Pharmacological treatment

Pharmacological treatment of insomnia

Primary insomnia usually begins in early or middle adulthood and is rare in childhood or adolescence. More than 50% of the population complains of insomnia in their lifetime.
Despite the prevalence of insomnia, only 5% of individuals seek medical attention for management of their insomnia. Approximately 10% to 20% use nonprescription drugs or alcohol to selftreat. Of the 3% of the population who are prescribed sedative–hypnotics for insomnia, 11% report use exceeding 1 year.

Medication used in the treatment of insomnia:

1-OTC Agents:
Antihistamines exhibit sedating properties and are included in many over-the-counter sleep agents. They are effective in the treatment of mild (tansient and short term) insomnia and are generally safe. Diphenhydramine (25-50mg at bed time) and doxylamine are more sedating than pyrilamine. Increasing the dose of antihistamines will not produce a linear increase in response but will increase side effects. The safety and efficacy of antihistamines over placebo have been documented in several studies. Antihistamines are considered to be less effective than benzodiazepines, and have the disadvantages of anticholinergic side effects, which are especially troublesome in the elderly.

Ramelteon is a melatonin receptor agonist that has recently been approved for the treatment of sleep onset insomnia. Ramelteon is selective for the MT1 and MT2 melatonin receptors that are thought to regulate the circadian rhythm and sleep onset. The recommended dose is 8 mg taken at bedtime to induce sleep and although generally
well-tolerated, the most common adverse events reported are headache, dizziness, and somnolence. Ramelteon is not a controlled substance and can be a viable option for patients with a history of substance abuse. The over-the-counter supplement melatonin is a popular treatment for insomnia. Although melatonin has demonstrated efficacy
for inducing sleep, its use for the treatment of insomnia is not well-supported by clinical studies.

Valerian is an herbal sleep remedy that has been studied for its sedative-hypnotic properties in patients with insomnia. The mechanism of action is not fully understood but may involve increasing concentrations of γ-aminobutyric acid (GABA). The recommended dose for insomnia ranges from 300 to 600 mg. An equivalent dose
of dried herbal valerian root is 2 to 3 g soaked in 1 cup of hot water for 20 to 25 minutes.

2-Antidepressants:
Antidepressants are alternatives for patients with nonrestorative sleep who should not receive benzodiazepines, especially those who have depression, pain, or a risk of substance abuse. Using antidepressants for insomnia without depression is common but not well studied. Sedating antidepressants such as amitriptyline, doxepin, and nortriptyline are effective for inducing sleep continuity, although daytime sedation and side effects can be significant. Anticholinergic activity, adrenergic blockage, and cardiac conduction prolongation can be problematic, especially in the elderly and in overdose situations. Some of the new generation of antidepressants such as mirtazapine and nefazodone are also sedating. Mirtazapine can cause daytime sedation and weight gain.
Trazodone in doses of 25 to 100 mg at bedtime is sedating and can improve sleep continuity. Trazodone is popular for the treatment of insomnia in patients prone to substance abuse, as dependence is not a problem. Trazodone is frequently used in patients with selective serotonin reuptake inhibitor (SSRI) and bupropion induced
insomnia. Caution should be used to avoid serotonin syndrome when used in these combinations. Other side effects include carryover sedation and α-adrenergic blockade. Orthostasis can occur at any age, but it is more dangerous in the elderly. Priapism is a rare but serious side effect.

Benzodiazepine Receptor Agonists
The most commonly used treatments for insomnia have been the benzodiazepine receptor agonists. All benzodiazepine receptor agonists are effective as sedative-hypnotics, and are Food and Drug Administration (FDA) labeled for the treatment of insomnia as (Estazolam (ProSom), Eszopiclone (Lunesta), Flurazepam (Dalmane), Quazepam (Doral), Temazepam (Restoril), Triazolam (Halcion), Zaleplon (Sonata), Zolpidem (Ambien)). The benzodiazepine receptor agonists consist of the newer nonbenzodiazepine GABAA agonists and the traditional benzodiazepines. All benzodiazepine receptor agonists bind to GABAA receptors in the brain resulting in stimulatory effects on GABAergic transmission and hyperpolarization of neuronal membranes. Traditional benzodiazepines have sedative, anxiolytic, muscle relaxant,
and anticonvulsant properties; newer nonbenzodiazepine GABA agonists possess only sedative properties.
Benzodiazepine Hypnotics
Benzodiazepines relieve insomnia by reducing sleep latency and increasing total sleep time. Benzodiazepines increase stage 2 sleep while decreasing REM, stage 3, and stage 4 sleep. Benzodiazepines are very safe, and fatal overdoses are rare unless they are taken in
combination with central nervous system (CNS) depressants or alcohol. Benzodiazepine hypnotics should not be prescribed for individuals with sleep apnea, a history of substance abuse, or during pregnancy. Patients should be instructed to avoid alcohol and other CNS depressants.
Pharmacokinetics The choice of a particular benzodiazepine can be based on its pharmacokinetic profile. When used as a single dose, the extent of distribution and elimination half-life is important in predicting the duration of action. However, after multiple doses, the elimination half-life and formation of active metabolites determine the extent of drug accumulation and resultant clinical effects. Elderly patients, liver dysfunction, and drug interactions can prolong drug effects. The pharmacokinetic profiles of benzodiazepine receptor agonists are summarized in Table 1.



TABLE 1: Pharmacokinetics of Benzodiazepine Receptor Agonists
Generic Name (Brand Name) tmax (hours) Daily Dose Range (mg)
Estazolam (ProSom) 2 1-2
Eszopiclone (Lunesta) 1-1.5 2-3
Flurazepam (Dalmane) 1 15-30
Quazepam (Doral) 2 7.5-15
Temazepam (Restoril) 1.5 15-30
Triazolam (Halcion) 1 0.125-0.25
Zaleplon (Sonata) 1 5-10
Zolpidem (Ambien) 1.6 5-10


Adverse Effects: Side effects are dose dependent and vary according to the pharmacokinetics of the individual benzodiazepine. High doses with long or intermediate elimination half-lives have a greater potential for producing daytime sedation and performance impairment. These effects include excessive drowsiness, psychomotor incoordination, decreased concentration, and cognitive deficits. Tolerance to benzodiazepine hypnotic effects develops sooner with triazolam (after 2 weeks of continuous use) than with other benzodiazepine hypnotics. Most traditional benzodiazepines maintain hypnotic efficacy for 1 month. However, tolerance can develop with time. Rapidly eliminated benzodiazepines have less potential for daytime sedation. Anterograde amnesia, an impairment of memory and recall of events occurring after the dose is taken, has been reported with most benzodiazepine receptor agonists. Rebound insomnia is characterized by increased wakefulness beyond baseline amounts that last for one to two nights after abrupt discontinuation of benzodiazepine receptor agonists. Rebound insomnia occurs more frequently after high doses of triazolam, even when ingested intermittently. The lowest effective dosage should be used to minimize rebound insomnia and avoid adverse effects on memory. Benzodiazepine half-lives are prolonged in older patients, increasing the potential for drug accumulation and the incidence of CNS side effects. Prolonged sedation and cognitive and psychomotor impairment are concerns in the elderly. Benzodiazepine receptor agonists with long elimination half-lives are generally not first-line agents. There is an association between falls and hip fractures and the use of benzodiazepines with long elimination half-lives; thus flurazepam and quazepam should be avoided in elderly patients.