National Sleep Foundation

Chapter 2: Insomnia

Insomnia Treatment: Hypnotics

Hypnotics

Hypnotics are drugs designed to induce sleep. The choice of hypnotic depends partly on the nature of the individual’s sleep complaint (i.e., problems falling asleep vs. problems staying asleep), and partly on the duration of drug’s efficacy.1

There are four classes of FDA-approved hypnotics:

  1. Benzodiazepine receptor agonist (BzRA)
  2. Benzodiazepine receptor agonist with a non-benzodiazepine structure (non-BzRA)
  3. Selective M1/M2 melatonin receptor agonist
  4. Orexin receptor antagonist

Table 2.1 provides an overview of these drug classes and orexin receptor antagonists.

Results from randomized clinical trials (RCTs) indicate that all FDA-approved hypnotics are effective in the short-term management of primary insomnia. There are currently only three hypnotics that are FDA-approved for long-term use: eszopiclone, controlled-release zolpidem, and ramelteon.

Eszopiclone: In four RCTs (including one in elderly patients), eszopiclone (a non-BzRA) demonstrated efficacy over placebo for both sleep onset latency and sleep maintenance for up to 12 months of nightly treatment.2, 3, 4, 5

Controlled-release zolpidem: Zolpidem (a non-BzRA) has been studied in four placebo-controlled RCTs in adults (one in the elderly), and has shown efficacy over placebo in improving sleep onset, but not in improving sleep maintenance.6, 7 Its controlled-release formulation, zolpidem ER, has shown efficacy in improving both sleep onset and sleep maintenance.8

Ramelteon: This melatonin-receptor agonist demonstrates long-term efficacy in promoting sleep onset compared to placebo in adults. It shows no evidence for abuse potential or dependence in clinical trials, and was the first non-scheduled prescription insomnia treatment. In an open-label safety study, no rebound insomnia was observed even after one year’s exposure. 9

Benzodiazepine receptor agonists (BzRA)

BzRA hypnotics (with the exception of triazolam) have long half-lives that contribute to their success in the treatment of sleep-maintenance insomnia.10 In placebo-controlled RCTs, temazepam demonstrated efficacy in improving sleep onset and sleep maintenance in adults with insomnia11

The drugs’ long-acting efficacy is associated with next-day impairments, however. Side effects and risks associated with BzRAs include daytime sedation, dizziness, impaired motor coordination (which may lead to falls and hip fracture), respiratory depression (of concern in sleep apnea), and anterograde amnesia. 12

Research suggests that problems with dependency, withdrawal, and addiction have been considerably exaggerated for the short-term use (i.e., 2-4 weeks) of BzRAs for insomnia, except in patients with a pre-existing history of drug dependence or abuse. 13, 14 The potential for abuse with long-term BzRA use to treat insomnia needs further study, however. 15, 16                                    

Benzodiazepine receptor agonists with a non-benzodiazepine structure (non-BZD)

In comparison to the BZD hypnotics, non-BZD hypnotics have limited evidence of next-day residual effects and a reduced risk for tolerance and addiction. Zolpidem products (especially in extended-release formats), however, can cause next-morning impairment for activities that require complete mental alertness, including driving. Women appear to be more susceptible to this risk because they eliminate zolpidem from their bodies more slowly than men do. 17

Zaleplon has been studied in three placebo-controlled RCTs in adults and two in the elderly, and has shown efficacy over placebo in improving sleep onset, but not sleep maintenance. 18, 19, 20, 21, 22 One long-term (6-12 months) open-label study of nightly zaleplon use demonstrated efficacy in both sleep onset and sleep maintenance; these results need to be confirmed with placebo-controlled trials. 23

Selective M1/M2 melatonin receptor agonist

The melatonin-receptor agonist, ramelteon, demonstrates long-term efficacy in promoting sleep onset vs. placebo in adults, shows no evidence for abuse potential or dependence in clinical trials, and was the first non-scheduled prescription insomnia treatment. In an open-label safety study, no rebound insomnia was observed even after one year of exposure. 24

Orexin receptor antagonist

Orexin is a chemical produced by the brain that is closely associated with awareness. Orexin bonds to the brain’s nerve receptors, sending signals that keep people awake. Orexin receptor antagonists block these receptors and prevent the chemical’s actions. The new drug, suvorexant, is the first sleep aid to target specific parts of the brain; because its action is more specific, the hope is that it will result in fewer side-effects, such as dizziness, sleepiness the following day, or worsening sleep apnea25, 26

Three clinical trials explored suvorexant’s effectiveness. Participants who took the drug fell asleep faster and spent less time awake during the night, when compared to those who received the placebo. It is not yet known how suvorexant compares to other insomnia drugs in terms of efficacy and/or safety. 27

According to the Food and Drug Administration (FDA), drowsiness was the most common adverse effect experienced by the drug’s clinical trial participants. Like other sleep drugs, suvorexant’s side effects include driving and engaging in other activities when not fully awake — these include making and eating food, driving, making telephone calls, and engaging in sexual activity. 28

Table 2.2: FDA-Approved Drugs for Insomnia 29, 30

Benzodiazepine Receptor Agonists (BzRA)
Duration Agent Trade Name Dose Half life Comments
Long acting Flurazepam Dalmane 15-30 mg 47-100 hours Do not use in older adults due to half life
Long acting Quazepam Doral 7.5 – 30 mg 39-73 hours Do not use in older adults due to half life
Intermediate acting Estazolam ProSom 1-2 mg 10-24 hours Sleep maintenance
Intermediate acting Temazepam Restoril 7.5 – 30 mg 3.5-18.4 hours Sleep maintenance
Short acting Triazolam Halcion .125-.5 mg 1.5 – 5.5 hours Caution: rebound anxiety, not first-line agent
Non-benzodiazepine Receptor Agonists (non-BzRA)
Intermediate acting Eszopiclone Lunesta 2-3 mg (1 mg in elderly and hepatic impairment) 6 hours Sleep onset and maintenance
Short- to intermediate-acting Zolpidem Ambien 5 mg for women; 10 mg for men (consider lower dose); 5 mg in elderly or hepatic impairment 1.4-4.5 hours Primary use for sleep onset
Short- to intermediate-acting Zolpidem ER Ambien CR 6.25 mg for women; 12.5 mg for men (consider lower dose); 6.25 mg in elderly or hepatic impairment 28 hours Primary use for sleep onset and maintenance
Short- to intermediate-acting Zolpidem Intermezzo 1.75 mg sublingual SL prn for women; 3.5 mg for men sublingual  prn; 1.75 mg in hepatic impairment 1.4-3.6 hours Middle of the night awakening
Short-acting Zaleplon Sonata 10 mg; 5mg in elderly, hepatic impairment, or use with cimetidine .9 – 1 hour Primary use for sleep onset; maintenance up to 4 hours
Selective M1/M2 Melatonin Receptor Agonist
Short acting Ramelteon Rozerem 8 mg 1- 2.6 hours Primary use for sleep onset
Orexin Receptor Antagonist
Intermediate Suvorexant Belsomra 5 mg, 10 mg, 15 mg, and 20 mg 12 hours Primary use for sleep onset and difficulty staying asleep

 

References

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