Current and New Thinking in the Management of Comorbid Insomnia | Page 2

Patients also self-medicate with over-the-counter options that contain the antihistamines diphenhydramine and doxylamine with or without analgesics. These options often result in next-day sedation and may cause significant anticholinergic effects, posing a specific risk to the elderly and to patients taking other anticholinergic medications (antidepressants, antipsychotics).¹³

Approximately 4.5% of those with insomnia (1.6 million Americans) used some form of complementary or alternative medicine to treat their condition in the past 12 months.⁵ The 5 most common dietary supplements used for all conditions were echinacea, ginseng, ginkgo biloba, valerian, and melatonin. However, there is little evidence as to the benefits of valerian, which may have toxic effects.¹ Meanwhile, the NIH panel noted that while melatonin “is thought to be safe” in shortterm use, “there is no information about the safety of long-term use.”¹

The only medications endorsed by the NIH State-of-the-Science panel on chronic insomnia were the FDA-approved benzodiazepine receptor agonists (BZRAs) indicated for the treatment of insomnia. (Since then, ramelteon, a selective melatonin receptor agonist, has been approved by the FDA.) The panel did not endorse sedating antidepressants, antipsychotics, or antihistamines because of safety concerns or a lack of evidence of efficacy.¹

Of the FDA-approved insomnia medications now on the market in the United States, 9 are BZRAs (Schedule IV controlled substances), while the tenth operates on melatonin receptors and has no risk of abuse. The BZRA s promote sleep by enhancing the normal inhibitory action of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor complex. All of the FDA-approved hypnotics are relatively rapidly absorbed and generally facilitate rapid sleep oset. Most of the BZRAs are approved for the short-term treatment of insomnia. Eszopiclone, ramelteon, and zolpidem extended-release (ER) have been approved with no implied limitations on their duration of use. In addition, eszopiclone and zolpidem ER are specifically approved for sleep maintenance insomnia.^16-19

Benzodiazepine hypnotics. With the introduction of the nonbenzodiazepine agonists, the older benzodiazepine agents (estazolam, flurazepam, quazepam, temazepam, and triazolam) have fallen out of favor and are prescribed less often. A metaanalysis of studies on their use found the most commonly reported adverse events were somnolence, headache, dizziness, nausea, and fatigue.¹⁵ There is also evidence that using them at higher-than-recommended doses and/or long-term use may be associated with dependency, impairment in psychomotor functioning and coordination, risk of falls in elderly patients, tolerance or dependency, residual effects on waking, respiratory depression, and withdrawal reactions after prolonged use.¹³

Nonbenzodiazepine hypnotics. The introduction of this class of drugs in the early 1990s advanced the pharmacologic treatment of insomnia, whether viewed as transient or chronic, primary or comorbid. The elimination half-life and dose determine the duration of action in promoting sleep or causing residual sedation.²⁰ Zaleplon has the shortest half-life (about 1 hour) and eszopiclone the longest (5-7 hours), with both immediate and ER zolpidem formulations falling in between.^16-19 A meta-analysis of studies on the benzodiazepine and nonbenzodiazepine hypnotics found no significant difference in terms of their effect on sleep latency, although the nonbenzodiazepines were considered safer than the benzodiazepines.¹⁵

The most commonly reported adverse events for nonbenzodiazepine hypnotics are headache, dizziness, nausea, and somnolence,¹⁵ although they appear to have a much lower risk for dependence.¹ Recently, language was added to the package information of all approved sleep-promoting medications concerning the potential for severe allergic reactions and complex sleep-related behaviors, including sleep-driving.^16-19

Melatonin receptor agonists. Ramelteon is the only approved insomnia treatment medication that is not classified as a controlled substance. It is a nonsedating sleep medication that acts on the suprachiasmatic nucleus to influence the circadian rhythm effects on the sleep/wake cycle. Adverse effects include somnolence, dizziness, and fatigue. Ramelteon is not recommended in patients with moderate-to-severe hepatic impairment or in those also taking fluvoxamine.¹⁸

Pharmacologic Studies in Comorbid Insomnia

Eszopiclone and zolpidem are the only compounds with published studies investigating their use in patients with comorbid insomnia.

Eszopiclone. Pollack et al studied the effects of eszopiclone in patients with comorbid insomnia and generalized anxiety disorder (GAD) during a 10-week study. The GAD patients were all treated with escitalopram 10 mg for the entire 10 weeks and randomized to concomitant use of placebo or eszopiclone 3 mg for 8 weeks followed by a singleblind, 2-week placebo period. Compared with the placebo group, the patients treated with eszopiclone experienced significantly greater improvement in sleep and daytime functioning (P <.05), greater improvement in anxiety scores (P <.05), and better Clinical Global Impressions (CGI) of Improvement at all time points (P <.02). The CGI of Severity of Illness was not statistically different after week 1. At week 8, the eszopicloneescitalopram–treated patients compared with the placebo group demonstrated better anxiety scores for response (63% vs 49%; P = .001) and remission (42% vs 36%; P = .09).²¹

Fava et al evaluated eszopiclone in a double-blind, placebo-controlled clinical trial involving 545 patients diagnosed with MDD. Patients were randomized to monotherapy with fluoxetine/placebo or cotherapy with fluoxetine and eszopiclone for 8 weeks. Compared with the control group, eszopiclone cotherapy was associated with greater improvements in nighttime sleep, daytime functioning, and more rapid antidepressant effects (assessed via the 17-item Hamilton Rating Scale for Depression [HAMD-17]) throughout the 8-week treatment period.²² A 2-week, singleblind, placebo, run-out phase of the study found that the improvements were maintained after discontinuing eszopiclone (with continued fluoxetine treatment) with no withdrawal-related adverse effects.²³