The Pathophysiology of Primary Insomnia

Insomnia, or difficulty sleeping, is a common problem. Most people experience transient insomnia at some point in their lives. But for others, insomnia becomes a chronic and significant problem. It is estimated that between 30% and 40% Americans suffer from insomnia.

Insomnia is considered chronic by some when it lasts a month. Others say three to six months.

Primary insomnia is often thought of as a self-fulfilling prophecy in which someone with transient insomnia begins to worry about falling asleep, causing more sleepless nights, which leads to more worrying and more insomnia. This is how it feels to many people.

Treatment can then be focused on interrupting the cycle. Relaxation techniques, and a variety of behaviors grouped together as “good sleep hygiene” might help. Even armed with these behavioral tools, many still cannot sleep. Doctors may prescribe hypnotic drugs such as benzodiazepines, hoping they will be used for only a short period of time.

In 2005, the National Institutes of Health State of the Science Conference on “Manifestations and Management of Chronic Insomnia in Adults” presented new research and different ways to understand and treat insomnia. Whereas in the past, primary insomnia was considered a symptom, it is now considered a disorder which needs to be treated. It may co-exist with other medical or psychiatric problems. These are called co-morbid conditions. But as a disorder, insomnia needs to be treated regardless of other issues. In addition, patients with primary insomnia are at risk for developing other psychiatric and medical problems.

Research focused on the pathophysiology of insomnia caused much of the change in thinking about insomnia. Patients with chronic primary insomnia are now considered to be in a state of hyper-arousal. In addition to having trouble sleeping, they may be anxious. They are more alert than expected despite having non-restorative sleep. This finding led to research to try and discover why they are more alert.

In one study, brain metabolism of patients with insomnia and healthy controls were evaluated using a type of positron emission tomography (PET scan) during both wake and non-REM sleep. The researchers observed increased metabolic activity in the frontal lobes of patients with insomnia while they were awake. During non-REM sleep they had increased whole-brain metabolic activity. Researchers also noted increased metabolic activity in the midbrain and brainstem of patients with insomnia during sleep.

There is now evidence that there is a physiologic reason for the hyper-arousal. Some of the measurable indicators of hyper-arousal found in patients with insomnia include increased basal metabolic rate, central nervous system metabolic rate and body temperature. High levels of catecholamines, hormones released as a result of stress are measurable, as is increased brain wave activity measured by electroencephalography.

Investigators trying to understand the pathophysiology of sleep continue to focus on the state of hyper-arousal. In major depressive disorders, there is abnormal regulation of corticotropin-releasing factor (CRF). Altered regulation of CRF, hyper-arousal and sleep disturbances occur both in patients with insomnia and depressed patients.

Current thinking about the main cause of hyper-arousal in insomniacs focuses on neuroendocrine dysfunction in these patients, including increased CRF activity. Researchers have found evidence that there is over activity of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may cause elevated levels of CRF, which then causes the pituitary to release adreno-corticotropic hormone (ACTH). This causes the adrenal glands to secrete excessive amounts of cortisol. Increased cortisol and ACTH levels have been found in patients with chronic insomnia. There seems to be a strong correlation between cortisol levels and sleep disruption or fragmentation. Some researchers think that chemical events in the brain associated with the HPA access also cause release of norepinephrine, which may also be disrupting sleep.

One model of insomnia stresses the fact that mediators in the brain which operate together may be in a loop which makes insomnia persist. High cortisol levels correlate with nocturnal wakenings. Increased HPA axis activity fragments sleep, but sleep fragmentation also increases cortisol levels.

Other investigators have found that patients with chronic insomnia have lower nocturnal levels of melatonin. Melatonin, a hormone produced in the pineal gland, is part of the regulation of circadian rhythm. When melatonin levels increase, sleepiness occurs. Not only do patients with insomnia have lower melatonin levels, the levels are more disturbed the longer the patients have trouble sleeping.

Research is ongoing in these areas, to further understand the pathophysiology of insomnia and to use the information to help treat patients. Clinical trials have been suggested to investigate whether an antiglucocorticoid agent might counteract the increased cortisol, and be useful in treatment of insomnia. Other researchers think that it is the CRH and its actions in the brain that need to be surpressed.

In the meantime, treatment strategies have changed. Giving patients hypnotic drugs to take for short periods of time never really worked well, because the body becomes habituated to the medications and they are then less effective. A new approach is called “discontinuous hypnotic treatment,” with a flexible dosing schedule. Patients have medication, usually a benzodiazepine receptor agonist, but they don’t take it every night. Some patients may be able to manage the regimen themselves and take medication only when really needed. Others may need a fixed dosing schedule which allows them to take medication only certain nights of the week. If patients use medication judiciously and do not take sedatives every night, they are more effective.

In addition to medication, all patients should be learning relaxation techniques and good sleep practices.

Better understanding of the pathophysiology of primary insomnia may very well lead to much better treatment in the future.

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