy individuals. In this case, the discussion with the patient about the risks and benefits of possible pharmacologic interventions can be similar to what would be done with a general medical patient.

However, patients who are approaching end of life or are more debilitated may be more susceptible to the side effects of pharmacologic treatment due to drug-drug interactions or the presence of end-organ impairment [1,16,17]. Thus, for any proposed treatment, it is necessary to have a heightened awareness of the potential adverse effects balanced with a consideration of the likelihood of benefit, the patient’s goals, and what matters most to them. In this case, the risks discussed with a patient, or their surrogate, should include a careful discussion of the possibility of delirium, general cognitive decline, lingering daytime somnolence, and falls. In this risk/benefit discussion, the clinician should fully consider the experiences described by the patient during the assessment of their insomnia. Patients may experience of insomnia as extremely burdensome, a time of profound worry with severe anxious and negative ruminations, contributing to daytime somnolence and loss of function. The impact of a patient’s insomnia on their caregivers should also be considered. For example, if a patient is awake much of the night and therefore needing their caregiver’s attention, the caregiver may start to suffer significantly as well.

Although there are no prospective studies that inform an evidence-based approach, common steps include managing the symptoms related to the sleep disorder and nonpharmacologic interventions to improve sleep, including managing the environment, lifestyle modifications, sleep hygiene, and behavioral modification. For many patients, a combined approach is most helpful.

Symptom management — Clinicians should aim to aggressively manage symptoms associated with sleep disturbances in the particular patient. For example, for patients who cannot sleep due to pain, the use of long-acting pain medications (or titration of doses at night) may help provide relief. Symptom management also includes removal or the judicious dosing of any stimulating agents that might be exacerbating insomnia, such as steroids and psychostimulants. For example, if agents with stimulant properties (eg, dexamethasone or methylphenidate) are required, they should be administered in the morning and not later in the day. For patients exhibiting signs of spiritual distress, this also includes the involvement of chaplaincy. (See "Overview of spirituality in palliative care", section on 'Approaching spiritual distress'.)

Nonpharmacologic interventions — Several nonpharmacologic interventions have been demonstrated to improve sleep among adults with advanced serious illness, although, in general, the small number of studies and wide variation of individual interventions within each category limit the generalizability of the findings [18].

Addressing the environment — In our experience, environmental steps that appear to help reduce insomnia include:

●Keeping patient rooms cool, well ventilated, and with low light at night

●The use of white noise machines [19]

●Limitations on the use of computers, smartphones, and iPads at night and other stimuli (eg, television, loud music)

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:

●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

Exercise — Exercise interventions have been evaluated for treatment of insomnia in patients with cancer, and meta-analyses have found inconsistent results, perhaps due to the heterogeneity of trials [20,21].

However, in a 2020 meta-analysis of 27 trials conducted among cancer patients with sleep disturbance using subjective and objective measures, 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 [21]. The duration of effect was longer for aerobic exercise (greater than three to fix months) than for mind-body exercise. While difficult to extrapolate to the entire palliative care patient population, if a patient is well enough to engage in one of these types of exercise, it may provide benefit for their insomnia without exposing them to risks of additional pharmacology.

Promote physical comfort — Patients should be provided with a comfortable palliative care environment. For example, if patients complain of discomfort due to their beds, the use of foam “egg crate” or memory foam mattress toppers can help.

Encourage healthy sleep-wake cycles — Helping to modulate a more normal circadian rhythm can restore sleep in patients. 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 [22]. Light exposure can be accomplished using artificial full-spectrum or blue lights when natural daylight exposure is not possible.

In addition, clinicians should encourage the maintenance of familiar routines so 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 a disease progresses, alternate bedtime routines may be created to allow for the types of activities that are tolerated by the patient.

Minimize disruptions — Clinicians and staff should minimize disruptions of a patient’s sleep. Regardless of setting, dimming lights in the vicinity of the palliative care patient’s room may provide a simple cue to others to maintain a calm, quiet, sleep-promoting environment.

For those in an inpatient setting, this includes concerted efforts not to interrupt patients during sleep:

●Medication or clinician orders should be performed only when the patient is awake.

●Avoiding medication administration, changes in the dosing and supply of parenteral medications, administration of fluids, and/or nutrition during the night.

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

Behavioral therapy — For patients with persistent insomnia despite environmental-associated modifications, behavioral therapy is the first line of treatment of insomnia. Although there are no prospective data to demonstrate efficacy in patients in palliative care, behavioral therapies should be tried initially because they avoid the potential risks associated with medications. Examples of these therapies include the following [23] (see "Cognitive behavioral therapy for insomnia in adults"):

●Sleep hygiene training (table 2)

●Cognitive behavioral therapy for insomnia (CBT-I)

●Mindfulness meditation

●Relaxation techniques

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 [24]. Additional research is needed in palliative care populations.

There are no studies specifically evaluating the benefits of CBT-I in palliative care populations. In a meta-analysis of eight randomized trials that compared CBT with control conditions (eg, waitlist control, usual care, or sleep education) in 752 cancer survivors with insomnia, self-reported sleep efficiency, sleep onset latency, frequency of waking after sleep onset, and insomnia severity each improved more with CBT-I, and the clinical effects favoring CBT-I ranged from small to large [25]. CBT has also been recommended for older adult patients to target insomnia [26]. A nurse-driven behavioral intervention was found to be effective for survivors of stage 1 and 2 non-small cell lung cancer [27]. CBT-I has been difficult for many patients to access in part due to 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 still unclear [28].

Multicomponent interventions — Several trials have examined the benefit of multicomponent interventions to improve sleep in palliative care populations (mostly nursing home residents), many of which demonstrate benefit from a combined approach. Three studies showed significantly better nighttime sleep outcomes when environmental modification was combined with sleep hygiene [29,30] or increased physical activity during the day [22]. One randomized trial combining physical activity and sleep hygiene showed better nighttime sleep [31], while a second trial that included physical activity, sleep hygiene, and an environmental component found no significant improvement in sleep [32]. Another study using both sleep hygiene and the mind-body practice of relaxation showed improved sleep in cancer patients with insomnia [33].

Although not all studies found benefit from combining specific interventions, layering different approaches appears to be helpful to at least some patients, and they are all low-risk interventions. A 2021 clinical practice guideline for behavioral and psychologic treatments of insomnia in the general adult population published by the American Society of Sleep Medicine continues to show evidence for using a multicomponent approach to the treatment of insomnia [34]. While this guideline is not specific to palliative care, these recommendations reflect our own anecdotal experience working with the palliative care population, in that a multicomponent approach is often what is needed to be effective, especially with patients who have been struggling with insomnia on a chronic basis.

Medications — The palliative care patient may have a varying sensitivity and risk associated with the use of the common pharmacologic treatments for insomnia. It is important to carefully discuss with a patient their overall goals, how their insomnia may be impacting their quality of life, and what risks may be acceptable to them as medications are considered to address their insomnia. As noted above, patients who encounter palliative care early in their disease trajectory, when they are still relatively healthy, may tolerate and respond to typical sleep aids as well as a medically healthy patient.

Patients at an advanced stage of illness are more likely to suffer adverse effects from sleep aids. The risk/benefit analysis may shift for the patient as their disease status changes. It will be important to revisit the decision to use medications and the overall treatment strategy for their insomnia over time.

We suggest that medications be prescribed for insomnia only after attempting nonpharmacologic interventions, as discussed earlier. In addition, careful attention to associated symptoms may be especially important in this population because of 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.

In the absence of prospective data, the approach to the selection of a sleep aid should be individualized, and the lowest effective dose should be administered. As with most drugs, patients in palliative care must be carefully and continually monitored for both positive effect and the development of adverse effects, particularly as the patient’s disease progresses. Although a more thorough review of medications is discussed separately, agents of common use in the palliative care population are listed below [35]. (See "Pharmacotherapy for insomnia in adults".)

Sedating antidepressants

Doxepin — Doxepin in a low dose is approved for the treatment of insomnia, although it has significant side effects, including dizziness, dry mouth, blurred vision, constipation, and urinary retention. Its mechanism of action for the treatment of insomnia is not yet known but is thought to be due to its antagonism of the histamine H1 receptor. Its primary side effects appear to be related to its antagonism of the muscarinic cholinergic receptors. When administered at a low doses (ie, 3 to 6 mg), these side effects may not be encountered [36]. The 10 mg dose can be used if the 3 or 6 mg dose is not available, although patients should be monitored carefully due to the increased risk of adverse effects.

Despite its potential side effects, doxepin is growing in popularity among clinicians treating older adult patients. While not yet supported in the literature, one may extrapolate from older adult patients to those with serious illness that this may be an option worth considering in patients with insomnia refractory to nonpharmacologic interventions.

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. It should not be used in patients with narrow-angle glaucoma or urinary retention. For patients with insomnia related to pruritus, doxepin may help treat the pruritus as well [36-40].

Trazodone — While controversial and acknowledging the lack of prospective data, the authors have had success in treating hospice patients with insomnia using the agent trazodone. This is supported by the 2014 Cochrane review discussed below and by observational data, such as the two studies below (see 'Dementia' below):

●One observational study reviewed the impact of trazodone for sleep disturbances in patients with cancer [41]. In this report, 50 percent of patients treated with low-dose trazodone (ie, 12.5 to 25 mg) experienced longer sleep times and a reduction in distressing nightmares. Of the half that reported no improvements with treatment, worsened sleep could be attributed to either evidence of disease progression or refractory physical symptoms.

●A separate observational study in patients with Alzheimer disease and other dementias reported that two-thirds of patients derived a benefit from trazodone (dosed at 50 mg) [42]. In addition, trazodone was reported to be well tolerated and without serious adverse effects [43]. (See "Pharmacotherapy for insomnia in adults", section on 'Antidepressants'.)

Mirtazapine — Although indicated for major depression, generalized anxiety disorder, and tension-type headaches, mirtazapine is associated with sedative side effects (at least at doses of 7.5 to 15 mg), which may be useful for the treatment of the depressed or anxious patient also experiencing insomnia [44,45]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine'.)

Benzodiazepine receptor agonists — Several benzodiazepine receptor agonists “eg, zolpidem” (table 3) are approved for the treatment of insomnia in the general population. For patients with respiratory issues (eg, COPD), limited data suggest that they may be safer than benzodiazepines [46]. While previous studies suggested they do not predispose patients to tolerance with longer-term use (ie, six months), subsequent data show that dependence may develop [47,48]. As with benzodiazepines, this class is associated with a risk of adverse effects and patients should be carefully selected and monitored. One study identified that hospitalized patients may be at an increased risk of falls with the agent zolpidem [49].

Coadministration with opioids can be problematic. In a study of over 400,000 older adults started on hypnotic therapy, an analysis of those patients already on opioid therapy revealed that initiation of nonbenzodiazepine hypnotics was associated with an increased risk of mortality compared with initiation of trazodone (hazard ratio [HR] 1.65, 95% CI 1.09-2.50), although the risk was not as high as among those started on benzodiazepines (HR 2.21, 95% CI 1.52-3.20) [50]. Although the study was not conducted in palliative care population, the risks are likely equal or greater in palliative care patients. (See "Pharmacotherapy for insomnia in adults", section on 'Nonbenzodiazepine BZRAs'.)

While insomnia is a common complaint in patients with a history of a substance use disorders (SUD), benzodiazepine receptor agonists should generally be avoided in this population. It is felt that the risk of misuse of this class of medication, or the potential for triggering relapse, is usually too high to balance out the potential benefits [51,52]. When a patient with a SUD is also requiring opioids, such as for pain or dyspnea, this risk/benefit analysis is even more important to consider carefully as the combination can become lethal if taken in excess. A prescriber should discuss this significant risk with their patient and consider setting up safeguards to help their patient maintain control over their use. Examples may include having a trusted caregiver keep medications with risk of abuse, dispensing a limited quantity each day, providing limited numbers with each prescription but allowing frequent refills, and ensuring that naloxone is prescribed as well. When pharmacologic intervention is needed to treat insomnia in a patient with a SUD, an alternative medication may be considered first. Typical alternatives have often included trazodone, gabapentin, or quetiapine, but doxepin should also be considered.

Taking these points into account, a clinician may decide to have a discussion with their patient about the patient’s overall goals, the severity of their insomnia and the burden they experience from it, and what interventions to address the symptoms are reasonable to try for their particular situation. For example, some patients may decide that the possibility of falls, cognitive impairment, delirium, and even increased mortality is worth taking to try improving their insomnia. In this situation, one may consider starting 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 goals and if the medication is improving the patient’s quality of life.

Selective melatonin receptor agonists — 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 benzodiazepines and benzodiazepine receptor agonists, it is non-habit forming and does not appear to have the side effects associated with other hypnotics. Ramelteon does, however, have 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.

Although there are no trials specifically addressing the benefit and risks in palliative care populations, growing evidence suggests that it is safe. In our view, a time-limited trial of ramelteon is reasonable for carefully selected patients as long as they are frequently assessed for efficacy and side effects.

In randomized trials conducted in general populations, short-term use of ramelteon is associated with improvement in some sleep parameters in patients with insomnia, but the effect size is relatively small. (See "Pharmacotherapy for insomnia in adults", section on 'Ramelteon'.)

There are no data on the efficacy or safety of ramelteon in palliative care populations. However, at least some data support safety. Ramelteon was investigated to prevent delirium [53] in severely medically ill older adult patients in the intensive care unit as well as on a standard medical floor [53]. While not specifically termed “palliative care patients,” this study patient population may indicate potential safety for the types of patients typically seen in palliative care. Compared with placebo, use of ramelteon was associated with a significant reduction in the risk of delirium, but notably there were significant differences in sleep or insomnia measures between the ramelteon and placebo groups [53]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Medications to prevent delirium'.)

Benzodiazepines — Benzodiazepines are associated with adverse effects that should be carefully considered in the palliative care patient. These include [1,46,54,55]:

●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 and, in patients with COPD, the concern for impaired respiratory function

●Potential for increased central nervous system depression when used in combination with opioids

In addition, there have been no prospective or long-term studies to assess the efficacy and safety of longer-term use (ie, two weeks or longer) in patients receiving palliative care. Therefore, use of these medications should be individualized based on the patient’s current status, prognosis, goals, and underlying medical condition. As noted above for benzodiazepine receptor agonists, a careful individualized discussion may be had with the patient to carefully assess their specific goals, severity and burdens of their insomnia, and what risks are acceptable to them when weighed against the possible benefit of a trial of a benzodiazepine to treat insomnia. As benzodiazepines are often used to treat other symptoms in the palliative care patient population, one approach may be to adjust the dose timing to bedtime rather than adding on an additional dose. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine hypnotics'.)

Over-the-counter agents

Diphenhydramine — Diphenhydramine is an over-the-counter antihistamine with sedating properties. However, the side effects, primarily related to the anticholinergic action (eg, dry mouth, decreased cognitive function, delirium); the rapid development of tolerance; and the lack of safety data in palliative care patients should discourage their widespread use, particularly in the palliative care context. Anticholinergic agents in general are common contributors to delirium. We do not use diphenhydramine in our own practice as a treatment for insomnia.

Melatonin — Melatonin is a neurohormone secreted by the pineal gland that can assist with maintaining sleep-wake cycle. 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. (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

Unfortunately, double-blind placebo-controlled trials have not demonstrated consistent findings in terms of dose-response relationships, benefits, and risks, although most experts believe that, at doses ranging from 0.3 to 20 mg, melatonin is well tolerated without adverse effects. In general, it does not appear to be particularly effective for insomnia in most patients, with the possible exception of patients who have delayed sleep phase syndrome and in a subgroup of patients with low melatonin levels. (See "Pharmacotherapy for insomnia in adults", section on 'Over-the-counter sleep aids'.)

In our experience, melatonin has been, at best, only modestly effective in reducing initial sleep latency and frequent nighttime or early morning awakenings for patients receiving palliative care, although we acknowledge the lack of prospective data to confirm this impression. However, for patients who find benefit from this agent, be aware that there may be dose and quality inconsistencies in preparation across various brands.

Other agents — A variety of other herbal products are purported to be useful for insomnia. There is little evidence from randomized controlled trials about the efficacy of many herbals, however, and for those that have been well studied (eg, valerian), there is little evidence of benefit, and none can be recommended. This subject is addressed in detail separately. (See "Pharmacotherapy for insomnia in adults", section on 'Over-the-counter sleep aids'.)

Special populations — The impact of medications may be especially important in older patients and those with baseline cognitive impairment, especially if it is moderate to very severe.

Older adult patients — Older adult patients often have multiple comorbid medical conditions that can contribute to sleep disturbances. This in turn can make them more susceptible to the adverse effects of sleep aides. Therefore, it is important to maximize treatment and palliation of any comorbid conditions as the primary approach to treatment of insomnia.

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, and reduced time spent in deep sleep [17]. These can result in increased daytime fatigue and more frequent napping. Given the potentially increased risk for adverse outcomes with pharmacologic agents, it is important to carefully weigh the risks and benefits of these medications through a discussion with older patients to determine if a drug trial aligns with their goals. In general, it is our practice to instead “prescribe” nonpharmacologic interventions such as education regarding sleep hygiene before using medications.

When we encounter older palliative patients who have been prescribed benzodiazepines or benzodiazepine receptor agonists, we discuss with the patient, or their surrogate if appropriate, the risks and benefits of continuing to use these agents. Deprescribing these medications is often advisable as the risk of adverse events increases as a patient ages or becomes more frail. Many patients have become very attached to their sleep aid and may find it difficult to stop. 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 'Inappropriate medications'.)

If drugs are necessary, choose drugs with the fewest likely adverse effects, start at the lowest potential effective dose, and use time-limited trials; note that for most hypnotics, starting doses are lower for older adult patients. For patients taking a pharmacologic sleep aid, frequent reassessments should be performed for efficacy, continued need, and the development of adverse effects.

Dementia — Patients with dementia 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 other delirium).

Management of insomnia in patients with dementia should include gathering a comprehensive history, ensuring medical conditions are maximally treated, addressing polypharmacy with regard to sleep-related side effects, and teaching care providers the basics of good sleep hygiene. Nonpharmacologic interventions that focus on environmental restructuring and maintenance of consistent sleep patterns are the mainstays of therapy. Maximizing exposure to natural light in the mornings and light exercise, when feasible, can help entrain more normal circadian rhythms.

Suvorexant, a dual orexin receptor agonist, was approved by the US Food and Drug Administration (FDA) for the treatment of insomnia in older patients in 2014. A review of trials investigating this agent found that improvement in subjective time to sleep onset was around six minutes, similar to other medications used for insomnia. While suvorexant is generally well tolerated, this review cited a number of possibly troubling adverse effects, including abnormal dreams, somnolence, fatigue, and dry mouth [56,57]. This agent has not yet entered into our routine practice caring for hospice and palliative care patients. Nonpharmacologic interventions are still the preferred means of treatment of insomnia in this patient population.

Lemborexant is also an option for patients with irregular sleep wake rhythm disorder and dementia of the Alzheimer type. It has been shown to help with sleep consolidation overnight and decrease daytime periods of sleep. The side effect profile is favorable as well. This agent joins suvorexant as a promising new approach to treat insomnia in some of the patients most vulnerable to adverse effects, such as those with major neurocognitive disorder [58].

In a 2020 Cochrane review of sleep aides for patients with dementia, several studies showed some benefit from the use of trazodone and the orexin antagonists for the treatment of insomnia [59]. The trazodone trial was small, including only 30 participants, used an average dose of trazodone at 50 mg and found that total sleep time increased by 43 minutes. However, total time number of awakenings did not change. There were no serious adverse events noted. The studies of orexin antagonists, including 323 subjects, found few adverse effects in patients with mild to moderate dementia of the Alzheimer type. The effect sizes were small, but some patients and caregivers may find any extra sleep welcome. For example, in the studies looking at orexin antagonists, the total time asleep increased by 28 minutes, but there was little impact on the total number of nighttime awakenings. Unfortunately, these studies did not look at measurements of quality of life for the patient or the caregivers. This review also looked at five trials evaluating melatonin, which did not show benefit in improving sleep.

The studies of trazodone and orexin antagonists reviewed in this Cochrane article are encouraging, but the authors noted that they did not actually find improvements in time of uninterrupted sleep for patients with dementia. They also found that side effects of the medications were not systematically assessed. Finally, the authors concluded that additional studies are needed, which resonates with our impression that studies specifically designed to evaluate outcomes in patients receiving palliative care are needed. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Insomnia and other sleep-wake disturbances'.)

IMPACT TO CAREGIVERS — Although the data are more limited, the patient’s insomnia can significantly impact their caregiver’s sleep quality and overall quality of life [60]. Impaired sleep in caregivers increases irritability, depression, anger, and guilt and decreases overall ability to provide care [61]. 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) [62]. The 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

●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 70 percent of palliative care patients. (See 'Diagnosis' above.)

●When insomnia is present, it is important for clinicians to evaluate the full impact this symptom is having on the patient and their family. Insomnia frequently correlates with severely diminished quality of life in multiple domains. Anxiety, including highly distressing negative anxious ruminations, should be assessed. Allowing time for a patient to describe their personal experience with insomnia can not only help with the evaluation but can also be therapeutic in itself. (See 'General principles' above.)

●If patients receiving palliative care report insomnia, clinicians should evaluate other factors that may contribute to sleep disturbances, which can potentially be addressed. (See 'Associated factors' above.)

●The approach to insomnia should take into account the patient’s clinical status. Patients receiving palliative care but who maintain a relatively better prognosis and have minimal comorbid conditions will likely tolerate typical pharmacologic treatments for insomnia similarly to medically healthy individuals. However, patients who are approaching the end of life or are more debilitated may be more susceptible to the side effects of pharmacologic treatment due to concerns over drug-drug interactions or the presence of end-organ impairment. When developing a treatment plan, the degree of suffering from the insomnia, as elicited in a thorough evaluation, needs to be considered. Patients may elect trials of medications, even though there is risk of adverse effects, for the possibility that their insomnia may be effectively palliated. (See 'Treatment approach' above.)

●Clinicians should aim to aggressively manage symptoms associated with and/or contributing to sleep disturbances in the particular patient. (See 'Symptom management' above.)

●Addressing environmental issues may help address external factors exacerbating insomnia in these patients. This includes keeping patient rooms cool, well ventilated, and with low light at night, the use of white noise machines, and limitations on the use of computers at night and other stimuli (eg, television, loud music). (See 'Addressing the environment' above.)

●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, large meals before bedtime, drinking a large amount of fluid in the evening, or stimulants, including caffeine. Daytime light exposure and activity levels should be increased when possible. (See 'Lifestyle modifications' above.)

●Clinicians and staff should minimize disruptions of a patient’s sleep. Regardless of setting, dimming lights in the vicinity of the palliative care patient’s room may provide a simple cue to others to maintain a calm, quiet, sleep-promoting environment. (See 'Minimize disruptions' above.)

●For patients with persistent insomnia despite environmental-associated modifications, when practical and available, cognitive behavioral therapy for insomnia (CBT-I) is a first line of treatment of insomnia. Although there are no prospective data to demonstrate efficacy in patients in palliative care, behavioral therapies may be tried because they avoid the potential risks associated with medications and may augment any medication intervention as well. (See 'Behavioral therapy' above.)

●In consideration of each patient’s unique place in their disease trajectory, their current level of medical debility, the intensity of the suffering associated with their insomnia, and the patient’s tolerance for risk of possible adverse effects, medications may be considered. When practical and in line with a patient’s goals, we suggest that medications be prescribed for insomnia only after attempting nonpharmacologic interventions. There is no single pharmacologic approach that can be recommended for all patients. The approach to the selection of a sleep aid must be individualized, and the lowest effective dose should be administered. As with most drugs, patients in palliative care must be carefully and continually monitored for both positive effect and the development of adverse effects, particularly as the patient’s disease progresses. (See 'Medications' above.)

●Clinicians should be cognizant of the impact of insomnia on the sleep quality of other members in the patient’s family or household members, particularly those who act as the primary caregivers. The negative impact on caregivers may affect the ability of the patient to remain at home. (See 'Impact to caregivers' above.)