Prescription Hypnotics Benzodiazepine Receptor Agent Biology Essay

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Walsh and Engelhardt (1999) estimated that insomnia sufferers spend over $285 million per year on prescription sleep medications. The most frequently prescribed hypnotic medications are benzodiazepine receptor agonists (BZRAs) (Wagner, Wagner, & Hening, 1998; Walsh & Engelhardt, 1999). These include several benzodiazepines (i.e., alprazolam, diazepamn, temazepam, triazolam, estazolam, flurazepam) and newer nonbenzodiazepine agents (e.g., zolpidem, eszopiclone, zaleplon) that act on the same gamma-aminobutyric acid (GABA-A) receptor complex binding site. Despite varying evidence for efficacy, sedating antidepressant drugs (i.e., trazodone and mirtazapine) and tricyclic antidepressants (e.g., amitriptyline, doxepin) as well as newer generation antipsychotics (e.g., olanzapine, quetiapine) have been used widely for insomnia treatment (Walsh & Engelhardt, 1999). Lastly, the melatonin agonist ramelteon has been recently approved by the United States (U.S.) Federal Drug Administration (FDA) for the treatment of insomnia.

Of the available prescription sleep medications, BZRAs have the greatest amount efficacy and safety data. In a meta-analysis of patients with primary insomnia, Nowell et al. (1997) found traditional BZRAs and zolpidem produce reliable short-term improvements in sleep-onset latency, number of awakenings, total sleep time, and sleep quality. Furthermore, the newer BZRAs such as eszopiclone may have continued efficacy and safety for periods of 3 to 12 months of nightly use (Krystal et al., 2003; Roth, Stubbs, & Walsh, 2005). Although ramelteon is FDA-approved for treatment of insomnia, there is limited published efficacy and safety data for this medication. Sedating antidepressants and most tricyclic antidepressants have very limited empirical support for insomnia management and lack FDA approval. Regardless, these agents are used widely "off-label" for insomnia treatment (Walsh & Engelhardt, 1999).

Prescription hypnotics have a number of advantages that support their continued use. BZRAs are widely available, generally well tolerated by patients, and typically produce rapid sleep improvements on the first night they are taken. As such, prescription hypnotics may be the treatment of choice for cases of transient or short-term sleep disturbances. For example, they may be particularly effective for helping a person sleep in response to stressful life events (i.e., death of a significant other), or following an unexpected change in one's sleep-wake schedule (i.e., jet lag). Likewise, they may useful for those who experience intermittent sleep disturbances due to episodic, though recurrent, stressful circumstances such as special work assignments or periodic travel. Presumably, sleep medications may be indicated for the management of these forms of transient insomnia compared to psychological treatments for insomnia.

However, hypnotic medications have a number of disadvantages that may make them less desirable for long-term management of insomnia. Long-acting BZRAs (e.g., flurazepam) may have "hang-over" effects leading to additional motor and cognitive impairment, especially among older age individuals (Roth & Roehrs, 1991). Among older age groups, long-acting BzRAs have been implicated in an increased rate of motor vehicle accidents (Hemmelgarn, Suissa, Huang, Boivin, & Pinard, 1997) and hip fractures (Ray, 1992). The shorter acting agents are less prone to cause these sorts of problems; however, residual daytime effects may occur in some individuals, particularly the elderly when higher doses are prescribed. Anterograde amnesia is a more common problem associated with short acting hypnotic agents (Jonas, Coleman, Sheridan, & Kalinske, 1992; Wysowski & Barash, 1991), which in some individuals may lead to episodes of sleep-related cooking or driving a motor vehicle (US Food and Drug Administration, 2007). Likewise, shorter acting agents are associated with drug tolerance and rebound insomnia (Greenblatt, 1992), a dramatic worsening of sleep occurring when the agent is abruptly discontinued or withdrawn. All sleep aids are associated with the risk of dependence, particularly psychological dependence that results in persistent difficulty sleeping and increased sleep-related anxiety upon their discontinuation.

Given the disadvantages of sleep medications, many healthcare providers are reluctant to prescribe these medications for a long-term treatment of insomnia. However, this reluctance has decreased as studies (Krystal et al., 2003; Roth, Walsh, Krystal, Wessel, & Roehrs, 2005) have demonstrated continued safety and efficacy of some of the newer generation hypnotics over extended periods of continuous use. Nonetheless, there is no evidence indicating the obtained sleep improvements are maintained after discontinuation. Morin, Gaulier, Barry, & Kowatch (1992) revealed that individuals with insomnia expect psychological therapies will produce more positive results with fewer treatment-related side effects than will pharmacotherapy. Thus, Cognitive-Behavioral Therapy for insomnia (CBT-I) may be favored over the prescription sleep aids by many of those with chronic sleep difficulties.

Adverse Effects of Benzodiazepines

Benzodiazepines are associated with several adverse effects. Short-acting agents may cause rebound daytime anxiety and greater amnesia, as well as more withdrawal symptoms (i.e., rebound insomnia) following cessation of their use. The effect of agents with long elimination half-lives may persist into the following day, producing daytime sleepiness, poor motor coordination, delayed reaction times, and cognitive impairment. Other adverse consequences of benzodiazepines include confusion, development of tolerance and withdrawal symptoms, and the risk of abuse or dependency. Due to the potential danger of respiratory depression, benzodiazepines should be given cautiously, if at all, to patients with untreated obstructive sleep apnea or profound obstructive and restrictive ventilatory impairment (e.g., severe emphysema and obesity-hypoventilation syndrome).

1. Impairment of cognition: Memory impairment appears to be directly correlated to the agent's affinity for the benzodiazepine-GABA receptor. For instance, triazolam, which has increased affinity for its receptor, also has a high potential for inducing amnesia. Anterograde amnesia, or the inability to register new memory after drug ingestion, is also partially influenced by the sedative properties of the medication. Confusion may develop among older adults.

2. Relapse: Recurrence of insomnia is common following discontinuation of benzodiazepines.

3. Rebound insomnia: Subjective and objective worsening of sleep (compared with baseline pretreatment levels) and daytime well-being can develop for several days after drug discontinuation. This is more likely to occur with short-acting and intermediate-acting agents. The duration of sleep deterioration can be protracted. Although rebound insomnia can develop following short term therapy with benzodiazepines, it is particularly prominent after chronic treatment. Rebound insomnia can be minimized by intermittent use of hypnotic agents and by gradual reduction of the dose administered.

4. Withdrawal symptoms after abrupt drug discontinuation: Following chronic use of benzodiazepines, abrupt discontinuation can also give rise to anxiety, irritability, restlessness, and tremulousness.

5. Risk of dependency: These medications generally have a low risk of dependency, and persons with insomnia typically do not self-escalate the frequency or dose of drug use. Dependency, nevertheless, can occur with long-term use, especially in individuals with a prior history of dependency to similar or related compounds.

6. Development of tolerance: Patients typically develop tolerance rapidly to these agents, and their sleep duration and quality may begin to deteriorate and possibly reach baseline levels within several weeks of drug administration. With chronic use, increasingly higher dosages are required to achieve similar therapeutic benefits.

7. Drug overdose: Benzodiazepines have a relatively good safety profile following overdose. Lethality with overdose of benzodiazepines, when ingested alone, is low but rises with co-ingestion of other compounds such as alcohol and other CNS depressants.

8. Safety issues: The risk of car accidents may be increased among chronic benzodiazepine users. Patients should be cautioned against operating motor vehicles or performing tasks that require vigilance and alertness when using these drugs.

9. Psychomotor impairment: Duration of psychomotor impairment (eg, increase in errors, slowing of response times) is related to the dose and half-life of the medication.

10. Respiratory depression and worsening of obstructive sleep apnea.

11. Increase in falls: The frequency of falls may increase among older adults.

Over-the-Counter Medications, Herbal Remedies, and Alternative Treatments

Not surprisingly, many of those who desire treatment for insomnia will initiate treatment without seeking appropriate medical advice or consultation. Although various self-help books (Edinger & Carney, 2008; Hauri, 1996; Jacobs, 1999; Morin & Wooten, 1996) are available that describe psychological strategies for managing insomnia, most insomnia sufferers resort to some form of nonprescription sleep aid. These may include over-the-counter compounds specifically marketed as sleep aids, herbal and dietary supplements, and alcoholic beverages. In general, these compounds have limited data to support their effectiveness for insomnia management and many may result in undesirable side effects or even adverse reactions. People may develop a psychological dependence on such agents with their long-term and continued use.

Antihistamine-Based Sleep Aids

With FDA approval, a variety of over-the-counter agents are manufactured and marketed specifically for treating insomnia. These agents contain diphenhydramine (i.e., Benadryl) or doxylamine as their active, sedating ingredient and are sold under numerous brand names. Some products contain one or the other of these compounds as the sole active ingredient whereas some products combine one of these compounds with an analgesic (e.g., aspirin, acetometaphan, ibuprofen) and are targeted for patients who have insomnia in the context of pain. Both diphenhydramine and doxylamine act on the H-1 histamine receptor and block the effects of histamine, an alerting neurotransmitter found in the central nervous system. Ingestion of these compounds may lead to drowsiness and sleepiness. Clinical studies in which doses of 12.5-50 mg of such compounds were used have shown subjective improvements in various sleep measures (Buysse, Germain, Moul, & Nofzinger, 2005; Morin, Beaulieu-Bonneau, LeBlanc, & Savard, 2005). However, a recent study showed that objective sleep recordings failed to corroborate improvements noted on self-reported sleep measures (Morin et al., 2005).

Although these products are sold without a prescription, they are not without notable side effects. Daytime sedation or "hangover" and impairments of psychomotor performance are commonly reported (Buysse et al., 2005; Meoli et al., 2005). Other reported side effects include dizziness, nausea, depression, malaise, dry mouth, weakness, headaches, tinnitus, gastrointestinal distress, impotence, and voiding problems (Buysse et al., 2005; Meoli et al., 2005). In a minority of users, paradoxical effects including restlessness, anxiety, and increased alertness seem to occur. Impaired cognition is also noted in a large percentage of older hospitalized adults who are given such compounds as sleep aids (Agostini, Leo-Summers, & Inouye, 2001). Serious, life-threatening side effects are extremely rare but have been described in selected case reports (Buysse et al., 2005).

Sedating Antidepressants

Sedating antidepressants have been increasingly prescribed as off-label agents for the treatment of insomnia over the past several years. However, despite their widespread use to aid sleep, data on their appropriate use among persons with insomnia, particularly in patients without mood disorders, is limited. The therapeutic efficacy and safety of sedating antidepressants used as hypnotics for patients with insomnia are incompletely understood. In general, serotonin-specific antidepressants have fewer adverse effects than the older tertiary tricyclics.

Other Prescription Agents

Quetiapine, an atypical antipsychotic with anti-histaminergic, anti-dopaminergic, and anti-adrenergic properties, has been used as a sleep aid for patients with psychiatric illness, although its effectiveness for this indication has not been established. Polysomnographic features include an increase in total sleep time, sleep efficiency, NREM stage 2 sleep and subjective sleep quality. Finally, antipsychotic agents (eg, chlorpromazine, haloperidol, olanzapine, and risperidone), buspirone, carbamazepine, clonidine, cyproheptadine, divalproex, gabapentin, and oxcarbazepine possess sedative properties and have been used to treat patients presenting with complaints of insomnia. Data on their efficacy and safety for the therapy of insomnia is either limited or absent.

Herbal Compounds and Dietary Supplements

A variety of herbal compounds and dietary supplements are sold as sleep aids. Included among these are valerian root, kava kava, hops, St. John's Wort, lemon balm, Jamaican dogwood, California poppy, passion flower, and lavender. With the exception of valerian root, data are lacking concerning the safety and efficacy of most of these compounds for insomnia treatment. In the case of valerian root, the results concerning treatment efficacy have been mixed. A recent study showed some subjective benefits of a valerian root/hops combination in the treatment of primary insomnia. However, objective sleep recordings did not corroborate these subjective benefits. In other trials, valerian root has produced some subjective and objective sleep benefits (Donath, Quispe, & Diefenbach, 2000; Schulz, Stolz, & Müller, 1994). Thus, despite the mixed findings, it seems valerian preparations may produce sleep benefits for some users.

Currently, there are very limited safety data concerning this class of compounds. Side effects associated with valerian generally have been mild and include morning sleepiness, lightheadedness, weakness, and headache (Buysse et al., 2005). In rare cases, hepatoxicity has been associated with the use of valerian and kava kava, whereas there is one report of heart failure and delirium upon the abrupt withdrawal of valerian (Meoli et al., 2005). Currently, data are lacking concerning the safety of most of the herbal compounds and supplements mentioned here so their use as sleep aids cannot be recommended.

Melatonin

Unlike the other compounds mentioned, melatonin is a hormone that is produced by the pineal gland and, thus, occurs naturally in the human body. Melatonin is synthesized from serotonin and mostly is secreted at night. Typically, melatonin concentration levels in the blood begin to rise around dusk, reach a peak during the middle of the night, and then decrease around dawn. Melatonin seems to have influences on the endogenous circadian system that regulates the timing of sleep in the 24-h day. For this reason, melatonin has been used to alter the timing of the sleep- wake schedule under such conditions as jet lag, or to reset the biological clock in those who have marked endogenous delay in the timing of their sleep onset each night. In applications to insomnia, some studies have shown that melatonin results in self-reported improvements in sleep onset latency and general sleep quality, but its effects on other self-reported sleep measures is more equivocal (Buysse et al., 2005). In addition, some studies suggest that melatonin administration leads to objective improvements in sleep latency (Hughes, Sack, & Lewy, 1998; Zhdanova et al., 2001). However, a recent comprehensive review of the melatonin literature suggested that the research supporting the use of this agent as an insomnia remedy is of questionable quality (Buscemi et al., 2004).

Currently, melatonin sold over-the-counter does not have an FDA-approved indication for insomnia and, therefore, it is not regulated by the FDA. As such, formulations sold to the general public are not standardized in their compositions. However, the side effects associated with melatonin use appear to be minimal. The most common side effect is headache. In rare cases, other side effects including disorientation, nausea, seizures, and shortness of breath have been reported (Buysse et al., 2005). Nonetheless, for most individuals, short-term use to address insomnia is safe, but little data currently exist concerning its long-term effects.

Alcohol

Alcoholic beverages are widely used as a common home remedy for sleep difficulties. In fact, it is estimated that as many as 30% of all chronic insomnia sufferers use alcohol as a routine sleep aid (Ancoli-Israel & Roth, 1999). Alcohol is a CNS depressant and, as such, has a relaxing and sleep-inducing effect, particularly on anxious individuals. It tends to reduce sleep onset time and increase the amount of nonrapid eye movement sleep (NREM) while reducing rapid eye movement sleep (REM) during the initial half of the night (Gillin, Drummond, Clark, & Moore, 2005). However, alcohol is metabolized very rapidly, typically at the rate of one glass of wine or about 8 oz of beer for 1 h. After several drinks, alcohol is fully metabolized by the body about halfway through the night resulting in shallow, broken sleep with increased REM (dreaming) sleep in the latter portion of the night (Gillin et al., 2005). In some individuals, sleep may be disrupted by stomach irritation, a full bladder, rebound wakefulness, sweating, or nightmares. Thus, whereas alcohol often makes it easier for the insomnia sufferer to fall asleep, sleep maintenance and overall sleep quality are usually disrupted resulting in an overall compromise of the total sleep period.

Alcohol has a number of side effects and risks associated with both its short- and longer-term use. In the short run, alcohol tends to increase the likelihood of snoring and apneic (i.e., breathing pauses) episodes even in those without any history of sleep apnea (Dawson, Lehr, Bigby, & Mitler, 1993). If alcohol is used routinely, tolerance usually develops resulting in the need for dose escalation to obtain constant subjective effects. In addition, alcohol is associated with considerable risk for dependence. If dependence does develop, the alcohol user typically reports difficulty sleeping without a drink. With prolonged use of alcohol, daytime hypersomnolence and cognitive dysfunction may be observed. Individuals who develop alcohol dependence often show marked sleep disruption upon becoming abstinent. Moreover, heavy and long-term users often show continued disruption of sleep even 1-2 years after becoming abstinent (Brower, Aldrich, Robinson, Zucker, & Greden, 2001; Gillin et al., 2005). Thus, despite its popularity as a sleep aid, alcohol cannot be recommended to address insomnia.

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