Managing Sleep Challenges after Transplant

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Managing Sleep Challenges after Transplant

Tuesday, May 3, 2022

Presenter: Dave Balachandran MD, Medical Director of the Sleep Center at the University of Texas, MD Anderson Cancer Center

Presentation is 35 minutes long with 23 minutes of Q & A.

Summary: Insomnia, which is defined as difficulty falling or staying asleep, is three times higher among transplant recipients than the general population. Cognitive behavioral therapy for insomnia (CBT-I) is a safer a treatment than sleep medications and more effective long-term.

Highlights:

• Medications prescribed to improve sleep can cause daytime grogginess, poor thinking and increase the risk of falls, particularly in older adults.
• Exposure to early morning light, being physically active during the day, establishing routines and minimizing daytime sleep can make it easier to fall and stay asleep at night.
• Having a consistent bedtime routine, having a comfortable mattress, and pillow using the bed only for sleep or sex, sleeping in a cool, dark room and avoiding phone or TV stimulation before bedtime can promote better sleep and reduce fatigue during the day.

Key Points:

(02:10): Almost half of cancer patients experience fatigue or insomnia and almost a quarter of them use sleep aids.

(05:38): Prolonged hospitalization, chemotherapy, pain and medications and their side effects can cause insomnia.

(12:34): Your brain likes consistency and wants you to go to bed at the same time each night and get up at the same each morning.

(14:46): If you can’t fall asleep, it’s best to leave the bedroom and do something relaxing before trying to sleep again.

(16:59): Smoking can interfere with sleep. Nicotine is a stimulant that can keep you awake at night.

(17:07) Alcohol may help you fall asleep, but wears off in two to three hours, and can then wake you up and disrupts your sleep.  

(17:31) Caffeine remains in your system eight to twelve hours and, if consumed too late during the day, can disrupt sleep at night.

(20:02): Light therapy in the daytime and melatonin at night can be an effective combination to promote sleep.

(22:29): Movement disorders, like restless leg syndrome, can occur in transplant recipients and interfere with sleep.

(26:23): Some studies have found that sleep disordered breathing, like sleep apnea, if left untreated, can increase the risk of cancer.

Transcript of Presentation:

Note: This presentation uses the terms “bone marrow transplant” and “stem cell transplant” interchangeably.  Statements made about bone marrow transplant apply to stem cell transplants as well, and vice versa.

(00:00): [Marsha Seligman] Introduction. Hello, everyone. Welcome to the workshop, Managing Sleep Challenges after Transplant. It is my pleasure to introduce to you Dr. Dave Balachandran. Dr. Balachandran is professor in the department of pulmonary medicine at the University of Texas, MD Anderson Cancer Center, and the Medical Director of the Sleep Center. His research focuses on sleep disturbances in cancer patients and interventions to address them. Please join me in welcoming Dr. Balachandran.

(00:33): [Dave Balachandran] Overview of Talk. Hello, thank you so much for taking your time to join us today. I'm very excited to give this talk to you about managing sleep challenges after transplants. We have had a sleep program here at MD Anderson Cancer Center for about 15 years. We've been able to gain some experience with these challenges, and I look forward to discussing that with you today.

(01:04): A number of factors can negatively impact sleep for transplant recipients including aging, pain, stress, sleep hygiene, other medical conditions and medication.  Sleep and cancer is a fairly broad issue, and I like to think about it starting with what people bring to their cancer diagnosis and their stem cell transplant or their bone marrow transplant. Obviously, there's a lot of patient related factors that impact the type of sleep disruption they may experience. These include aging, pain, their experience with stress, their experience with sleep hygiene, other medical conditions and medications that they take.

(01:33): Then, of course, cancer itself and therapy related to cancer, such as bone marrow transplant may also cause sleep disruption. There might be primary sleep disorders. We're going to be discussing some of them today that also may relate to sleep disruption.

(01:47): Poor sleep can impact many facets of life. Unfortunately, once you have sleep disruption, it can impact many facets of your life. It can increase things like fatigue, anxiety, and depression. It can cause cognitive impairment, it can lower your pain threshold, make you more sensitive to pain. It can cause hormonal imbalances, weight gain, and even other medical conditions such as high blood pressure or diabetes.

(02:10): Nearly half of cancer patients experience fatigue or insomnia, and almost a quarter of them use sleep aids. Sleep and cancer disturbance and cancer are fairly prevalent. You can see in this study of over 1000 patients, that up to 44% of patients complain about fatigue, or they may report that they have insomnia. In addition, almost 20% to 25% of patients with cancer takes some sort of sleeping pill, some sort of sleep aid, either over the counter or prescription to help them sleep at night. It's a fairly common problem.

(02:42): Insomnia is the most common type of sleep disorder seen in cancer and transplant recipients. There are many different types of sleep disorders, and this is just a partial list of some of the ones that we may talk about today. Insomnia is the most common problem in sleep, both in cancer patients, as well as specifically in cancer patients. Unfortunately, cancer patients, and those with transplant have higher rates of sleep disturbance compared to the general population.

(03:07): Sleep disordered breathing or sleep apnea is also an issue, and there are actually links that show that people with insomnia and sleep apnea may actually be predisposed to cancer. It's really important for us to try to understand these sleep disorders, what they mean and how they impact our patients.

(03:26): Insomnia is defined as difficulty falling or staying asleep. It is three times higher in cancer patients than in non-cancer patients. As I mentioned, sleep disorders are more common in cancer patients. In fact, insomnia is three times higher in cancer patients than non-cancer patients. Again, the burden of disease or the burden of disturbance is more challenging in patients with transplant and in cancer in general. These are some of the symptoms associated with insomnia. Some of you may have experienced this yourself.

(03:51): Insomnia is defined as difficulty falling or staying asleep. It can lead to daytime impairment because people are not refreshed. Insomnia is defined as difficulty falling asleep and difficulty staying asleep. Oftentimes, because of insomnia, the sleep does not feel refreshing in the morning and you feel more tired and fatigued during the day. Insomnia can cause significant distress and also daytime impairment because you don't feel refreshed, you don't feel rested and you have trouble doing the things that you'd want to do.

(04:16): Medications for sleep problems cause can make you feel groggy and increase your risk of falling. Pharmacological therapies, such as sedatives and hypnotics are often prescribed, and these themselves can have problems. They can make you feel groggy in the morning. They can increase the risk of falls.

Some of these things that we use for treatment for sleep disorders can also be problematic. Therefore, what we really try to do in our center and in centers around the country is to really stress something called cognitive behavioral therapy as a treatment for insomnia, because it's much safer than pharmacological therapy. We'll discuss some of the tips that you can do at home to help you sleep better in a few slides.

(04:55): Some people may be predisposed to sleep problems even before transplant. I wanted to talk a little bit before we get to that about some of the factors that contribute to insomnia. As I mentioned, there's some factors that happen even before cancer and before stem cell transplant. Those can be related to aging. Some people are just more hyper arousable, they're just a little bit more sensitive to noise and different things that happen in the night and just wake up a lot faster than other people.

(05:17): You can have a family history or a personal history of insomnia that may carry on after your cancer diagnosis or your stem cell transplant. You could also have psychiatric disorders and adjustment disorders related to the cancer diagnosis that can also predispose you to developing insomnia during your cancer journey.

(05:38): Factors that can cause insomnia include prolonged hospitalization, chemotherapy, pain, medications, and their side effects. There are also precipitating factors: surgery, long hospitalization. The average stem cell transplant requires about a 25-day hospitalization, and that can be very disruptive to sleep and have very long-term-effects.

(05:52): Chemotherapy, nausea, vomiting, steroid therapy are some of the things that are associated with stem cell transplant and also can contribute and precipitate insomnia. Hormonal therapy, especially if you're on some sort of hormonal therapy, that's suppressing normal hormonal function, which can cause hot flashes. Then, of course, pain associated with cancer or therapy and delirium associated with cancer and therapy can also precipitate long-term sleep problems.

(06:21): Habits that can make insomnia worse include too much time in bed, an irregular bedtime and wake up cycle, sleeping too much during the day and poor sleep hygiene. Then there are the perpetuating factors. These are really important to understand, because this is really where we can intervene and try to make things better. Over time when you've developed insomnia related to your cancer, what can happen is, you start developing habits that make the insomnia worse, and these can include spending more time in bed, having irregular sleep-wake cycle, sleeping during the day more, sleeping less at night. Increasing your napping or more frequent naps and developing poor sleep hygiene. We're really going to focus on what sleep hygiene is and how we can impact that.

(06:56): Misconceptions about what causes insomnia can increase anxiety and make it more difficult to fall asleep. We can also start to develop faulty beliefs and attitudes about sleep that can make it really hard to calm down at night, reduce anxiety and actually help yourself fall asleep. We start to develop unrealistic sleep expectations. We think that if I go to bed, I'm going to fall asleep right away, and I'm going to wake up at a certain time. That might not be always realistic in every circumstance, and we really get anxious when those things don't happen, and that anxiety can actually precipitate more insomnia.

(07:26): There can also be faulty appraisals of sleep disruption. What I really mean by that is, we tend to attribute different things to the sleep disruption that we have, that may not actually be the actual cause, but we tend to focus on them, and it's really hard to get past those. We misattribute the lack of sleep to all of our problems during the day: the bad conversation I may have had, the feeling tired all the time. It may be more than just sleep and we may miss other attributes. It's really good to keep a holistic approach to saying why you may have fatigue. Maybe is it anemia, maybe is it a hormonal imbalance, maybe is it something else that's medical or psychological that's contributing in not just sleep.

(08:10): Then we may have misconceptions about why insomnia, the etiology or why insomnia occurs. These faulty beliefs can really be damaging. It's really important, with the cognitive portion of cognitive behavioral therapy, to understand these expectations and misattributions and misconceptions, to try to get a handle that so we can substitute more positive ways of thinking about our sleep and what we can do to make it better.

(08:36): There are a number of therapies to treat insomnia that do not include drugs such as improving sleep hygiene and cognitive behavioral therapy for insomnia (CBT-I).  Here's some of the options for sleep. We have a few slides, but they're broken down into these two general categories; there's non-pharmacological therapy and pharmacological therapy. The non-pharmacologic therapy is some of these things that I have just been talking about, improving sleep hygiene, and we're going to talk a little bit more about that; getting involved, if needed, in a good program of cognitive behavioral therapy, and there's different ways to do this. You can go to a therapist, there's online programs now that you can do, and there's other handbooks and other materials that you can find from the National Sleep Foundation and other good sources that can help you with that.

(09:15): Light, Melatonin, and daytime exercise can improve nighttime sleep. Sometimes we use light and Melatonin, and we have a lot of studies here at MD Anderson looking at that. There's some really brilliant work on daytime exercise, daytime, yoga, Tai Chi, other ways of approaching what you do during the day to help you sleep better at night.

(09:32): Medications for insomnia can help in the short-term, but generally don’t work well in the long-term and have lots of side effects. Then, of course, there's this multi-billion-dollar industry out there that provides sedatives hypnotics. You've heard the names; Ambien, Lunesta, Sonata all for insomnia There are all these wonderful drugs that are very good for, perhaps, the short-term treatment of insomnia, especially right after a stem cell transplant, but really, for the most part, don't work so well in the long-term and can have a lot of side effects.

(10:00): Sometimes if we find that depression or something else is causing the insomnia, antidepressants can be very useful. Also, there's stimulant medications can help with some of the daytime fatigue and the daytime sleepiness that we sometimes use, and that can actually help promote paradoxically good sleep at night, if you have more activity and feel better during the day.

(10:23): Let's talk a little bit about sleep hygiene, because this is really something that you could do at home, and there's this wonderful link from the sleepfoundation.org that you can look at that has even more information on this. But I just want to give you some of the highlights.

(10:38) Sleep hygiene, which includes comfortable mattress and pillow, sleeping in cooler temperatures and in a dark room, and avoiding phone or TV screen stimulation can help reduce insomnia. Finding a pain free mattress, finding a pillow that works for you. Everyone's a little bit different. You may have a catheter in a certain area that you don't want to put pressure on. All of those things, find a way of sleeping that you feel comfortable in.

(10:58): Keeping the temperature on the cooler side can really help promote sleep. Cool temperatures actually do promote sleep. Finding comfortable sheets and blankets that you can modulate that temperature with can be also very helpful.

(11:13): Light is something that we talk about a lot, because light actually activates the brain. It's actually a signal for us to be alert and awake, and it's really important to sleep in a dark room to minimize excess sources of light so that you can sleep.

(11:31): I would add to that, bringing your iPad or your phone or your laptop, or having a TV in the room is also a source of light. I know a lot of the technology now is trying to block out some forms of light. There's a particular spectrum of light called blue green light. That is really activating, that actually promotes wakefulness and interrupts sleep. A lot of our electronics now have mechanisms - you've probably seen day mode and night mode - where they block out some of that blue green light. But honestly, I think the best advice I can give is to avoid all of those kinds of activities, whether it's with a phone or a laptop or a device of any sort from your bedroom. If you need earplugs or a white noise machine to drown out exogenous or outside noise, that could be very important.

(12:22): Some people find things like aroma therapy - find the fragrance that works for you, that's not going to make you nauseous, that's not going to cause problems. But if that helps you, by all means, try it.

(12:34): Your brain likes consistency and wants you to go to bed at the same time each night and get up at the same each morning. Here's some more rules for good sleep hygiene: being consistent. Your brain really likes consistency. It wants you to go to the bed at the same time every night and wake up at the same time every morning. That way, having that consistent routine will help really structure your sleep at a certain time and help you fall asleep better.

(12:56): A consistent bedtime routine helps promote sleep. Having a consistent bedtime routine, whether that's reading, praying, meditation, whatever that might be for you, whatever helps. Doing that, finding a way to settle down, having, if you need to, a cup of milk or something that helps you fall asleep. Whatever that might be, being very consistent, almost creating a ritual is the term that we use for that, sometimes. Having a bedtime ritual or routine can be really useful and telling your brain, this is the time to wind down, this is the time to fall asleep.

(13:30): Avoid stimulating activities like electronics or heavy exercise at bedtime. Unplugging electronics, I can't stress that enough, very important to do, and we already discussed a little bit why that's important. Winding down, avoiding things that are very alerting, avoiding that movie or that conversation that's really going to cause anxiety or provoke a lot of alertness.

(13:52): Exercise, if you're going to do any, this is the time to not do heavy exercise, but stretching, those kinds of things that may help you.

(14:03): Dimming the light stimulates production of melatonin which signals the brain to fall asleep.  Dimming the lights, even before you turn them off completely can help because that will help with melatonin, your own melatonin secretion from your brain. That can also help you send that signal to your brain, that it's time to fall asleep.

(14:16): Use the bed only for sleep and sex. Creating a mental connection between being in bed and sleep by doing other activities elsewhere is helpful. Then create this mental connection between being in bed and sleep. Very important. Again, we want to use the bedroom only for sleep. We don't want to use it for activities, such as working, reading for a long period of time, watching television. If you can take those outside the bedroom and reserve your bedroom environment for sleep, that's going to help you fall asleep.

(14:46): If sleep does not come, leave the bedroom and do something relaxing before trying again. This last bullet point is very important. If, for whatever reason, you're in bed and you're not falling asleep and you're starting to look at the clock and starting to worry and being anxious, "why can't I fall asleep? I really would like to sleep now". It's really important to get out of that bedroom environment, do something relaxing. Go back to the stretching, the reading, the relaxation exercises, the soft music, do those things until you're ready to fall asleep again, and then go back to that environment, try to fall asleep. You may end up doing this a few times, but over time, you will send that message to the brain that the bedroom environment is for sleep and not for these other activities, and really help your brain makes that association with your bedroom environment and sleep.

(15:32): Here's some really good daily habits, because if you think about sleep and wakefulness, they do work in a continuum. The more alert and more awake and more you do things on a routine during the day, it's going to set you up for more success to sleep at night.

(15:48): Exposure to early morning light signals the brain to wake up. One of the best things you can do is getting that early morning light. I know we're coming into summer in the Northern hemisphere. For those of you in the northern hemisphere, morning light is going to be very important this time of year and substituting that with whatever bright lights you have in the wintertime, for those who are in more Northern cities, is also very important. Getting that early exposure to light tells your brain, this is the time to be awake. Then in shutting off those lights at night, tells your brain it's time to fall asleep.

 (16:19): Being physically active during the day promotes better sleep at night. Being as physically active as you can manage within the parameters that your doctors and nurses have provided you is really important. The more active you are during the day, the better off you're going to sleep at night. That always seems to work in a nice continuum. If you can avoid naps, that's wonderful, but if you can't, try to keep them short and try to limit them to the early afternoon, rather than later in the afternoon or evening, when they may interfere with sleep. The more sleep debt that you pay off during the daytime, the less sleep debt you accrue, that'll help push you [inaudible 00:16:55]

(16:59): Not smoking and avoiding late evening alcohol improves sleep. Stopping smoking is very important. Nicotine is a stimulant and it can interrupt sleep. Avoiding alcohol later in the evening is important.

(17:07) Alcohol is a sedative but is a very short acting sedative. That means that it may help you fall asleep, but when the alcohol wears off in two to three hours, it actually will alert you. Actually that withdrawal from alcohol is alerting and actually can wake you up from sleep and disrupt your sleep. It can also contribute to things like sleep apnea, which may make your sleep quality worse.

(17:31): Avoiding caffeinated beverages and heavy meals at night can also help with insomnia. Avoiding caffeine in the late afternoon and in the evening is important. The half-life or how long caffeine works is actually can be up to eight to 12 hours. The caffeine can still be in your system even eight or 12 hours after you drink that last cup of coffee or that last soda. It's very important to try to avoid caffeine.

(17:52): Avoiding heavy meals at night can help. And again, creating this association between your bedroom environment and sleep. Using your bed only for sleep and sex is really important as well.

(18:06): Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment for insomnia. I want to touch a little bit on cognitive behavioral therapy as a treatment for insomnia because it's very important. The rationale for CBT-I is that we have negative thoughts related to sleep that we develop. We also feel differently about our sleep. We start getting anxious about it, and that affects how we think about our sleep and then how we feel and how we think about our sleep affects our behaviors, and that prevents us from falling asleep.

 (18:34): Cognitive behavioral therapy is trying to take that thought and emotion and create new behaviors that promote sleep. It's redirecting our negative thoughts towards sleep, to more positive thoughts. It's redirecting our negative emotions toward sleep, to more positive emotions and creating that more positive behavior. Following these sleep hygiene tips that we just went over will be a very strong way of doing that.

(18:59): CBT-I is an effective as medication with fewer side effects and longer lasting benefits. Study after study in cancer patients and in non-cancer patients has shown that CBT-I, cognitive behavioral therapy for insomnia, is as effective as pharmacological therapy for insomnia. The effects of CBT-I are longer lasting, and the benefit in terms of safety is much higher.

(19:21): All of the sedative hypnotics have been associated with things like cognitive dysfunction, poor thinking, grogginess in the morning, and even to the point of deliriums and falls, especially in the elderly. We really want to use pharmacological therapy for insomnia very carefully. We want to select those patients very carefully and only use them in the short-term. Maybe right after admission or during that long hospital stay, they may have an important role. But as soon as that role is accomplished, we really want to move on to the sleep hygiene and the CBTI, cognitive behavioral therapy for insomnia, as our main stage for treating insomnia.

(20:02): Light therapy in the daytime and melatonin at night can be an effective combination to promote sleep. Light and melatonin are being used more often now to help regulate sleep. Melatonin, as a drug, is used in small doses, can actually help promote sleep by retraining your circadian rhythms that may become off cycle a little bit because of a long hospitalization or because of the stem cell transplant. Light, as I mentioned from certain screens, especially that blue light, can actually reduce that production of melatonin. It's really important to avoid those before at bedtime. Using light therapy in the daytime, especially in that early morning, can really promote sleep during the day.

(20:41): Early morning or daytime exercise trains your body to be active during the day and ready for sleep at night. It builds with this slide I have here on yoga and exercise. If you do those activities in the early morning, you're almost getting a double whammy. You're not only getting light exposure, but you're also getting another alerting system going, which is that physical activity, and that can really be a wonderful mechanism to say, "this is the time to be awake". On the converse, relaxing and turning off the light tonight is a really good signal to say time to shut down, time to go to sleep. They work hand in hand.

(21:12): Regular to moderate to vigorous exercise can reduce the time it takes to fall asleep at night. It reduces daytime sleepiness and also helps modulate your weight and other things that may cause things like sleep apnea, which also affect your sleep. We'll talk about that a little bit more.

(21:29): Commonly advertised sleep medications may help in the short-term but are not effective for more than six months or a year. These are some of the more common, and I'm using these generic names here that you might see: the sedatives hypnotics of pharmacological therapy for insomnia, resulted in this Ambien and Zopiclone, and Lunesta, and Suvorexant - these are all these different medications that you may see on the market. You see the ads on TV, they do have a good role for short-term therapy, but none of them have been shown to promote sleep in the long-term after six months and certainly after a year. We really want to think of them as a short-term solution for an acute exacerbation of insomnia.

(22:08): Sometimes antidepressants can be helpful and, really, the side effect profile for some of these drugs can be pretty significant in terms of increasing grogginess, decreasing your mental abilities, decreasing and increasing rather your risk of falls and delirium, which are really important things to consider.

(22:29): Movement disorders, like restless leg syndrome, can affect transplant recipients and interfere with sleep. I do want to spend a little bit of time that we have remaining talking about some other sleep-related disorders that do affect patients with bone marrow transplant and cancer. Movement disorders, especially there's something called restless legs. The reason I bring this up is many patients with cancers are anemic. There is a relationship between iron deficiency anemia, B12 deficiency anemia, and this syndrome of restless legs.

(22:52): What restless legs is, is this unpleasant tingling, creeping feeling and nervousness in your leg, that you may actually think is neuropathy related to some of the chemotherapy agents that you had, but it might actually also just be this restless leg syndrome that has other treatments. If you do have those kinds of symptoms, and they usually happen at bedtime, so they can interrupt with sleep and cause insomnia, it's a really good thing to think about. Maybe ask, say, "hey, could this be restless legs, and maybe could I get treated for it and make both my sleep and my restless legs better?"

(23:26): Certain chemotherapies cause periodic limb movement disorder that disrupts sleep. There's also another limb movement disorder of sleep called periodic limb movement disorder. This can happen in cancer patients, especially if they've been on certain chemotherapeutic drugs or have stem cell transplant or have B12 folate deficiency. We've seen it in all of those. Therefore, another thing, if you're having a lot of movement at night that's new after your bone marrow therapy, it may be something good to talk about, because a sleep study may uncover this disorder that also has treatments. And the treatment for this is directed at either neuropathy or they're directly at the restless syndrome with certain medications that are also used for Parkinson's disease.

(24:09): Hypersomnia is excessive daytime sleepiness. Let's move on a little bit. I do also want to talk about another sleep disorder, which is hypersomnia, which is another fancy way of just saying excessive daytime sleepiness, being really sleepy during the day. That affects a lot of people throughout the United States and throughout the world, but it especially can impact patients with cancer in stem cell transplant. There is this diagnostic test we do in our sleep clinic, and we're bringing this into more clinics here at MD Anderson to try to screen for that daytime sleepiness. It's available in many languages.

(24:41): Sleep studies that track rapid eye movement can help diagnose sleep disorders. This is actually what a sleep study looks like if you're ever asked to do one. I just wanted to go over that really quickly. You can see the red and black at the top, and that's actually looking at the sleep stages. We actually cycle through stages of sleep. When we say that someone's sleep is disrupted, what we're actually saying is that normal cycling through the stages of sleep is impacted and you don't get as much deep sleep and you don't get as much REM sleep.

(25:09): You may have heard that term, Rapid Eye Movement. Those black boxes at the top, are actually these patients REM sleeping. We don't see as much of that, and we don't have as much deep sleep and you don't have as much REM sleep. You wake up feeling a lot less rested, and you feel like your sleep quality hasn't been as good.

(25:26): This patient actually here that I'm showing you had actually has pretty normal sleep, but what's really interesting in this patient is we did this test called a multiple sleep latency test. It actually showed that this patient had as much sleepiness, and this is after cancer therapy, compared to someone with narcolepsy. This is where the people fall asleep all the time. You may have heard of it.

(25:49): Excessive daytime sleepiness may require stimulant medications. There's this association with certain cancer treatments, with this daytime sleepiness, and sometimes we need to use stimulant medications such as described on this slide. We do, some of the studies we've done here at MD Anderson and elsewhere that have been done, primarily in patients with solid tumors, by using stimulants to help prevent the day type sleepiness, which can also help us sleep better during the night. When you come into our sleep clinic, we actually assess for both of these things, so we can get you on the right therapy. I'm going to move on a little bit.

(26:23): Sleep apnea, may increase the risk of cancer as well as result from cancer. I do want to touch a little bit on sleep disordered breathing, because that is a sleep disorder that has this bidirectional relationship with cancer. What I mean by bidirectional relationship is that we know now that sleep apnea, there's some key studies that show that it can increase the risk of cancer, and also increases the risk of cancer mortality, or cancer related death. That patients with cancer may be at risk of having sleep disordered breathing as well and other sleep disorders. That's why the bidirectional relationship between the two.

(26:59): What sleep apnea is, is the syndrome where people stop breathing in their sleep or their sleep pattern is altered during their sleep. And it can cause things like excessive daytime sleepiness, and that can be problematic. We usually diagnose that in the sleep lab and we do sleep testing. We treat it with a device called Positive Airway Pressure or CPAP is what it's more commonly caused to help treat the sleep apnea.

(27:29): Cancer itself and stem cell transplants can disrupt the circadian that tells your body when to sleep and when to be awake. I want to finish with an important topic that we spend a lot of time studying here at MD Anderson. It's this role of circadian rhythms in cancer. And there are studies even bone marrow transplant, that after bone marrow transplant and that long hospitalization, that the normal rhythms that your body creates that tell you when you should be awake, and when you should go to sleep, are reduced.

(27:55): Sleep therapy can help restore these rhythms and healthy sleep. So that the signal that your brain gives you to fall asleep is decreased, and the signal the brain gives you to be awake is decreased. It leaves people feeling less able to fall asleep at night and sleepier and more fatigued during the day. It's a double whammy. Then we spend a lot of our attention trying to figure out ways with light, with melatonin, with sleep hygiene, with cognitive behavioral therapy, with light and melatonin, to try to restore those circadian rhythms so that we can get people back to where they are, where they need to be with.

(28:27): These different cancers, and I have ALL here and chronic myelogenous leukemia, some of the most common indications for stem cell transplant - we find that there's gene alterations from these tumors that it impacts circadian rhythms. It's really important for us to try to understand this complex interaction between cancer and circadian rhythms, so that we can try to devise strategies to improve that.

(28:55): Melatonin promotes sleep but is inhibited by excessive light or screens at bedtime. One of the things that's been studied quite a bit is this relationship between melatonin. Melatonin is this hormone that's made in the brain. It's governed by the circadian rhythms, and it's very closely governed by light. As I mentioned, the light from the iPad of the phone or natural light from the room, or even turning on your lights in your bedroom, all would inhibit the melatonin. That's why it's really important to keep that room dark at night. We're actually, sometimes, in some of our cities giving melatonin to try to promote sleep and restore circadian rhythm, especially in patients we've identified have circadian rhythm disturbance. There are studies that show that we can tailor this treatment to improve outcomes.

(29:41): A combination of therapies can restore a healthy circadian rhythm. I'm going to move on here. This is just a slide that shows that we can use things like melatonin and light therapy as a form of circadian therapy to try to impact sleep at night and promote sleep. This is a recent study that we just published, where we try to combine all these different streams that I've talked to you about: the behavioral therapy that we talked about, the light therapy, keeping people's daytime schedule intact by having scheduled meals, having scheduled exercise. Again, everything we do during the day impacts how we sleep at night and how we sleep at night can impact the day. It's a continuum. When we look at it, we want to think about it as a 24- hour cycle. By restoring that 24-hour cycle, improving the circadian rhythm, increasing that signal to fall asleep and increasing that signal to stay awake during the day.

(30:39): Research shows these combined non-pharmacological approaches are as effective as medication with fewer side effects. We developed this study where we had different arms, where we used bright light therapy, we used melatonin, we used methylphenidate. Every patient was instructed in sleep hygiene and cognitive behavioral therapy. We wanted to see if that improved their sleep. We were able to show a significant improvement in their sleep quality, and it was as durable and as good as seen with pharmacological therapy.

(31:04): Again, I think going forward, this is really the strategy that we'd like to see used more to treat sleep disturbance in patients with stem cell transplant cancer. This combined therapy, where we look at what's going on in the day, try to increase light exposure, try to increase exercise, schedule meals, to keep that on a nice timeframe. Then have that downtime routine at night, use melatonin if we need to, and improve sleep at night through sleep hygiene and those kinds of things. Really, using that whole 24-hour cycle to our advantage to try to improve sleep throughout the day and increase function throughout the day.

(31:54): Sleep centers diagnose and treat sleep problems in a variety of ways. If you were to come to our sleep center, these are some of the tools that we would use to evaluate your sleep. We would measure whether you may have a risk for sleep apnea. We measure your sleepiness, we measure your sleep quality, we measure your fatigue levels. We do a physical exam to look for other factors in your physical exam that may predispose you to a sleep disorder such as sleep apnea, such as high weight or BMI or a thick neck.

(32:21): We may think about doing imaging, especially of the brain, if we think there might be some circadian rhythm disorders. We may do pulmonary function tests to see if there's low breathing volumes at night, that may impact your sleep and lab studies such as checking an iron count to see if you have iron deficiency anemia, or a folate level.

 (32:44): Those kinds of things, are you predisposed to things like restless legs, a periodic limb disturbance? This is our overall way of evaluating a patient who comes to us with a sleep disorder so that we can look at every factor which may impact their sleep, so that we can address those individual factors to try to improve sleep.

(33:06): Treating sleep disruption is important to prevent problems like fatigue, anxiety, depression and insomnia. I'll just conclude here so that we have plenty of time for questions. Sleep is really essential for life. Without sleep, we can't function. Sleep disruption, unfortunately, is more common in patients with transplants and cancer. We know that if there is sleep disruption, which can precipitate and cause other symptoms: fatigue, anxiety, depression, insomnia, all of these things work together. It's really important for us to be systematic and identify underlying sleep disorders so that we can impact each one of those to try to improve overall sleep quality.

(33:45): Sleep and wakefulness are a continuum; what you do during the day influences how well you sleep at night and nighttime sleep influences daytime functioning. I would really stress, that third circle I have there, circadian. Thinking about sleep and wakefulness as a continuum, I think, is a very important concept that I'll just try to reiterate right now. What you do during the day will help you sleep at night. The earlier light you get during the day, the more active you are during the day, the more you can schedule those meals during the day, is going to help you fall asleep at night.

(34:13): In the evening, you want to follow the same kind of rules. You want to stress that bedroom, that nighttime routine, or that nighttime, bedtime ritual, then you want to be able to follow the sleep hygiene rules that we discussed. Some of those things will also help you during the day. Then if you're not falling asleep, getting out of bed, using the bedroom environment just for sleep.

(34:35): What you do during the day can impact what you do at night and how well you sleep at night can affect your function during the day. When you do that, think about it as a continuum, you're helping potentiate those circadian signals to have a structure to your alertness and a structure to your sleep, which can really be beneficial.

(34:56): Better sleep can impact tumor behavior, mortality and hopefully improve overall quality of life. I'll leave you with this fact of why we think this is so important, is that we're finding out that how you sleep can actually impact tumor behavior and mortality. Further study is needed, but I'd like to think at some point we might be able to show that if you can sleep better, you will do better through your cancer journey and actually have a better quality of life. That's really what our goal is in the end. I'll leave some time now for questions and thank you again for allowing me to join you today.

Question and Answer Session

(35:28): [Marsha Seligman] Thank you so much, Dr. Balachandran for the wonderful presentation. We will now take questions. The first question asks, how can I find a CBT insomnia specialist near me?

(35:54): [Dave Balachandran] That's a great question. You can find them in unexpected places. I would start by talking to your oncologist because there may be networks in your institution that they're familiar with so that they can refer you to people that they understand, and they have good feedback and a good relationship with. I would start there.

(36:17): If that's not available, there are two websites that I would direct you to. One is the American Academy of Sleep Medicine. That's AASM, and I believe their website is aasm.org. They actually have a list of providers who are board certified by the American Academy of Sleep Medicine in both sleep disorders, as well as in CBT. I think those would be my two resources.

If you can stay within the system that you work with and maybe benefit, in terms of communication, because I know we do a lot of back and forth with our therapists to try to understand what's medical and what's more therapy-related so that we don't miss anything. It'd be good if you have that benefit of that. But I think both the National Sleep Foundation have resources, as well as the American Academy of Sleep Medicine can point you to providers in your area.

(37:19): [Marsha Seligman] The next question is, does sleep quality impact rebuilding your immune system after a transplant?

(37:27): [Dave Balachandran] Wow, that is a fantastic question. I can tell you what we know and what we do not know. What we know is that sleep disruption impacts the immune system. We know that patients who have poor sleep quality have decreased immune function and we have increased inflammation, so the negative consequence of the immune system is inflammation that can actually cause more problems and more symptoms. That, we do know. Unfortunately, although we have some evidence, there's some good evidence with CBT, if you can believe it, that you can actually reconstitute some of that immune dysregulation and also improve that pro-inflammatory framework with sleep disruption.

(38:15): Now, specifically with bone marrow suppression that occurs with stem cell transplant and then re-engraftment, I do not think we have any data to suggest that improving sleep will impact that, but please stay tuned because I think that's a very, very intriguing question, and I think we may be surprised that there is an impact. I tried to tell you what we do know and what we don't know. We don't know the exact answer to your question, but I think we have some signals to suggest that it may be important to look at sleep as a modifiable factor to improve immunity.

(38:55): [Marsha Seligman] The next question, someone wants to know if senior citizens naturally sleep less efficiently than when they were younger? They used an example of waking up multiple times at night.

(39:07): [Dave Balachandran] That is a great question. If you recall one of the slides, I showed you the cycling between the stages of sleep, and I didn't really get into it very in detail because I wanted to spend a lot of time talking about insomnia and the sleep tips. But we do cycle through different stages of sleep at night. In normal elderly patients, this is patients without cancer or transplant, but just patients without - forgive me for using the word normal, but that's the word that's used in the literature, not to suggest that people with stem cells that cancer are abnormal in any sense. But in the patients without cancer or stem cell transplant, as we age, the cycling through those stages of sleep decreases. As a norm, there is less REM sleep and there is less deep sleep. Your ability to perceive your sleep as good quality sleep goes down.

(40:03): What also tends to happen in the elderly is sleep shifts. It's actually what we call phase advances. Elderly patients get sleepier earlier and they wake up earlier. Both of those factors that decrease perception of that cycling through sleep and the advancement of sleep phase make you wake up more often during the night, because if you're phase advanced, you're more likely to wake up at 3:00 AM or 4:00 AM or 5:00 AM, earlier than you might have been in the past.

(40:35): If you're having less deep sleep on REM sleep, your sensitivity to pain, to light, to noise and other things that may interrupt your sleep or needing to go to the bathroom, all of those things increase. Yes, sleep disruption increases primarily for those two reasons because that cycling is decreased and the deep sleep and REM sleep decreases. Also, because that circadian phase advances.

(41:04): [Marsha Seligman] Someone would like for you to address night sweats and what to do about them. They are four years post breast cancer and therapy induced menopause, and 10 months post bone marrow transplant due to therapy induced AML. And weaning off steroids has helped, but still have them two to three nights a week.

(41:24): [Dave Balachandran] Boy, that's a really tough question. In our breast cancer, one of our most common complaints is night sweats interrupting sleep. Of course, hormonal therapy is not an option when you have breast cancer to replace estrogen is not an option because obviously many breast cancer patients are actually on hormonal block growth therapy, which actually induces the night sweats in the first place.

(41:50): There are some studies using certain antidepressants that can help with night sweats in that setting of breast cancer in patients who are on hormonal therapy, which blocks estrogen in particular. We have seen that to some extent being beneficial. I don't know any data about night sweats in acute leukemia, to be honest. I haven't seen any studies on ways to improve that. Obviously, also patients with lymphoma, one of the symptoms is night sweats. That would be. But I have seen some data using some of the tricyclic anti-depressants is what they're called Imipramine, or Amitriptyline are two of the drugs that have been used with some success in that scenario.

(42:47): [Marsha Seligman] Okay. Any suggestions on ways to calm the mind, so they're able to fall asleep initially or return to sleep? Counting sheep does not work.

(43:00): [Dave Balachandran] Yeah, I get it. Another fantastic question. When I think about that question, it gets to be very individualized what precisely works. I will tell you some of the common things we talk about. One is that is coming to mind, to me also suggests some degree of anxiety and worrying, and that can be very hard to overcome. If you're dealing with stem cell transplant and how it impacts you and how it impacts your family, that can be, really, of course, a considerable source of anxiety and worry.

(43:34): One of the things I ask patients to do is to keep a journal and make lists. The reason for the journal is for them to be able to write down or somehow signal what's important to them, what is disturbing them today. Get those out. Then the list is to actually list what they might do the next day to try to address that. Would it be talking to that family member? Would it be talking to your physician? Would it be getting some sort of counsel, would it be... Whatever it might be.

(44:07): But making a list of potential solutions and making a plan on how you are going to address those concerns or worries. When you do that, I think in some ways, it gives your brain or your mind permission to relax and wind down because you have a plan, you've reflected on those issues, and you've given yourself time to do that before you've tried to fall asleep. So that when you do try to fall asleep, those issues are in some ways, obviously not ended in any way or finished, but at least partially addressed. So that it gives you almost permission to fall asleep and to try to calm down.

 (44:45): There's obviously other strategies. There's white noise, there's music, there's aroma therapy, there's different meditational techniques, relaxation techniques, all of those can work. But when I think about calming the mind, a very simple strategy is I think keeping a journal, making a list of your plan for the next day or the next week on how you're going to address some of the things that are worrying you. [It] can really be helpful in allowing yourself that permission to sleep that night. Some of the other strategies, whether it's music, reading, prayer, meditation, structured relaxation techniques, all of those have been found to be useful.

(45:36): [Marsha Seligman] The next question says, I had a transplant 15 years ago and was on maintenance Revlimid for six years that caused leg cramps that persist to this day. They wake me up and it's hard to go back to sleep after I walk around to get rid of the cramps. I take Ambien sometimes to get me back to sleep and sometimes over the counter drugs for leg cramps. Any suggestions?

(46:02): [Dave Balachandran] Yeah, that's a great question. Revlimid is one of the medications that can cause pretty severe neuropathy and can cause those periodic limb movements of sleep. I don't know if you've noticed if your sheets are more in disarray than they used to be after you took Revlimid. Or if you have a bed partner, if they notice more activity or movement. Those might be signs.

(46:28): Again, one of the last slides I had is that structured approach we have for doing a physical exam and getting some lab work to try to understand what the causes of that might be. Doing an exam to look for neuropathy, looking if your pain and temperature sensation is the same in your legs, as in your upper extremities, that's something your physician may be able to assess.

(46:55): Also, I'm sending off some of that lab work - iron studies, B12, folate - to see if there's reversible causes of neuropathy. If needed, doing direct treatment for neuropathy. Ambien is a wonderful thing to try to bring down that alertness that it comes from your movement or pain, or that need to move. But it's not really treating the cause, it's putting a band-aid on it. But, actually, thinking about, if there is a neuropathy, being on a pill or medication for neuropathy may help, then may help with the leg cramps. Or being on a medication to treat restless legs or limb disorders, that's what we've found on a sleep test may actually help.

(47:41): I'm talking in general, I don't know your case specifically, but if I had to approach that set of symptoms that you described; getting a physical exam, doing appropriate lab tests, maybe doing a sleep test to find out what's causing it. If I can identify a treatable cause, and then actually using medications tailored for that, rather than just trying to suppress your awareness of the symptom with a drug like Ambien.

(48:12): [Marsha Seligman] The next question says, I am getting phlebotomies for iron toxicities. Can iron toxicity cause sleep apnea? Says, I need CPAP. I'm hoping that after my ferritin gets back to normal, I won't need CPAP anymore.

(48:37): [Dave Balachandran] Well, that's a really good question. The iron toxicity was severe enough that there was iron to position, especially in certain areas of the head and neck and that caused... Sometimes iron deficiency can cause nerve issues and dysregulate the control of breathing that way. I can see a connection, but I don't think in the literature, there's a very clear connection between iron toxicity and sleep apnea and sleep disorder breathing.

(49:13): I'm not sure that it is the cause. I can see a mechanism for that, but I'll be honest with you, I don't think there exists in the literature, something so that there's a clear connection between iron toxicity and sleep apnea or there may be just change reports or something very minimal, but not in a structured way. I'm not sure, to be honest with you, if just correcting the iron toxicity, bringing that ferritin level down, if that will impact your sleep disorder, breathing and meaning that you won't need to use CPAP.

(49:49): I think if you had your ferritin come down, I would want to retest your sleep apnea, if you feel like your symptoms are better, and prove that there's actually an improvement in your sleep apnea, before I took you off with something for CPAP. The CPAP is really important for sleep apnea, especially if your oxygen levels are low at night, because that can increase your risk of heart attacks and strokes and arrhythmias.

(50:14): We don't want to minimize that treatment just because your iron gets better, especially if it's for another reason other than the iron toxicity. I would be very careful about getting off sleep apnea if your iron gets better without doing some sort of sleep assessment, a sleep test, to make sure that your sleep apnea is actually better.

(50:39): [Marsha Seligman] Okay. Speaking of sleep apnea, someone would like to know if a stem cell transplant can cause sleep apnea?

(50:46): [Dave Balachandran] Yeah. There's no evidence in the literature that stem cell transplant can cause sleep apnea. The causes of sleep apnea are multifactorial and not 100% understood. There's obviously genetic predisposition and there's also anatomy. Some people just have small airways, or they have a recessed chin, and that just predisposes them. The other two factors that increase the risk of sleep apnea are obesity and age. Actually, the older you are, the more likely to have sleep apnea, and the higher your BMI is, especially over 30, the more likely you are to have sleep apnea. But I'm not aware of stem cell transplant.

(51:35): That being said, if you're on your stem cell transplant and steroids has been a part of your treatment, and the steroids have made you gain weight and also caused, sometimes, the fat deposition with steroid use can be asymmetric, it can actually affect the areas of the airways, or it can cause truncal of obesity or cause your face to swell. We call that cushingoid syndrome. If that's the case, then yes, it's possible. But it's probably more related to the steroid than the stem cell transplant itself.

(52:10): [Marsha Seligman] The next question says, I've been told by nurses that I have central sleep apnea. Because my breathing slows so significantly that alarms go off. I was put on one and a half liters of oxygen in the hospital but was not continued at home. Are the headaches I get in the middle of the night possibly related to the low blood oxygen?

(52:40): [Dave Balachandran] Yes, and yes. Usually what we would call that is. There are different types of central sleep apnea, that there's something that we're missing. Central sleep apnea is the syndrome of where we actually, if you can think about it, your brain forgets to, for whatever reason, to tell your muscles of respiration, your diaphragm and your rib muscles, to take a breath, if you can believe that. We see it in certain conditions such as heart failure and maybe sometimes after a stroke or certain brain lesions, including cancer related brain lesions.

(53:17): What's happened in central apnea is exactly what the person who asked the question said, that they stopped breathing. Probably when they're in the hospital, the nurse saw that, that the oxygen went low and prescribed oxygen. I think it would be very important for you to find a sleep doctor or a doctor who can order a sleep test so that they can actually tell you what you have.

(53:42): Because sometimes just by looking on the oxygen curve in the hospital, you really can't tell whether it is central sleep apnea or structural sleep apnea. You really needed to do a sleep test to actually know that. It would be really important for you to know, just because the nurse witnessed apnea, what is truly the cause of it, so that you can be on the right treatment. Because the treatment for obstructive sleep apnea and central sleep apnea can be different. Therefore, you'd want to know what the actual disease process is so that you can get on the right treatment.

(54:21): Maybe more than just oxygen. I'll just put it this way. If you're wearing oxygen and you have obstructive sleep apnea, and your airway closes at night, the oxygen is not going to get into your lungs. So, it's not going to do much good. Whereas, for central sleep apnea, because of the way your brain works, oxygen therapy, actually, sometimes is sufficient to help your brain know when to breathe because there's these receptors in the body that respond to oxygen and carbon dioxide, that actually modulate how you breathe at night or how you breathe during the day, for that matter.

(54:54): Oxygen can help sometimes reset those modulators in your body that tell you when to take a breath. But if you have obstructive sleep apnea, that's a completely other physiology and a different disease process. The treatment may be different. That would be more like CPAP. I think it would be very important for you to get tested with a formal sleep test, to know what kind of sleep apnea you have so that we can make sure that you're actually on the right therapy.

(55:23): [Marsha Seligman] Okay. This is going to have to be our last question. We are running out of time. Someone would like to know what kind of drug is Eszopiclone?

(55:38): [Dave Balachandran] It's a solvent that's sedative hypnotic. I think you're talking about Lunesta, eszopiclone, perhaps. Eszopiclone is a long-acting sedative hypnotic. It's like a long-acting Ambien and it's a wonderful drug for short-term insomnia, but I don't recommend it for long-term use.

Just to backtrack a little, when I talked about pharmacological therapy, there are these sedative hypnotic class. The traditional medicines that were used in the past were the benzodiazepines, the drugs like Valium. You may still see some patients on things like Klonopin or Xanax, those kind of drugs for insomnia, not the greatest choices. They actually have the most addictive potential. They're the most habit-forming and they also have the most daytime drowsiness. And they're the ones that are most associated with falls and delirium, especially in the elderly.

This non-benzodiazepine sedative hypnotic class, which is like your Ambien and your Lunesta and your Sonata, those are a little bit better on the safety profile, but they're not perfect. They can still cause falls; they can still cause delirium. You need to be very careful, especially when using it in patients with neurological issues or in the elderly, who might be at a fall risk.

(57:13): I don't know, some patients with cancer, because they had blood clots are on blood thinners. You have to be really mindful. You don't want someone to hit their head if they're on a blood thinner. You do need to be very mindful when you are using these medications, especially in the long-term. If you are being prescribed this for a long-term, and by long-term, I mean more than six months to a year, they want to ask your physician, are there other options? Is there cognitive behavioral therapy that I could do to see if it's possible to get off some of those medications?

(57:49): [Marsha Seligman] Closing. Thank you so much for all that wonderful information. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Balachandran for your very helpful remarks, and thank you, the audience for your excellent questions. Please contact BMT InfoNet, if we can help you in any way. Enjoy the rest of the symposium.