Both nonbenzodiazepines and benzodiazepines are associated with adverse effects that include fatigue, dizziness, ataxia, and the development of dependence and tolerance with long-term use. Although head-to-head studies comparing these classes of hypnotics have been minimal, a recent meta-analysis supports the finding of reduced adverse effects for the nonbenzodiazepines.18 The nonbenzodiazepines typically have a shorter half-life and are more selective at the γ-aminobutyric acid receptor, factors that are partially responsible for less residual daytime sedation and other adverse effects.
In the treatment of anxiety disorders with comorbid insomnia, the latter should be treated concurrently with, but independently of, the anxiety disorder per se. The idea that one should wait to see whether the insomnia resolves with only the treatment of the anxiety disorder is no longer valid. Clinical experience has shown that without targeted insomnia treatment, insomnia frequently persists.3,19
When adding a hypnotic to an antidepressant in the treatment of anxiety, the risk to benefit ratio must be considered. Pollack and colleagues20 looked at a large group of patients with GAD comorbid with insomnia (N = 595). The patients received either 10 mg of escitalopram coadministered with 3 mg of eszopiclone or the escitalopram with placebo. Those in the active hypnotic treatment group had a significant response in their insomnia by the first week. The combination of medications was well tolerated with no significant increase in adverse effects.
Most surprisingly, the anxiety scores for those patients who received the hypnotic significantly improved starting at week 4 even after removing insomnia symptoms from the anxiety assessment. The time to onset of the anxiolytic response was also reduced. In addition, the combination treatment led to a slightly better symptom response and remission rate for the anxiety disorder.
Similar results were reported in a 12-week open-label study (N = 27) undertaken by Gross and colleagues.21 The researchers evaluated ramelteon (8 mg/d), a melatonin agonist, in patients who had GAD comorbid with insomnia and whose condition was partially responsive to an SSRI or a serotonin norepinephrine reuptake inhibitor. The hypnotic was well tolerated, effective for insomnia, and appeared to facilitate the treatment of GAD.
A double-blind placebo-controlled study by Fava and colleagues22 evaluated the efficacy and safety of zolpidem extended-release (12.5 mg/d) versus placebo in patients with comorbid GAD and insomnia who were being treated with escitalopram (10 mg/d). Sleep measures improved significantly by the end of week 1, and there was no added burden of adverse effects. Zolpidem did not show a beneficial anxiolytic effect.
Approximately 50% of patients with insomnia continue to have insomnia 3 years after initial diagnosis, and many patients require months to years of treatment. Nonbenzodiazepines for primary insomnia were found to have continued efficacy and to be well tolerated with no evidence of abuse or withdrawal symptoms on discontinuation of use after 12 months.23,24 Ramelteon was also found to be efficacious with no significant issues of abuse or tolerance in a 24-week open-label study.25 The literature for longer use of hypnotics is scarce.
Anxiety disorders are frequently comorbid with alcohol or substance use disorders.4,26 Consider ramelteon or low-dose sinequan to avoid potential issues of abuse and addiction. Nonbenzodiazepines are preferred over benzodiazepines; there is evidence that the former have decreased potential for abuse and a better adverse-effect profile.
In some patients with insomnia, benzodiazepines are clearly necessary. The other hypnotics may not be as effective for some patients, and the anxiolytic properties of benzodiazepines may be helpful.
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