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10 Articles in Volume 14, Issue #3
Practical Guide To Safe Use of Nonprescription Pain Medications
Common Causes of Acute Abdominal Pain
Early Treatment of TMD May Prevent Chronic Pain and Disability
Insomnia: Focus on New Dosing Concerns In Women
Is Marijuana Use Associated With Non-adherence To Opioid Therapy—Insights Gained From Urine Drug Monitoring
New Evidence-Based Diagnosis Criteria for TMD
New Rating Scale Helps Evaluate Refractory Chronic Migraine Patients
The Effect of Prolonged Knee Extension Immobilization on Knee Active Range of Motion: A Case Study on Arthrofibrosis
Opioid Bias Hurts Pain Patients
Can misoprostol be used for refractory chronic constipation?

Insomnia: Focus on New Dosing Concerns In Women

Of all the sleep disorders, insomnia is the most prevalent, accounting for 10% to 20% of complaints in primary care settings. The treatment approach for insomnia disorders has remained largely the same since 2008; however, recent research on gender-related pharmacokinetic differences for some drugs has led to a change in the way physicians should prescribe certain agents in women.

Sufficient sleep increasingly has been recognized as a key component of chronic disease prevention as well as overall health promotion.1 Insufficient sleep is associated with both the onset of, as well as difficulty in managing, chronic diseases. In fact, the increased number of motor vehicle crashes, industrial disasters, and occupational harm associated with sleep insufficiency raises it to the level of a public health concern.2 It is estimated that 50 to 70 million adults in the United States suffer from a sleep or wakefulness disorder.2,3 Of all the sleep disorders, insomnia is the most prevalent, accounting for 10% to 20% of complaints in primary care settings.4 The treatment approach for insomnia disorders has remained largely the same since the publishing of clinical guidelines in 2008; however, recent research on gender-related pharmacokinetic differences for some drugs has led to a change in the way physicians should prescribe certain agents in women.2,5 This review will highlight these new data and the resulting dosing considerations.

Types of Insomnia

Currently, classifications for insomnia are available in 2 references, the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-V) and the International Classification of Sleep Disorders, Second Edition (ICSD-2).4,6 Both references identify various subtypes of insomnia, with the DSM-V classifying insomnia either as a primary disorder or as secondary to some underlying cause. The ICSD-2 is intended for use by sleep specialists and classifies insomnia into various categories; however, these specific categories are beyond the scope of this review.6 Insomnia is further classified based on its duration, with transient insomnia generally classified as symptoms lasting only a few (1-3) nights; acute insomnia, occurring when symptoms last 3 days to less than 4 weeks; and chronic insomnia, occurring when symptoms last more than 4 weeks.7

According to the DSM-V, patients with insomnia complain of difficulty initiating or maintaining sleep or having nonrestorative sleep; the specific diagnostic criteria are summarized in Table 1.4 Nonrestorative sleep is characterized as sleep that is restless, light, or of poor quality.

There are numerous secondary causes of insomnia, including underlying mental disorders, other general medical conditions, and illicit substance or medication use.2,7 Patients with chronic pain syndrome or degenerative diseases may have trouble sleeping because of their pain. Examples of chronic pain syndromes associated with insomnia include fibromyalgia, arthritis, back pain, and headache.8,9

Pain and Sleep

The relationship between pain and difficulty sleeping is complex and has been described as a vicious cycle.8,10-11 Pain intensity has been shown to increase the severity of sleep disturbances, and vice versa.11 Pain-related arousal has been shown to differ from somatic and cognitive arousal.10 In addition, pain is associated with the development of depression and anxiety, which can contribute to sleep difficulties and insomnia. Conversely, pain thresholds may be decreased as a response to disturbed sleep, and it has been observed that a disruption in sleep may actually directly affect nociceptors.12,13 Therefore, management of both pain and insomnia are required for the most benefit.

Insomnia also can be drug induced, especially by substances that result in central nervous system (CNS) stimulation. A list of medications and substances that may adversely affect sleep are summarized in Table 2.2,7,8,10

Risk Factors

According to the National Institutes of Health (NIH), there are various risk factors for insomnia.14 The first is age, with rates of insomnia increasing in older patients. This primarily has been attributed to the high prevalence of medical and psychosocial conditions in this patient population, coupled with the frequent use of polypharmacy to treat these conditions.15 Higher rates of insomnia in this patient population also may be a result of older patients having a substantial decline in their arousal threshold (the mechanism that preserves sleep) compared with younger patients.16 Data suggest that older patients are more easily awakened by external noises such as traffic because of diminished sleep intensity.

The NIH also noted that women have a higher prevalence of insomnia, particularly in the postmenopausal years.14 These higher rates have been attributed to a multitude of factors, such as a more frequent occurrence of depression and anxiety in women compared with men, insomnia related to pregnancy, and sleep disorders occurring during the menopausal transition period.17 Furthermore, several studies and surveys have shown a link between pain syndromes and insomnia in women, making this group of patients especially difficult to manage.18 Other NIH-identified groups who have a higher prevalence of insomnia include patients with lower education and income and those who are divorced, separated, or widowed.14 The data for differences in insomnia rates among various racial or ethnic groups are inconclusive.

Insomnia also is commonly observed in patients with comorbid mental disorders.4 In a cohort of the general American population, it was reported that 40% to 60% of patients with insomnia showed symptoms of depression, including 10% to 25% of cases with diagnosed clinical depression; anxiety disorders were diagnosed in 20% to 30% of patients with insomnia.19

Diagnosing Insomnia

A 2008 Clinical Guideline for the Evaluation and Management of Chronic Insomnia provides recommendations for the assessment and treatment of patients with insomnia.2 Patients presenting with insomnia should have a detailed history taken to identify any medical, psychiatric, or substance-related factors that may be contributing to their insomnia. In addition, a thorough sleep history should be obtained. Some elements of the sleep history include characterization of the primary complaint (eg, difficulty falling asleep vs awakenings vs poor sleep), the frequency and duration of insomnia, nocturnal symptoms, impact on daytime activities and functioning, and any past or current treatments and the patient’s responses to them. A physical exam also is recommended to identify risk factors for other sleeping disorders (eg, sleep apnea), such as obesity, increased neck circumference, and upper airway anatomical changes. At minimum, the guideline recommends that clinicians perform the general medical assessment as described above in addition to having patients complete a sleep questionnaire and a 2-week sleep log/diary to help identify sleep patterns. An example of a sleep questionnaire is the Insomnia Severity Index, a 7-item rating to assess patient’s perception of insomnia.

In patients experiencing pain or those with chronic pain, careful assessment is required to determine how well the pain itself is being managed.10 The presence of comorbid psychiatric disorders also should be considered. As previously mentioned, depression and anxiety are common in patients with chronic pain and may further exacerbate sleep disturbances and insomnia.

Treatment of Insomnia

Insomnia should be treated if the condition affects a patient’s daytime functioning, overall health, or sleep quality.2 The first step for treatment is the identification and management of comorbid conditions that are associated with insomnia, such as depression or chronic pain, followed by the modification of behaviors or medications (see Table 2) that can worsen insomnia. If medications that are associated with insomnia cannot be discontinued or switched, consideration should be given to adjusting the timing of administration. The main goals for treating insomnia include improving sleep time and/or quality and reducing daytime impairments. The recommended treatment approach involves pharmacologic and nonpharmacologic interventions.

Nonpharmacologic Therapies

There are numerous cognitive and behavioral interventions for patients with insomnia.2 Some of these interventions include stimulus control, relaxation training, cognitive-behavioral therapy for insomnia (CBT-I), sleep restriction, paradoxical intention, biofeedback, sleep hygiene, and multicomponent therapy. The 2008 guideline recommends stimulus control, relaxation training, and CBT-I with or without relaxation therapy as the standards of care for nonpharmacologic management of chronic insomnia. The other interventions also are noted to be useful but have less evidence supporting their efficacy.

Stimulus control focuses on having patients go to bed only when sleepy and avoid staying awake in bed for prolonged periods of time.2 Patients are instructed to remove themselves from bed if they are not asleep within 20 minutes and to engage in a relaxing activity until they are drowsy again. Relaxation training can include techniques such as progressive muscle relaxation, guided imagery, or abdominal breathing. Progressive muscle relaxation, specifically, decreases arousal and is especially useful in patients with chronic pain.10 Finally, the last standard, CBT-I treatment, combines cognitive therapy with behavioral interventions such as stimulus control or sleep restriction. Cognitive therapy is designed to help patients change their beliefs and unrealistic expectations about sleep. For patients with chronic pain who are experiencing insomnia, a hybrid approach involving CBT-I combined with pain management programs has been suggested.10

Educating patients with insomnia about proper sleep hygiene techniques is a common nonpharmacologic intervention used by many clinicians.7,20 The guideline recommends that sleep hygiene education be performed in conjunction with stimulus control, relaxation training, sleep restriction, or cognitive therapy.2 Elements of good sleep hygiene education are summarized in Table 3.

Pharmacologic Therapy

According to the 2008 guideline, the choice of drug therapy depends on many factors, such as specific symptoms and sleep patterns, previous response to treatment, patient preference, cost, comorbid conditions, and drug–drug interactions.2 Several classes of medications have been used to treat insomnia; however, only 3 classes have FDA-approved labeling for insomnia. These are the benzodiazepine receptor agonists (benzodiazepines and nonbenzodiazepine hypnotics), the antidepressant doxepin, and the melatonin receptor agonist ramelteon.21 Table 4 summarizes the FDA-approved medications as well as other prescription products that have evidence for use in managing insomnia.10,14,21-24 The 2008 guideline recommends that pharmacotherapy be initiated in combination with CBT-I.2 A recent meta-analysis of all FDA data for nonbenzodiazepine hypnotics showed that objective and subjective sleep outcomes were improved compared to placebo, especially in younger and female patients, but the placebo effect was quite large, underscoring the need for CBT-I.25

Prescription Medications

First-line therapy is a short- or intermediate-acting agents such as zaleplon (Sonata), zolpidem (Ambien), eszopiclone (Lunesta), triazolam (Halcion), or temazepam (Restoril), or the melatonin receptor agonist ramelteon (Rozerem).2 Benzodiazepines have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties through agonistic effects at the g-aminobutyric acid (GABA) receptor.24,26 The newer nonbenzodiazepine sedative-hypnotics have only sedative properties. The guideline does not give preference to a specific medication.2 Zaleplon and ramelteon are effective in reducing sleep latency, but because of their short half-lives, they are not as effective in reducing wakefulness after sleep onset.24,26 Intermediate-acting agents such as temazepam and eszopiclone can be used to improve sleep maintenance. One caveat is that longer-acting agents have a greater potential to lead to residual sedation or next-day effects. Because of their potential for abuse, benzodiazepines and nonbenzodiazepine sedative-hypnotics are categorized as schedule C-IV by the Drug Enforcement Agency.21,25,26 The melatonin receptor agonist, ramelteon, is not scheduled.

Patients with chronic pain managed with opioids should avoid benzodiazepines because of overlapping CNS effects that can lead to increased sedation and confusion.10 Other side effects associated with benzodiazepines include anterograde amnesia and rebound insomnia when the agents are discontinued.24 These agents should be used with caution in elderly patients because of the increased risk for falls in this population. Tolerance to benzodiazepines can develop after 1 month of use. Nonbenzodiazepine sedative-hypnotic agents have demonstrated similar efficacy to benzodiazepines but have the advantage of less residual sedation.

Patients with comorbid depression may be managed with low-dose sedating antidepressant therapy,2 with agents such as trazodone, mirtazapine, doxepin, and amitriptyline. The guideline does not give preference to any specific antidepressant. It has been suggested that patients with chronic pain can be successfully managed with sedating antidepressants because there is a high prevalence of comorbid depression, and antidepressants have some analgesic effects.10 Daytime side effects can be problematic because of the prolonged half-life of many of the antidepressants (Table 4). Tricyclic antidepressants (TCAs) have been associated with anticholinergic effects (urinary retention, constipation, dry mouth) and cardiac conduction abnormalities. Trazodone is not associated with significant anticholinergic effects to the extent that the TCAs are, and it is not associated with dependence; therefore, it may be a valuable option for patients with a history of substance abuse.2,24,26 However, trazodone has been associated with orthostatic hypotension and priapism in men.7,24 Of note, the low doses of antidepressants used for insomnia are inadequate to manage depression but can have additive efficacy for depression when used in combination with full-dose antidepressants.2 Additionally, antidepressants have analgesic properties independent of their effect on depression.10

Once an agent has been selected, it is reasonable to treat acute insomnia for 2 to 4 weeks with most agents, except for triazolam and temazepam, which are approved for use in insomnia for 7 to 10 days.10,21-22,24 The lowest effective dose of the agent should be used for the shortest duration of time necessary. Consideration may be given to treating chronic insomnia intermittently, for example, 2 to 5 times per week.2 There is a lack of data on chronic use of sedative-hypnotics; however, such use is noted to occur in practice.2,24,26 Open-label extension trials have been conducted for eszopiclone and zolpidem for up to 12 months.2 Patients receiving long-term sedative-hypnotics should be followed and reevaluated at least every 6 months. For patients who do not respond to initial therapy, it is reasonable to try another agent from the same class with careful consideration of specific sleep disturbances.

Insomnia is treated in the same manner in patients with or without chronic pain.2 However, pain control must be optimized and any comorbid psychiatric disorders should be identified and managed when treating patients with chronic pain and insomnia. The guidelines suggest the use of gabapentin or pregabalin (Lyrica) for pain control for selected patients as appropriate because these agents are associated with somnolence.

Zolpidem Dosing in Women

In January 2013, a FDA Drug Safety Communication was issued about new evidence of next-morning impairment associated with zolpidem use.5 According to data submitted to the FDA, when serum zolpidem levels exceeded 50 ng/mL, driving impairment was severe enough to increase the risk of a motor vehicle accident.5,27 In a study of 250 men and 250 women, zolpidem concentrations exceeded this level in approximately 15% of women and 3% of men 8 hours after a 10-mg dose. The difference between men and women was less pronounced after an extended-release dose of 12.5 mg, with the zolpidem level exceeding 50 ng/mL in 33% of women and 25% of men. Age was a factor in the levels following a 6.25 mg dose, with 15% of women and 5% of men exhibiting increased levels and 10% in both elderly men and women. As a result, the FDA concluded that women appeared to be at a greater risk of serious next-morning impairment due to decreased drug clearance compared to men. The FDA recommended that the labeling be changed for both the immediate- and extended-release zolpidem formulations as summarized in Table 5:

  • Intermezzo, a low-dose zolpidem product, was exempt from these recommendations since labeling already reflected lower dosing in women.5 In fact, it was the data from the approval of this drug that supplied the 50 ng/mL level as a marker for increased risk of motor vehicle accidents.27
  • In May 2013, the FDA approved the zolpidem labeling changes and added a warning that all patients—both men and women—taking the extended-release formulations should not drive the next day because drug levels may remain high.28

Other Gender-related Considerations

In the safety communication, the FDA outlined their intent to investigate other medications used for sleep problems, including over the counter (OTC) medications, for risk of impaired mental alertness.5 As of February 2014, no updated communications have been released. Labeling for zaleplon, eszopiclone, and ramelteon include a statement expressing that the pharmacokinetic properties between men and women are similar.21 Mirtazapine labeling mentions gender under special populations, stating that females of all ages have significantly longer elimination half-lives compared to men. However, a separate dosing for women is not supplied.

OTC Agents/Dietary Supplements

Sedating antihistamines and certain dietary supplements have been used for the management of insomnia.2,24,26 Antihistamines are generally safe and effective for mild insomnia; however, definitive evidence of efficacy is lacking. As with TCAs, anticholinergic side effects occur with antihistamines, and these effects are likely to be more problematic in elderly patients. Diphenhydramine and doxylamine are the agents used. Dietary supplements including valerian, melatonin, and l-tryptophan also have been used to treat insomnia.12 Dietary supplements are not regulated by the FDA, and there may be variations in the content of the product compared with the labeling. The OTC agents, including dietary supplements, used for insomnia are summarized in Table 6.2,14,21


Insomnia is a common medical problem associated with significant quality of life impairments for affected patients, including difficulty concentrating, memory impairment, decreased productivity at work, and an increased risk for accidents. Patients with chronic pain have an increased incidence of insomnia compared with the healthy population. The underlying mechanisms between chronic pain and insomnia are complex, but it is believed that emotional and somatic arousal plays a role in insomnia, and sleep disturbance lowers the pain threshold, causing a reciprocal cycle of insomnia and pain.

Furthermore, women more commonly have pain disorders, anxiety and depression, and sleep difficulties than men. Treatment of insomnia employs both nonpharmacologic interventions and drug therapy. Management of patients with chronic pain and insomnia should first be directed at adequate pain control and assessment for concurrent depression. Clinicians should be aware of the potential for additive sedation in patients receiving opioid analgesics and sedative-hypnotic agents. Sedative-hypnotic agents should be used at the lowest effective dose and shortest duration possible with close follow-up of the patient to assess response. Recent information on the pharmacokinetic gender differences for zolpidem products led to updated dosing recommendations in the labeling that clinicians should apply when initiating pharmacotherapy with these agents.


Last updated on: March 5, 2019
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