Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Milton Erman and Dr. Joseph Lieberman. This program is available as read only and with accompanying audio.
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Slide 1: Welcome to Insomnia Management in Primary Care: New Approaches to Improve Patient Quality of Life. This activity is jointly sponsored by the University of Kentucky College of Medicine and Princeton CME, and is supported by an educational grant from Takeda Pharmaceuticals North America, Inc.
I am Dr. Joseph Lieberman, Professor of Family Medicine at Jefferson Medical College, Thomas Jefferson University in Philadelphia, Pennsylvania.
I will be your presenter, along with Dr. Milton Erman, Voluntary Clinical Professor of Psychiatry at the University of California, San Diego.
Please note that all faculty disclosures for this activity are included in the front of your activity booklet.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form located in the back of the activity booklet. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Slide 2: Thank you again for joining us.
Slide 3: Now to begin with our case.
Slide 4: The first thing we want to discuss is the patient’s background. She is a 72-year-old widowed white female—she has been widowed for 10 years now. Her chief complaint is of “insomnia.” She is brought to your office by her daughter. You have seen her infrequently in the past because she gets her routine care from her obstetrician/gynecologist, but because of her sleep problem, the obstetrician/ gynecologist referred her to you for therapy.
Slide 5: So, pertinent history. No history of sleep disorders prior to the onset of these episodes of similar episodes of insomnia, and this has developed rather insidiously over the past 3 to 4 years. Her usual bedtime is 10 to 11 o’clock at night, and what she relates is that she has an “inability to stay asleep” occasionally problems “getting to sleep, occasionally awakening too early, and then being unable to get back to sleep,” so she has multidimensional symptoms with regards to her insomnia. As to next day consequences, she feels “tired and sluggish” following an episode of insomnia, and she frequently experiences what she would describe as “unrefreshing” sleep. Symptoms were initially very infrequent, but insidiously over the years they have become more and more frequent, so that now she is experiencing them approximately 5 out of 7 nights. And of course she tried the usual over-the-counter remedies, but they didn’t work particularly well after a couple of days, their effectiveness waned, and she did have some side effects that were discomforting to her so she discontinued the OTC products.
Slide 6: As far as additional patient information, she is a gravida III para III ab 0 with no significant gynecological history, and she does have, as I had mentioned, her routine examinations performed by her obstetrician/gynecologist. She did take some hormone replacement therapy (HRT) for 10 years postmenopause, but she hasn’t taken any for the last 10 years.
She describes her overall health as “good.” All she takes is an occasional aspirin when she “overdoes the gardening,” she doesn’t take any regular medication, and she does exercise every day. She denies any neuropsychiatric symptoms, she’s not feeling depressed, she’s not experiencing any loss in pleasurable activities, she doesn’t snore, according to her daughter with whom she resides, and she denies any unusual sensations in, or movements of her limbs or things like this while going to sleep. Her review of systems, past medical history, family history, and social history all were noncontributory.
Slide 7: Physical exam – blood pressure was normal for her age as was her pulse rate, respiratory rate, temp, and her height/weight ratio was good and had been maintained for about the past 5 years. Head, eyes, ears, nose, and throat were within normal limits and significantly there was no respiratory obstruction observed – no crowding in the oral pharynx. Neck – her thyroid was not enlarged, there were no masses, and her carotid pulses were fine. Chest – her heart and normal sinus rhythm, no murmurs, her lungs were clear; abdomen was soft without tenderness or masses; bowel sounds were normal; rectal exam was negative. Her pelvic exam was deferred because it had just been done 3 months ago by her obstetrician/gynecologist and it was reported to you as being within normal limits. She had good peripheral pulses and no edema, and her neurological exam was essentially within normal limits.
Slide 8: Laboratory tests and patient risk factors – CBC, urinalysis, and SMAC all were within normal limits, as were her TSH and ferritin levels. So, she has the risk factors of female gender, being elderly, and widowed, so these can contribute to a higher incidence of insomnia. So, with that in mind, as you listen to the main presentation, please consider the treatments options that could be most appropriate for this patient. I would now like to introduce to you, Dr. Erman for his presentation. Dr. Erman.
Slide 9: Thank you, Dr. Lieberman.
Slide 10: Today we're going to be starting our program with a slide that takes a brief look at the electrophysiology of sleep. This is a fascinating topic usually for practitioners because it goes into sleep stages, and we're looking on the slide here at the EEG recording that we would typically obtain from a sleep record. The left hand side of our slide here shows the traces going from very nondreaming sleep stages to traces with high altitude slow waves all the way up to traces from waking and REM that really look quite similar in many ways where we're seeing very fast activity.
We use this information to help to generate a sleep hypnogram, this is what we have on the right hand side here, a picture of the progression of sleep over the course of the night, and in a healthy normal individual we would expect to see a short sleep latency, falling asleep quickly, we're going to see some deep nondreaming sleep stages 3 and 4 in the early part of the night, and some REM occurring 90 minutes to 2 hours into the night. Sleep is dynamic; it progresses over the night, and we're going to see much more REM sleep later in the night. We see a few arousals in the night as we would typically expect to see in any normal individual.
Slide 11: The situation is very different for insomniacs, so we can define insomnia using some terminology that's pretty widely accepted, now included also in a recent NIH consensus and state of the science conference on insomnia is that there are 4 different conceptual models for how insomnia may present problems falling asleep, staying asleep, waking too early, or poor quality sleep. See the consequences of these listed, any of these or all of these may be present at one time, and more than 1 disturbance is present, and they also can change over time. What's important to appreciate is that there are next day consequences. This is a symptomatic complaint that we assume is going to be linked with next-day complaints.
Slide 12: So in classifying insomnia, we can think of this as really a primary insomnia, this is the type of insomnia that we study in research studies used to generate work on developing new medications. The patient who says I have no reason for my insomnia, it's always been very bad is different from what we see in most of our patients, which is comorbid insomnia. This used to be called secondary insomnia, the terminology has changed a bit here, and it has changed because the insomnia isn't necessarily secondary, it's not caused by another condition, but rather it is often associated with it, examples would be depression, pain, et cetera. Conceptually we can talk about acute insomnia, which is lasting up to several weeks, specific causes often are apparent, it can progress into a more chronic state; and chronic insomnia, which is present for those individuals who have complaints that are persistent for more than 30 days.
Slide 13: Well we have a slide here that is a bit provocative, intended to be, and that is why treat insomnia? And it's a source of discussion, because some physicians might say well, you know, nobody would die from lack of sleep. Rationale here is that like many other conditions, we have reasonable reasons to think it causes distress, it impairs functioning, increases healthcare costs, we'll go into this in a moment, associated with increased risk of comorbid disease, these other diseases, like depression, can be made worse by persistence of insomnia, and it is indeed responsive to treatments.
Slide 14: So, as we go into our slide labeled “Annual Cost of Insomnia,” this is some recent data that was published in the Journal of Sleep, and it tried to look at both direct and indirect costs of insomnia.
The direct costs are primarily these healthcare costs that we're talking about, and looking at these numbers, the authors were able to document very highly significant increased costs associated with these direct care expenses, certainly some of this we would not be surprised if people were taking medications. But other elements play a role as well; these people are fatigued, they're being worked up for other conditions, they have headache, they have worsening of pain.
We also see that there are indirect costs, and part of these relate to issues like absenteeism from work and short-term disability, and in the population that was of relevance here in terms of the primary working age population, the authors were also able to show that there were significant increases in these indirect costs as well. We see from these numbers, by the way, a very large sample of patients in healthcare plans compared with insomnia patients and control.
Slide 15: Insomnia is a prevalent condition. There are various ways of defining the prevalence, and if we look at complaints of sleep disruption, we see something like 30% of the general population. If we look at chronicity, those people who have a chronic problem and functional impairment—we’re looking at 10%, and as we've seen already, very significant increases in costs that can be associated with these conditions.
Slide 16: It does increase in prevalence in association with increased age. We don't sleep as well as we age, but the primary contributing factor, it turns out as we find from meta-analyses, is that these comorbid medical conditions, things like pain, like arthritides, like nocturia, like psychiatric problems, these increase also with age, and these are the primary determinants of this increase in insomnia prevalence associated with increased age.
Slide 17: Going forward, we can look at the notion of functional impairments. This is data that was generated from a Gallup Poll survey that was sponsored by the National Sleep Foundation. They do these polls every year in relation to National Sleep Awareness Week. And I have always liked this data because of its linearity, what we see is that across the board as we look at these various tasks that are being assessed coping mood, relationships, the more chronic the problem, the worse the performance. We're looking here on the Y axis at the percent of patients who say that their functional abilities in these areas are poor, and we can, I think, understand this. As we think about our own lives with a poor night of sleep, we don't do as well in our empathy, we're more irritable, we don't handle tasks as well. If this becomes a chronic problem, this is going to become worse.
Slide 18: This has been looked at as well. Gary Zammit, in a study that was published in Journal of Sleep in 1999, looked at this, and showed across the board that the quality of life for insomniacs was worse relative to age- and sex-matched control who did not have insomnia complaints.
Slide 19: Looking at the issue of risk factors and associated features, first of all let's try to understand how it is that insomnia develops.
Slide 20: You've got a slide here that is titled Determining Factors of Insomnia. This is a model that was developed by Dr. Art Spielman, who is on the faculty of SUNY University of New York. And what it says is that we have this arbitrary theoretical insomnia threshold, we are all closer to or further away from this threshold, and that's the baseline level. This is the predisposing contributions to insomnia, these are various traits, biologic, genetic, et cetera, that can predispose. We can imagine a stressor for all of us that would be enough of a precipitating factor to take us over this threshold, a personal injury or illness, illness in the family, life stress. What we want to recognize, though, is that many individuals will develop perpetuating factors that make it more likely that their insomnia is going to remain present over long-term periods of time. And these include things like conditioning factors, and we'll talk about this as we talk a bit more about some of the behavioral therapies we can use, conditioning factors, poor sleep hygiene, excessive anxiety, worry about sleep, all of these can lead to chronic insomnia. Our goal is to try to minimize the probability that chronicity will occur to make interventions to prevent this from occurring.
Slide 21: We've addressed this issue of risk factors somewhat already. There is a risk factor as well of female gender. We don't fully understand this; certainly some contribution from this relates to another component of comorbidity. Hormonal status in women is a factor. Women―perimenopausally and menopausally—have increased rates of insomnia. We've dealt with this advancing age, and high percentages of individuals over the age of 65 are likely to have problems. Occupational status, shift work, variable work schedules play a major role, as do these comorbid, medical, and psychiatric disorders. Substance use, certainly substance use, other agents like alcohol and caffeine, and a family history of insomnia—if people have a family history, this is a contributing component. And this may be one of these predisposing factors we were talking about as a genetic component; it may be that certain individuals have predispositions; these are more likely to be our primary insomnia subjects.
Slide 22: When you look at associated features, and all of these come through in many surveys that have been done: increased risk of depression, increased absenteeism. We see our list, including these reductions in performance. So once again, we're talking about why it is that we would think about treating this condition, and why we're motivated to treat it; beyond symptom relief, it's also to try to reduce the impact that insomnia may be having in all these areas of function.
Slide 23: The absenteeism was looked at in this study that we had mentioned before from Dr. Zammit, and what we're seeing here is an almost 10-fold increased risk of absenteeism in this insomnia group. This is the number of days of work per year that people were absent. Lots of factors may play a role, people just not feeling that they're capable of working, including issues like use of over-the-counter agents that might predispose to residual sedation the next morning, and perhaps interfere with the capacity for people to get to work the next day.
Slide 24: Accidents have also been shown to be associated with patients with chronic insomnia. There certainly is a psychic distress factor that's looked at here. Is this just a component of patients who have psychiatric illness, which is why they have insomnia? The answer is no. It is higher in those with chronic insomnia than it is in those without chronic insomnia. Yes, it is higher in those with high psychic distress, should not be surprised that the impact of chronic sleep loss may be impairment of function, poor capacity to attend to details, and therefore consequences in terms of safety.
Slide 25: We've mentioned some of these precipitating factors, we'll say a little bit more about some of the specific issues here, they include circadian rhythm disorders, specific sleep disorders, and we'll talk more about psychiatric disorders, and very briefly about medication.
Slide 26: As we can see from our slide here on the relationship of circadian sleep phase sleep disorders, most of us we hope are going to be here in the middle: bed time, 11 pm, midnight, and we're getting up in the morning when we'd like to get up, and our body clock is in sync. There are people who have alterations in 1 of 2 directions, there are people who have an advanced sleep phase, and these are individuals who get sleepy early in the evening and wake up in the early morning, and then we have people with a delayed sleep phase, something we often see in adolescents, young adults, where there is a tendency to feel sleepy – not feel sleepy until the early morning hours, 2, 3 in the morning, and then they have trouble getting up in the morning to get to work, on school, this is an obvious concern.
Slide 27: We may see problems in association with restless legs, which is associated as well with periodic leg movements. This is a sensory motor disturbance that is characterized by this sense of the need to move the legs. Relatively high prevalence, we see a broad range here, but most studies we're going to see in the 5%, 6%, 7% range in the general population. It is underdiagnosed, and it does have impact on sleep, on cognitive function, on capacity to function throughout the day in general.
Slide 28: Finally from our issues of these primary disorders, we have our prevalence of sleep apnea in the general population, this is taken from work by Terry Young. It shows that the numbers are high and go up with age, they're up – in general we're going to talk maybe 8% to 12% of the population we're seeing a range in age here from the 6% to 7% range, up to about the 20% range in older populations.
Slide 29: And as we mentioned previously, the restless legs syndrome may be associated with actual leg movements. When we study people in the lab with restless leg complaints, there is a very high probability that this syndrome will be present. These complaints are associated with disruption of sleep with these actual leg movements, and this is diagnosed on the basis of sleep studies that show that sleep is being disrupted by this leg movement activity.
Slide 30: We've also mentioned this issue of comorbidity, and this goes back to the specific language from this State of the Science Conference that was organized by the NIH in 2005.
Slide 31: Their point is that most cases of insomnia are comorbid, and that it's a more appropriate term than primary, but the notion of secondary insomnia really gives the notion gosh, if we just treat this primary condition, the insomnia will go away doesn't happen. Great example here, excellent data showing that even with effective treatment of depression, that insomnia persists.
Slide 32: And there is this model again that, well all insomnia or a vast majority is really depression, this is what's causing it. Our slide here showing the circular relationship between these disorders shows that there is this relationship that yes, psychiatric disorders cause insomnia, but that there is also excellent evidence from many, many studies that show that the persistence of insomnia will lead to a greater risk of psychiatric disorders.
Slide 33: We have data we're going to show from 2 studies here, the first is from Breslau et al, this is a group that works out of Henry Ford Hospital in Detroit. And showing that there is this increased risk, if you follow individuals over 3-and-a-half years who do not have problems at baseline with psychiatric illness, we look at those who have insomnia versus those that don't, we see what the numbers are like 3-and-a-half years later, what is the incidence rate that has developed? We see these very highly significant differences between those with insomnia in relation to development of anxiety, of depression and of drug abuse.
Slide 34: And another study that should ring very close to home is data that Chang generated from survey work. This is a survey that is filled out by Johns Hopkins medical graduates. This is looking at people as we see over many years, data of the mean period of time for analysis is about 13 years. And what we see is that those individuals who had problems with insomnia or whose sleep was disrupted by stress in med school as they were followed over the years, there's a point of divergence. And the longer that they are followed, the greater the probability that depression will develop, and the sole determining factor here was insomnia versus no insomnia.
Slide 35: Evaluating and Treating Insomnia
Slide 36: We’re going to look now at some materials related to the evaluation of insomnia. As you see, the evaluation of insomnia is based primarily on information that is obtained during the interview. We may have some written information, but we’ll come back to that in a moment, but patients, family members may cue us into the fact that this problem is present. The medical history and physical examination are helpful. We saw before that the issue of comorbidity is a very real one, and we’ll come back to this in a moment, so if we know that there is a specific medical condition that plays a role, it may be helpful. It is very important to understand that insomnia is multifactorial - there can be multiple components that contribute. Certainly levels of stress, other issues, but also predisposition to insomnia as well as the presence of these comorbid medical conditions that may increase the probability that a disorder will be present.
Slide 37: There are various evaluation tools that can be used. Sleep questionnaires can be quite helpful. They allow patients to give us some specific information. In sleep labs we may use very elaborate questionnaires that can be as long as 15 pages or more, but a questionnaire can be quite brief simply asking about sleep, sleep quality, hours of sleep, usual habits, and may be enough to help the practitioner focus on how to understand the symptom and how to treat the complaint.
Sleep diaries are quite helpful and these are available from many sources – they allow patients the opportunity to track their sleep over a period of time; a week, 2 weeks. This is helpful in understanding what has been going on prior to evaluation, but also quite helpful as we are working with patients and able to see how they may show improvement over time and to be able to help them to perceive the differences they’ve had as a consequence of treatment.
Polysomnography formal sleep testing does provide objective data, but really is rarely used, at least in the early stages of insomnia evaluation, and may be used later on for more complex cases.
Slide 38: Well, back to this issue of comorbidity. How does comorbidity impact on treatment choices? Just reminding ourselves that comorbidity means that we’re not talking about a primary and a secondary condition. Another condition may be present, pain or depression, but there is a 2-way relationship. These conditions will make insomnia worse; insomnia will make these conditions worse. So that a simple treatment for the other condition is not necessarily going to get rid of the other sleep complaints. This is something that the NIH recognized in its recent consensus conference as well, recognizing that insomnia may be a chronic condition that is going to persist on the basis of these comorbid problems. And, it is rational to consider that the treatment for the insomnia may not only be of benefit in regard to the symptomatic relief of the insomnia complaint, but may be helpful as well in reducing the severity of the comorbid medical condition.
Slide 39: And so, we have a broad range here of nonpharmacologic therapies that can be used. We have our listing of the strategies; we have our listing of the goals. Some of these are practical some of these are not practical, for primary care physicians. But the point here is to recognize that we can look at these goals and say gosh, I can help patients using some of these nonpharmacologic techniques. The one that is most widely studied, and that has been shown really to be quite effective, is this approach of cognitive behavioral therapy. This has been used for other conditions, used for depression as well. It's a multi-component approach. It uses sleep education and sleep hygiene, but also helps with various cognitive therapeutic approaches.
Slide 40: So, if we look at our slide that says Cognitive Therapy on it, one of the goals: challenge patients' dysfunctional belief perceptions. The patient that says, “’If I don't sleep tonight, I will just not be able to function tomorrow.’” We can look at that patient's history and say, “Gosh, last Wednesday you didn't sleep at all, did your boss get onto you at work? Did you function okay?” Try to help change some of these attitudes.
Slide 41: So, let's say a word about general sleep hygiene measures. These are some techniques that I have and have modified from approaches that we're likely to see published elsewhere. My recommendations are to try to get up at the same time every day, and to get morning light exposure. I worry less about when do you go to bed—don't go to bed by the clock, go to bed when you feel sleepy, restrict napping. If we nap, we're going to reduce sleep drive that night; we want to certainly avoid caffeine in the hours before bedtime, and also to try to avoid alcohol and heavy meals close to bedtime. Exercise is good. It alone will not cure insomnia, but if we can do it in the morning or afternoon, it's better. If it's done close to bedtime, it may wake the individual up and really interfere with the capacity to sleep, and we want to have the bedroom as dark, quiet, and comfortable as possible. We also want to try to recognize that the bed is a place where relaxation should occur.
Slide 42: If reading is helpful, great―use a low-light level, read things that are not stimulating, don't read a new action adventure novel, or something that you get to the end to find out what happens. Journals may be helpful for people to fall asleep. We want to minimize work and stress in the bedroom, no computers, television, and patients say well it puts me to sleep, but you know what, people work very hard to keep you involved in that program until the end of the show or the commercial, really we should try to avoid this. We want to help people relax before bedtime, use relaxation techniques, meditation, warm bath; we want the bedroom to be associated with capacity to sleep, and so we want relaxing activities, so sexual activity for most people probably okay. And we don't want them using the alarm clock to look at during the night. This just wakes them up. It's very hard for insomniacs to give up on this. Instead, let them set an alarm for as late as they could sleep in the morning. If the alarm hasn't gone off, it's irrelevant what time it is. Again, it’s very hard to break insomniacs of these habits.
Slide 43: We're going to talk now about some of the agents that are approved, there are 2 general classes of agents. What we have listed here is BZRAs, benzodiazepine receptor agonists. These are compounds that work through the benzodiazepine receptor site in the gabba A complex in the brain. Two subgroups, the actual benzodiazepine and the agents that are nonbenzodiazepines, also work through these receptor sites, and one agent, which is a melatonin receptor agonist.
Slide 44: So, we have our drugs here, which are indicated for short-term use. Going from the older benzodiazepine drugs, we've got florazepam to temazepam, triazolam, these are some of the older drugs. These are actual benzodiazepines, the newer compounds that are benzodiazepine receptor agonists included zolpidem and zaleplon, and we see the half lives in these.
Slide 45: We now have 3 agents that are indicated for use without a restriction on duration; it does not have the statement in their packaged labeling for the short-term treatment of insomnia, eszopiclone, zolpidem ER. These are both the BZRA – benzodiazepine receptor agonist type. And we have ramelteon which is a melatonin 1, MT1, MT2 receptor agonist.
Slide 46: We'll see some data from some of these that help us to understand why the approval has been generated for longer-term use. The first is data with the extended-release formulation of zolpidem, and what we're seeing is a 6-month study compared to placebo. This actually was a study that allowed individuals medication as needed 3 to 7 times per week, and we see that there is a significant improvement in the active treatment group looking at sleep onset latency as well as wake times showing at the end of 1 month, sustaining itself over a 6-month period of time.
Slide 47: And this is data that in the next slide that looked at the efficacy. The side-effect patterns here showed that headache was the most prevalent complaint. There was impression on the basis of the clinicians involved showing that yes, there was a significant improvement in performance for these individuals as well.
Slide 48: We also have data on ramelteon looking at patients with chronic insomnia. This is data that has recently been presented at the American Psychiatric Association meeting held in San Diego and of the Associated Professional Sleep Societies. The data for the ramelteon, our first slide on this is from work that was done—Lewis Mini first author looking at safety in females with chronic insomnia, looking at the 8-mg dose, which is the recommended dose, looking at latency to persistent sleep, and looking at both short-term 2-night studies. And this is data that was sleep laboratory data looking at polysomnographic findings and showing that this 8-mg dose led to significant reductions in latency to persistent sleep compared to placebo.
And a 5-week study, this is looking at subjective reports over a 5-week period of time that compared to placebo the ramelteon 8 mg significantly reduced the reported latency to persistent sleep. At all the time points you see very robust P values throughout the duration of the study.
Slide 49: Another study was done looking at the potential impact of ramelteon on balance. This was a comparison study looking at comparison with zolpidem with a middle-of-the-night awakening. This I guess was intended to try to look at safety issues if people have to get up in the middle of the night, there is very good data from multiple sources showing that ramelteon does not have a lot of impact on balance, on memory cognition, et cetera, in this situation of awakening in the middle of the night. There was a very clear difference between these 2 agents with regard to their functional impact. The sensory organization testing, which included a balance measure, turning speed, stability, memory showed significant impairment with zolpidem compared to placebo. And a memory task as well showed significant decline with zolpidem compared to placebo; no impact of ramelteon compared to placebo.
Slide 50: We have some data here that has been presented at a number of settings, and is published now on eszopiclone. This is also part of some of these changes in recommendations about duration of use. Six-month data showed that in a double-blind format that the eszopiclone 3 mg showed superiority to placebo with regard to sleep latency. The following 6 months was an open-label phase when those who had been on placebo were shifted over to active treatment. And they moved into the same general range as those who had been on the active drug in the first 6 months, showing that there was not a sense of loss of effect, of tolerance developing over the 6-month period, something we've seen as well in the studies with ramelteon and the data that we saw earlier with regard to the extended-release zolpidem.
Slide 51: Over-the-counter agents (OTC). There are some statements about these compounds mentioned in the NIH consensus conference study report, basically saying that there are adverse effects in cognitive impairment, and that there is no data on their safety with regard to the herbal agents, not FDA approved, so there are significant concerns about hangover effect with the general OTC agent.
Slide 52: Well, we've got our slide here about over-the counter agents, and going on to some new data that has been generated on drugs and development.
Slide 53: This is all data recently presented at the APA. Just very briefly, we have a compound that is working as a partial agonist, this is NG2-73. It has a preference for the alpha three receptor sub unit, slightly different from the agents that are currently available. The data showed that it was generally well tolerated, the adverse effects that were seen were seen as the primary extension of drugs that is in fact in essence talking about some residual sedation beyond the period of time desired for the therapeutic actions.
Slide 54: A sublingual zolpidem preparation, also this is an agent that's being developed for middle-of-the-night use, with low doses of zolpidem. Its 3.5 and 1.75 doses were tested, both of these dote efficacy with regard to the latency, the return to sleep. Looking at the risk/benefit analyses, they were able to identify the 3.5-mg dose as what appeared to be their optimal dose going forward.
Slide 55: And data as well on an agent—really an old agent looking at it in a new formulation, doxapin―now available as a generic, and looking at a low-dose strategy with this agent for longer-term administration. The notion is here up to 35 days of treatment for patients with chronic insomnia complaints. Both doses were effective. The 3- and the 6-mg doses, quite low relative to the therapeutic doses for depression, were effective when measured on nights 1 and 29 of administration. So, not a sensation here of any tolerance developing, either.
Slide 56: Well, why not treat insomnia? This is really a companion to our earlier slide. Why do physicians have hesitancy? They don't understand that they may not appreciate that it has impact, they're busy. We like to hope that by education we can help them to be more aware and more understanding of this. There are fears of the complications associated with the extended use. Are people going to become dependent? There are certainly concerns about scheduled agents. We have 1 agent now that is not a scheduled agent available, and that is the melatonin receptor agonist ramelteon, and concerns about abuse tolerance and dependence.
Slide 57: Among the other barriers that are present to effective management are the lack of training and this type of experience we hope will help to ameliorate that. It's very tough. Time constraints certainly play a role. If you're busy seeing 20, 30 patients a day, tough to fit this in, there are some screeners that can be used. But simply asking a few questions in the office may be one way to address this. I think lack of appreciation that there is all of this impact that is present on sleep, and I think it'd be educational help. And, I think a perception that the risks outweigh the benefits. Again, we have newer agents that have fewer limitations, some of which are nonscheduled, and certainly I think we can make a very strong argument that the benefits appear to outweigh the risks.
Slide 58: Guidelines for practice. We'd like to encourage asking questions about sleep, what is going on, how are you sleeping, what's interfering? Trying to recognize that there is this issue of comorbidity that when insomnia persists it makes these other conditions worse. We would certainly like to work on sleep hygiene. These elements really should be incorporated as part of our routine with all patients. CBT and options primarily for specialists; we want to be aware of the options we have available and of the suitability of these various agents for individual patients, and to try to recognize that patient materials are available that may help us to assess therapy, to see how effective it is, and to help us to evaluate outcomes.
Slide 59: For our summary slide, chronic insomnia is a major health problem. It affects millions of individuals. It has impact on their families, has impact on their work settings, it can be the cause of or it can be a result of associated problems. This is our comorbidity model. Like to have appropriate and accurate diagnoses in order to have effective treatment, and we have a number of approaches that really show promise. We saw some drugs in development, and we have 3 agents that are now approved for use without limitations in terms of duration of treatment. We can certainly help to feel much less concerned about the issue of chronicity of treatment on the basis of this data. Well, I want to thank you now for your participation. We will now turn back to Dr. Lieberman for a discussion of the case study that was presented at the beginning of this activity.
Slide 60: Thank you, Dr. Erman. Now let’s revisit the case. Let’s look at the treatment plan. We will start this patient on a sleep diary, and then note that in 2005 the NIH convened a State-of-the-Science Panel which endorsed treatments for chronic insomnia of cognitive behavioral therapy and FDA-approved benzodiazepine receptor agonists. Now, subsequent to this conference, the FDA also approved ramelteon, a selective melatonin receptor agonist, and this is recommended for treatment of sleep onset insomnia. And also, of course, you want to recommend good sleep hygiene practices to your patient.
Slide 61: Behavioral approaches available to us include cognitive therapy, which challenge patient’s dysfunctional beliefs and misconceptions about sleep and insomnia. And this is usually provided by a professional trained in its use. Most of us in the general practice of medicine do not have special training for cognitive therapy, but cognitive behavioral therapists are available in the community and this has a very, very favorable impact on insomnia. Relaxation training we can do, and in fact there are resources available in most communities that will help us instruct our patients in relaxation techniques, such as transcendental meditation, yoga, and biofeedback. Progressive muscular relaxation you can teach patients in your office. Sleep restriction and stimulus control are both linked. Sleep restriction is the notion that you only want the patient in bed for the time that they are sleeping. You don’t want a patient going to bed for 12 hours and trying to catch 5 hours of sleep. You want the patient to go to bed, and if they have not gotten to sleep within a half an hour they should get up, do something other than trying to sleep, but something that is not stimulating, perhaps they need to read a book or just sit down and sip on a glass of warm milk or something to that effect. And then stimulus control of course is imbedding in the patients’ psyche the notion that the bed is for 2 things: sleep and sex, and if you’re not doing one or the other, you shouldn’t be in bed.
Slide 62: How about the pharmacologic approaches to treating insomnia? Well, we have a number of medications – 10 that are approved by the FDA at present. We have the old-line benzodiazepines, and they have pretty much been replaced in this day and age, but they were widely used and had acceptance over the past 20 to 30 years because they were such an improvement on what they had succeeded. The preceding medications were largely barbiturates and clorylhydrate preparations, and so the benzos came along and they had a much better side-effect profile and were safer agents. But they have been replaced now largely by what are known as the nonbenzo benzodiazepines. These are drugs that are called nonbenzos because chemically they are not benzodiazepines, but they are called benzos because they act at the benzodiazepine receptor site, and these are in wide use today. Zolpidem, zolpidem extended release, zaleplon, and eszopiclone. Now the zolpidem extended release and the eszopiclone have the additional benefit of not having any restriction to their length of use and they are also indicated for the treatment of sleep-maintenance problems. The melatonin receptor agonist ramelteon has the advantage of not being a scheduled agent because it acts on different receptor sites in the brain, and it has also been approved for sleep-onset insomnia.
Slide 63: To conclude, this patient was started on an appropriate treatment plan, including behavioral and pharmacological therapy. Because of the multiple medical and emotional problems associated with insomnia, the patient needs to be followed closely and her therapy may need to be adjusted to obtain optimal results. In the event she doesn’t respond, or responds poorly to therapy, the diagnosis needs to be reconsidered, and/or a consult with a sleep specialist obtained. Thank you for your participation in today's teleconference.
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