Drug+Therapy

Drug Therapies and other Treatments for Sleeping Disorders Frederick Leung as part of the Neuroscience of Sleep group Neurowiki

toc  Sleep is an essential activity that allows humans to function. Without proper sleep, the body can be put to great stress. Drug Therapy has been a common way to aid those suffering from sleeping disorders. Insomnia is the most common sleeping disorder[1]. Sedatives and hypnotics are the most common types but can result in unrefreshed sleep because they do not produce the regular sleep stages or a natural sleep cycle. Furthermore, hypnotics or sedatives do not target the cause for sleep deprivation, rather they treat the symptoms. This can lead to dependence or tolerance to the drug. A combination of behavioral therapy and drug therapy is effective for treating short term and long term sleeping problems. Sedatives induce the potentiation of GABA at the GABA A receptor which increases the GABAergic pathway promoting sleep[2]. The wakefulness-promoting systems are due to the histaminergic system which utilizes excitatory histamine receptors. Hypnotics and sedatives can induce sleep by blocking these histamine receptors reducing wakefulness[2]. Serotonergic neurons control the system that increases arousal. 5HT 2A is a receptor, and its antagonists reduce the amount of arousal caused by serotonergic neurons[2]. 5HT 2C receptor activation prolongs sedation effects. A combination of 5HT 2C activation and deactivation 5HT 2A may be an effective design for drugs in order to maximize their effect. Introduction of melatonin promotes NREM sleep by activating the melatonin receptors in the Suprachiasmatic Nucleus[3]. Drug therapy is effective, short term, for those suffering sleep deprivation; however, a combination of different therapies should be adopted to treat long term sleeping problems.

=**Drug Therapy**=

Sedatives and Hypnotics
There are two main types of drugs for treating sleeping problems. Sedatives reduce irritability and excitement; however, when used in too high amounts, it can result in an over-calming effect. Hypnotics, also known as soporifics, are psychoactive drugs that induce sleep. Benzodiazepine based sedatives are the most commonly used drug for anesthesia[4]. They are also used to treat insomnia, but the drawback of using drugs to induce sleep, is that a natural sleep cycle is not experienced. The body does not feel refreshed because no regular sleep stages have been gone through[5]. Furthermore, the continual use of sleep inducing drugs, can result in a dependence and tolerance to them. Those that use the drug too often may develop a psychological or biological need for the drug in order to sleep[6]. Furthermore, people that use the drug are much more likely to fall since sedatives and hypnotics affect balance[7]. As a result, there are other treatments that can be used. These include alternative sleeping patterns, improving sleep hygiene, or exercise[8]. To improve sleep hygiene, it is necessary to control behavior and the environment to lead to better sleep.

Benzodiazepines
Short and intermediate acting Benzodiazepine hypnotics, such as Flurazepam and Temazepam result in rebound insomnia and withdrawal[9]. Although Benzodiazepines help maintain sleep and decrease the amount of time it takes to fall asleep, the effects often are maintained till the next day[9]. Benzodiazepines, the traditional hypnotics, target synaptic GABA receptors causing intermediary inhibition[10]. The effect on GABA receptors due to Benzodiazepines is different than GABA receptor agonists which may be the cause of the rebound insomnia. Non-Benzodiazepine hypnotics, Zolpidem and Zolpiclone may be much better as drug treatments because they do not produce rebound effects on the duration of sleep[8]. They are described as more "natural" agents because they do not interfere with normal sleep and have a high affinity with the GABA complex.

Alternative Treatments
Often times, the use of drug therapy does not treat the source of the insomnia or sleeping problem. Rather it treats insomnia, a symptom of an underlying condition or disease[6]. It has been found that 23% people in a study that were stressed in their daily lives also had insomnia[1]. Frequent heavy drinkers and obese individuals were also prone to insomnia[11]. People suffering anxiety disorders were also likely to develop sleep difficulties[12]. Treating the anxiety disorder, the cause of the insomnia, has been found to positively improve sleep. It is better to use drug therapy only in extreme cases in which the sleeping problems greatly damages health or if the sleeplessness is temporary. Exercise has been found to reduce the chances of acquiring insomnia[1]. Hypnotic and sedative agents are useful as short-term therapy; however, individuals that were given cognitive-behavior therapy were much less affected by insomnia[13]. Those that used cognitive-behavior therapy were asleep longer and had much less time awake two years after the treatment. Overtime, drug therapy is less effective, and unlike behavioral intervention, it cannot treat chronic insomnia[14]. Cognitive-behavior therapy includes education regarding effective sleeping habits that decrease insomnia short and long term. Proper sleep hygiene is also crucial, and it includes light control, activity during the day, and relaxing at the night time[14]. It is important for those suffering insomnia to monitor their own behaviors to develop their own sleep hygiene for the long term. Although cognitive-behavior therapy takes longer to establish, it is much more effective long term[13].

=**Influence of Sedatives and Hypnotics**=

**Wakefulness and Sleep Promoting Systems**
Sedatives usually strengthen the sleep promoting GABAergic pathway by potentiating the ionotrophic GABA A receptor which monitors chloride channels. Many drugs, as a result target this pathway, for example benzodiazepines[2]. The wakefulness and sleeping promoting hypothalamic and brainstem nuclei regulate arousal and the change between nonrapid and rapid eye movement sleep. The ventrolateral preoptic nucelus of the anterior hypothalamus is the main nucleus which promotes sleep, and it uses the neurotransmitters y-aminobutyric acid and galanin. In contrast, wakefulness is promoted by the histaminergic system which begins in the tuberomammillary nucelus and projects to the cerebral cortex. By inhibiting the wakefulness-promoting histaminergic system, a sedative effect can be produced by blocking H 1 histamine receptors. Wakefulness is also caused by the serotonergic neurons from the raphe nuclei[2]. By inhibiting the 5HT 2A receptor, which regulates arousal by serotonergic neurons, sedation can also be produced. Furthermore, the activation of 5HT 2C promotes an increased amount of sedation.

Melatonin and the Suprachiasmatic Nucleus
There are many Melatonin receptors in the Suprachiasmatic Nucelus (SCN), and Melatonin affects sleep via G-protein coupled receptors. MT 1 and MT 2 Melatonin receptors influence different G-protein receptors[3]. The activation of MT 1 leads to cytosolic calcium and inositol phosphate accumulation, while the activation of MT 2 activation leads to an inhibition of adenylate cyclase. This suggests that there are multiple pathways for activating Melatonin receptors. Both MT 1 and MT 2 promote circadian effects of sleep. Melatonin inhibits the neuronal firing of SCN which serves as a regulator of sleep; furthermore, SCN promotes wakefulness and also the urge to sleep. This is likely via GABAergic activation. Germain and co-workers have shown that Melatonin administration during the day leads to sleepiness in the evening due to the delay of the onset of circadian rhythms[3]. This suggests that Melatonin or Melatonin like drugs may be an effective method for dealing with sleep disorders.

=**Recent Research**=

Cognitive-behavior therapy is effective for treating sleeping disorders for the long term; however, often times the sleep disorder may present in a severe condition. A combination of cognitive-behavior therapy and drug therapy has been found to be optimal. Germain and co-workers have demonstrated the use of behavioral and drug therapy to treat military veterans suffering chronic sleep disturbances due to Post-Traumatic Stress Disorder (PTSD)[15]. A combination of Prazosin, cognitive-behavioral therapy, and placebo were given to military veterans suffering chronic sleep disturbances. There was a 61.9% sleep improvement for the soldiers that were given cognitive-behavioral and Prazosin treatments. It is believed that Prazosin reduces nightmares that disrupt Rapid Eye Movement sleep by monitoring the noradrenergic tone during sleep. Behavior therapies also reduced the nightmares leading to uninterrupted sleep. Behavioral interventions were more beneficial than Prazosin therapy; however, a combination of both treatments is efficient. A limitation of this study was the use of subjects suffering PTSD because the majority of the people suffering Insomnia do not have PTSD. Further studies on the effectiveness of cognitive-behavior therapy and Prazosin should be done on the general population.

=**References**=

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