New Seep Medication Shows Less Potential To Foster Abuse and Dependence

Sleep Medication

As part of the effort to develop effective behavioral and medical sleep therapies, scientists consider the potential for dependence and abuse associated with prescription sleep drugs. This line of research has produced findings showing [news] that a recently approved prescription sleep drug may spare users the potential for dependence and abuse found with other sleep aids. Laboratory studies of the effects of ramelteon suggest that the drug's targeting of the brain's melatonin receptors rather than its benzodiazepine receptors make its subjective side effects different from those of old and new sedative hypnotics. The research is reported in the June issue of Behavioral Neuroscience, which is published by the American Psychological Association (APA).
At the University of Texas Health Science Center in San Antonio, pharmacology researchers led by Charles P. France, PhD, assessed whether ramelteon instigated the same kinds of broad cognitive effects as other, more commonly prescribed sleep aids. That other group includes traditional hypnotics and newer drugs such as zaleplon (Sonata) and zolpidem (Ambien), all of which bind to the brain's benzodiazepine receptors and may result in impaired thinking, hangover, withdrawal symptoms and rebound insomnia.
Laboratory tests and clinical studies also show that even low-dose benzodiazepines, especially in long-term use, create the potential for dependence and abuse. Says Dr. France, "Although medication might not always be indicated for insomnia, when they are prescribed, it is essential to limit the adverse side effects as much as possible."
The U.S. Food and Drug Administration (FDA) approved the use of ramelteon (brand name Rozerem) in July of 2005. Prior to FDA approval, Dr. France and his colleagues researched drug side effects, capitalizing on the fact that monkeys� � - just like humans - can be trained to recognize the specific effects of a drug class, presumably by how they feel. Says Dr. France, "Those experienced with the 'feeling' of a particular drug can easily recognize when they have received that drug and can reliably detect when they have been given a drug from a different pharmacologic class."
In one experiment, the researchers trained monkeys to press a lever only when given a benzodiazepine called midazolam (Versed). Then the team gave the monkeys ramelteon. The animals did not press the lever associated with midazolam, their lack of response indicating that they felt different after receiving ramelteon than they did after receiving midazolam.
In a second experiment, the researchers determined that ramelteon and the benzodiazepines have different pharmacologic mechanisms. The team gave monkeys diazepam (Valium) for at least a year. Then they administered flumazenil (Romazicon), which reverses the effects of benzodiazepines. The subsequent administration of ramelteon did not change the effects of flumazenil, further evidence that ramelteon works altogether differently. Says Dr. France, that difference makes ramelteon unlikely to promote a benzodiazepine type of dependence.
In a third experiment, the team carefully watched how monkeys who'd been given ramelteon for a year behaved when the drug was withdrawn. To assess whether the monkeys had come to depend on the drug, Dr. France and his colleagues measured clinical behavior, operant (learned) behavior, and blood levels of the drug. The first type of measure was the most revealing: Of the 33 usual withdrawal-related signs of dependence, such as teeth grinding, rubbing lips on bars, nose rubbing, scratching, biting fingernails, shakes and tremors, 10 were never seen; all but one of the other behaviors didn't change in frequency.
The authors say that together, the findings highlight significant differences between ramelteon and the prototypical benzodiazepines studied. They say their results, "suggest that ramelteon does not likely share subjective effects with benzodiazepines in humans and, thus, should not be expected to share abuse liability with BZRAs [benzodiazepine receptor agonists]." The findings also indicate that ramelteon will not produce benzodiazepine-like physical dependence in humans. Thus the authors say these findings are potentially important for the treatment of sleep problems.

Machine Works Best for Treating Sleep Apnea, but Few Prefer It

Sleep Apnea

A machine that delivers air through a nasal mask worn during sleep can reduce daytime sleepiness and other symptoms associated with sleep apnea, but apnea patients are not always happy with the treatment, according to two new reviews of recent studies.
In apnea patients, the airway in the nose and throat periodically narrows or closes off during sleep, stopping breathing for seconds at a time. People with apnea usually snore and feel sleepy and less alert in the daytime. Some studies suggest apnea can contribute to high blood pressure, heart disease and stroke and may be a factor in traffic accidents.
The reviews appear in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
Air mask treatment, also known as continuous positive airway pressure or CPAP, is the main treatment for apnea. In their review, Tammie Giles of the Queen Elizabeth Hospital in Adelaide, Australia, and colleagues concluded that CPAP can significantly improve apnea symptoms compared to no treatment or treatment with less invasive methods, such as oral spacers or tongue depressors worn in the mouth to open up the airway.
Patients using CPAP reported feeling less sleepy and more physically and mentally healthy than those not using CPAP. They also had 17 fewer apnea episodes per hour of sleep, the researchers found. CPAP patients in several of the studies also lowered their blood pressure after starting the treatment.
"The overall results demonstrate that in people with moderate to severe sleep apnea CPAP can improve measures of sleepiness, quality of life and mood and associated daytime sleepiness," Giles said.
In a second review, Jerome Lim and colleagues found that spacers and other oral appliances can improve apnea symptoms compared to no treatment, but they do not work as well as CPAP for most patients.
Lim and colleagues say their findings suggest oral appliances should not be used as "first choice therapy" for people with severe apnea.
However, "it would appear to be appropriate to recommend oral appliance therapy to patients with mild symptomatic obstructive sleep apnea and those patients who are unwilling or unable to tolerate CPAP therapy," Lim says.
Despite CPAP's benefits, "certain people tend to prefer oral appliances to CPAP where both are effective. This could be because they offer a more convenient way of controlling obstructive sleep apnea," Giles said, explaining that many patients find the nasal mask uncomfortable to wear and the CPAP machine too noisy.
Tricia Haynes, a psychiatry professor at the University of Arizona who has studied patients' reactions to apnea treatment, says the average person may think "the cons of using CPAP outweigh the perceived benefits."
Haynes said many people with apnea are used to daytime sleepiness by the time they start therapy, "and CPAP is uncomfortable, unwieldy, and inconvenient. Moreover, it is a nightly reminder that one has a chronic medical illness. When operating in a sleep-deprived state, it's often easier to put the machine in the closet permanently and avoid thinking about it than to problem-solve obstacles with CPAP use."
The Giles review included 36 studies of 1,718 people, mostly middle-aged and overweight. The Lim review included 16 studies with 745 people, mostly middle-aged men.
According to the National Heart, Lung and Blood Institute, 18 million Americans have sleep apnea. The majority of adult apnea patients are obese, which may make weight loss an important behavioral component of treatment, although the short-term effects of weight loss on apnea symptoms are still uncertain, Giles says.

CPAP boosts energy in 3 weeks for sleep apnea patients

Obstructive sleep apnea patients who comply with CPAP (continuous positive airway pressure) therapy report increased energy after just 3 weeks.

The greatest benefit from CPAP was found for patients who reported the highest levels of fatigue and daytime sleepiness that are hallmark symptoms of untreated obstructive sleep apnea, found in a new study.
The findings, published in the journal SLEEP is one of the first double blind studies showing the impact of CPAP on reducing fatigue and increasing energy, according to lead author Lianne Tomfohr, graduate research assistant in the joint doctoral program at San Diego State University and the University of California, San Diego.
Tomfohr says, "These results are important, as they highlight that patients who comply with CPAP therapy can find relief from fatigue and experience increases in energy and vigor after a relatively short treatment period."
Fatigue levels were analyzed using the Multidimensional Fatigue Symptom Inventory – Short Form and the fatigue-inertia subscale of the Profile of Mood States – Short Form in a study of 59 adults with an average age of 48. Using the former scale, fatigue symptoms improved from 8.76 at baseline to -0.10 post-treatment and went from 7.17 at baseline to 4.03 post-treatment, using the latter.
On the Epworth Sleepiness Scale, the participants treated with CPAP for obstructive sleep apnea experienced a drop from 13.0 at baseline to 8.9 after treatment.
Obstructive sleep apnea (OSA) that affects two to four percent of the adult population is treatable with CPAP therapy. Controlled pressure delivers air during sleep when the muscles of the throat relax by way of a fitted mask. Symptoms of OSA include snoring, low levels of oxygen during sleep that can lead to a variety of other health problems and periods of not breathing, known as sleep apnea or intervals of shallow breathing.
For the study, diagnosis of OSA was confirmed in a sleep lab using a standard test known as overnight polysomnography. Patients studied who received CPAP therapy versus placebo CPAP experienced increased energy and relief from fatigue in just three weeks. The study authors suggest it may be that CPAP therapy reduces inflammation among patients with obstructive sleep apnea, leading to renewed vitality.

Sleep Apnea Treatment Benefits The Heart

Sleep Apnea and Heart
Shape and function of the heart improves with apnea treatment
Patients with obstructive sleep apnea have enlarged and thickened hearts that pump less effectively, but the heart abnormalities improve with use of a device that helps patients breathe better during sleep, according to a new study in the April 4, 2006, issue of the Journal of the American College of Cardiology.
"Not only are the shape and size of the heart affected, the right side of the heart was dilated and the heart muscle on the left side was thicker in patients with obstructive sleep apnea, but the pump function was also reduced. The changes were directly related to the severity of the problem. Treating the problem brought significant improvements in the affected parameters, as well as in symptoms, in a relatively short period of time of six months," said Bharati Shivalkar, M.D., Ph.D. from the University Hospital Antwerp in Antwerp, Belgium.
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder associated with increased risk of cardiovascular disease. The OSA syndrome is characterized by repeated partial or complete closure of the pharynx, gasping episodes, sleep fragmentation, and daytime sleepiness. Previous studies have shown that sleep apnea is associated with high blood pressure and other cardiovascular risks, including stroke, ischemia, arrhythmias, or sudden death.
This study included 43 patients (32 men and 11 women) with obstructive sleep apnea. Sleep lab studies measured the severity and frequency of complete or partial interruptions of airflow. The shape and pumping action of the participants' hearts was measured using ultrasound. The researchers also examined 40 similar control subjects who were healthy and did not report any symptoms that would indicate sleep apnea.
Compared to the control subjects, the hearts of the sleep apnea patients were significantly enlarged on the right side and had thickened walls between the pumping chambers. The hearts of sleep apnea patients also pumped less blood per beat, and the velocity of wall motion was slower for both the left and right compared to the control subjects. The sleep apnea patients also had higher blood pressure and faster heart rates than the control subjects. The severity of the heart abnormalities was correlated with the severity of obstructive sleep apnea.
The sleep apnea patients were then given continuous positive airway pressure (CPAP) devices to treat their breathing problems. An air pump that is connected by a tube to a face mask helps keep the patient's airways open during the night. CPAP is a common sleep apnea treatment that often helps patients sleep better and then remain alert during the day.
In this study, the 25 sleep apnea patients who were evaluated after six months of CPAP treatment were not only sleeping better, and were more alert during the day, but there were significant improvements in the size, shape and pumping action of their hearts.
"From a cardiovascular standpoint, OSA still remains an important under-diagnosed and under-treated problem. Our study highlights that the changes in the shape and function of the heart can be assessed quite easily in a non-invasive manner and can alert the physician of impending cardiac problems. Most importantly, treatment can cause substantial improvement in a relatively short time. We hope that this paper will contribute towards improved awareness of cardiovascular and general physicians of a fairly common problem in the western society," Dr. Shivalkar said.
She said clinicians should also address issues such as alcohol and sedative use, which can affect sleep, as well as weight loss. However, she noted that not all sleep apnea patients are obese.
In her own clinical experience, Dr. Shivalkar said she has seen several patients who had high blood pressure that was not adequately controlled with medication. In many cases, she discovered these patients had obstructive sleep apnea.
"After treatment with CPAP, the antihypertensive medications could usually be substantially reduced. I am sure there are a lot of my cardiovascular colleagues out there who are often faced with such scenarios of difficult to treat hypertension. There should be a multidisciplinary approach to this problem, with a close association with cardiovascular physicians and sleep doctors in diagnosing and treating this problem," she said.
Eighteen of the 43 sleep apnea patients in this study did not complete the six months of CPAP treatment. Dr. Shivalkar said that although CPAP is a simple and noninvasive solution, a number of patients do not tolerate having the face mask on during the entire sleeping period at night. Some sleep apnea patients are treated with surgery, but Dr. Shivalkar said there is no long term data available on the effects of surgical treatment for these patients.
Ian Wilcox, M.B., Ph.D. from the Royal Prince Alfred Hospital Medical Centre in Newtown, Australia, who was not connected with this study, said earlier studies had produced some mixed data, and now these results move the field forward.
"This study brings it all together, particularly the treatment arm. In earlier treatment studies, patients didn't use CPAP the whole night. Here they used it almost seven hours a night, and showed quite nicely reduced septum thickness, along with improved performance and stroke volume," Prof. Wilcox said.

Sleep disturbances affect classroom performance

As a night of bad sleep can have an adverse effect on an adult's performance at work the next day, an insufficient amount of rest can also have a negative impact on how well middle or high school students perform in the classroom. A study published in the February 15th issue of the Journal of Clinical Sleep Medicine (JCSM) finds that adolescents who experience sleep disturbances are more likely to receive bad grades in school.
James F. Pagel, MD, of the University of Colorado School of Medicine, examined the results of 238 school district-approved questionnaires, filled out by students attending middle school or high school, which included a high frequency of sleep complaints. According to the surveys, students with lower grade point averages (GPAs) were more likely to have restless, aching legs when trying to fall asleep, difficulty concentrating during the day, snoring every night, a hard time waking up in the morning, sleepiness during the day, and falling asleep in class.
"While a series of previously-conducted studies all found that adolescents reporting inadequate sleep, irregular sleep patterns, and/or poor sleep quality do not perform as well in school as students without sleep complaints, this study provides additional evidence indicating that sleep disturbances occur at high frequencies in adolescents and significantly affect daytime performance, as measured by GPA," said Pagel.
Both restless legs and difficulty concentrating during the day are symptoms associated with the diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), a diagnosis that can be associated with poor school performance. It is important for parents to discuss their teen's sleep-related problem with a primary care physician, and to have their teen screened for ADHD if necessary, added Pagel.
Teens are advised to follow these recommendations to getting a good night's sleep, which will help lead to better school performance:

• Get a full night's sleep on a regular basis. Do not stay up all hours of the night to "cram" for an exam, do homework, etc. If extracurricular activities at school are proving to be too time-consuming, consider cutting back.

• If you are not asleep after 20 minutes, then get out of the bed and do something relaxing, such as reading a book or listening to music, until you are tired enough to go back to bed.

• Get up at the same time every morning.

• Avoid taking naps after school if you can. If you need to lie down, do not do so for more than an hour.

• Keep a regular schedule.

• Don't read, write, eat, watch TV, talk on the phone or play cards in bed.

• Do not have any caffeine after lunch.

• Do not go to bed hungry, but don't eat a big meal before bedtime either.

• Avoid any rigorous exercise within six hours of your bedtime.

• Try to get rid of or deal with things that make you worry.

• Make your bedroom quiet, dark and a little bit cool.