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Medications may be keeping you up. What to do to stop the tossing and turning.
When to Get Help for Middle-of-the Night Awakening
By Tim Bonfield
Reviewed By Michael W. Smith, MD
You set the alarm for 6 a.m., but for the third day this week you wake up at 1 a.m. instead. You know you need more rest, but falling back asleep takes a long time. When you finally do doze off, before you know it, your alarm clock is ringing.
If that sounds familiar, you may have a common form of insomnia that makes it hard for you to stay asleep.
What Makes You Wake up in the Night?
Middle-of-the-night insomnia affects almost twice as many women as men. It becomes more common in middle age.
Chronic pain, sleep apnea, and the need to get up over and over to use the bathroom are some things that can interrupt your sleep. So can the hot flashes of menopause.
Meanwhile, life's stresses take their toll. Marriage troubles, job losses, aging parents, or children leaving home all can leave your mind racing in the night.
Once you start waking up at night, a vicious cycle can begin. The more you worry about losing sleep, the harder it becomes to stay asleep.
"Everyone wakes up at night once in a while. Most people roll over and go back to sleep. But some people begin to fret about it," says clinical psychologist Theresa Lengerich, PsyD. She's the director of behavioral sciences at the Bethesda Family Medicine Residency Program in Cincinnati.
"As you lay there, you become tense, which makes it harder to fall back asleep. And then you become even more upset," Lengerich says. "If this continues night after night, it can become a conditioned response that can cause insomnia all by itself."
Sleep Hygiene to Help You Get Better Sleep
"Sleep hygiene" sounds like it has to do with cleanliness, but it actually refers to improving some of your habits to give you a better night's sleep.
Some of the steps you can take are changes to your daytime routine:
Avoid naps during the day
Get regular exercise
Make sure you go outside during the day to get exposed to natural light. This helps you maintain a healthy sleep-wake cycle.
There are also steps you can take as you get close to bedtime that can improve sleep:
Avoid caffeinated drinks and alcohol
Don't use tobacco products
Don't have a large meal close to bedtime
Avoid emotional discussions before going to bed
It's also important to keep up a regular sleep-wake schedule -- during the week and on weekends too. Try to go to bed and wake up the same time every day.
When to Call the Doctor
Achieving Optimal Outcomes for Patients With Multiple Sclerosis: Considerations for Treatment Selection and Comprehensive Management in Relapsing-Remitting Disease
So the modern era of MS therapy can be thought of in terms of the disease-modifying therapies that have been approved by the FDA and European Medicine Agency and other agencies over the course of the last 20 years, with hopefully subsequently quite a few more coming down the road in just perhaps the next year or two. Prior to this, of course, we used a variety of other different agents that didn't ever really show any significant efficacy.
And in today's world, we have what many people might refer to as a first-line therapy versus a second-line therapy approach, with the first-line therapies being the older therapies—the interferons and glatiramer acetate—which have relatively low risk, long-term safety track records, modest reward, some difficulties with tolerance and compliance because they're injectable, some data in combination with others and in comparison to others, and a relatively lower cost, and certainly that's in italics there.
Second-line therapies, then, have been used really more as sort of a rescue approach, more commonly used for patients with more severe disease who have failed other therapies, and are the medicines that are listed there, including many others coming down the road. Newer, greater reward, with perhaps better tolerance, and the IV medications often quite well tolerated, but at a higher cost.
So is this a paradigm that makes sense, or should we really consider, in today's world with the embarrassment of riches, that perhaps there is a different paradigm that makes more sense? And it might be based on this logic: That is, that disability is a likely outcome for the majority of patients with MS, and we would like to try and intervene in that.
The thing that perhaps is the most important, though, is the first 5 years matter. The things that occur clinically, radiographically, and otherwise in the first 5 years have incredibly important impacts later on when disability occurs, when people oftentimes go into a secondary progressive phase of the illness.
We now know that we can identify a significant number of patients, however, who are at high short-term risk of disease activity and long-term risk of disability. But we need to do better. We need better markers over time that we can use at the very beginning, as opposed to along the way.
And so this is just a reminder of old data. The majority of patients do really develop disability over time. This is showing that about 50% of patients by 15 years will end up needing a walking stick, an EDSS of 6 on the 10-point scale.
And then [in] patients that they saw in that data set from Canada, from the onset of symptoms, it actually might even be sooner, even 10 years. So a significant number of patients will develop disability. And these are, of course, untreated patients, because this is an older database, and the data was published many years ago.
In terms of the effects of the medications that are available now, we know that these are all about the same, at least with regard to relapse rate. You can also look at MRI outcome measures, you can look at effects on progression of disability, and the data is relatively the same. In the case of acute relapse rates or annualized relapse rate, about a 30% reduction for the interferons and for glatiramer acetate. And those are all compared to, of course, placebo in different studies.
There is however some new data, and whether or not this has impact on the way these medications are used remains to be seen. The so-called GALA trial, with glatiramer acetate, looked at patients who used the medication not once per day, but three times per week, and not 20 mg but 40 mg—so a slightly less weekly dose, 120 versus 140 mg per week—but had very similar outcomes compared to placebo with the 40 mg three times per week as seen in the earlier study, with the every-day preparation.
Similarly, the ADVANCE trial using pegylated interferon—in either every-2-weeks or every-4-weeks preparation—showed very similar outcomes, especially in the every 2 weeks, again, compared to placebo. Very similar outcomes to what was seen in the pivotal trial with interferon beta-1a intramuscular, with an effect on disability, an effect on annualized relapse rate, and new and enlarging T2 lesions.
So these are different preparations that might allow us to have greater convenience using these medications, and whether or not these then go on to get FDA approval, of course, remains to be seen. But this was an attempt to try and improve the compliance and the utility of these medications that have long-lasting utility that we've had already with them over 20 years.
And of course, there have been a variety of different comparative trials, as noted here, BEYOND, BECOME, REGARD—and more recently the CombiRx trial comparing interferon beta-1a to glatiramer acetate to a combination of the two—all of which have shown pretty much that these medications are quite similar to one another. I'll just show a couple of examples of that here.
This is the REGARD trial, comparing interferon beta-1a subcutaneously versus glatiramer acetate, and noting that the time to first relapse over the 2-year trial was really essentially identical. Patients were free from relapse. Annualized relapse rate in the first 24 months before the study was similar, and then during the study was essentially identical, as well.
There were some mild differences, with enhanced MRI lesions, but very modest differences.
This is the CombiRx trial, looking at the combination of the two medications, glatiramer acetate and interferon beta-1a, and also comparing each one individually against each other.
And although there are modest effects seen in this outcome measure, which was a combined measure, protocol-defined exacerbation plus EDSS changes plus combined unique activity MRI scan—that is, those individuals who were free of those over about a 3-year period of time—was slightly greater in the combination. But notably, really no different between the patients who were treated either with glatiramer or interferon. And this is essentially the same, but adding in non-protocol-defined exacerbations, as well.
So, again, multiple studies over multiple years showing very little difference between these medications, although in this study, one or two of the outcomes did favor glatiramer.
So the first 5 years matter. Relapses are very common shortly after the onset of the disease, but diminish over time. This is a well-known phenomenon. Multiple databases have shown this over time. The highest rate is in the first 5 years.
Relapses frequently produce disability, and Dr. Lublin had a review of placebo-controlled trials published many years ago showing that about 28% of patients have a change of one point on their EDSS score after relapse in these various studies, again, with early relapsing patients.
And we know that higher relapse rates are associated with faster time to an EDSS of 6, or using a walking stick, and time to secondary progressive MS. And we also know that early treatment is associated with less mortality.
So this is the data from the Vancouver database, most recently explored by Dr. Tremlett, and showing what's been known for quite a few years with a variety of databases—that either looking at time from onset of disease or age of the patient, that over time the relapse rate goes down substantially, with some slight differences between males and females.
Very similar data would be seen if you had a similar slide showing MRI measures, as well, looking at gadolinium-enhancing lesions, which clearly diminish over time. If you look at new T2 lesions or FLAIR lesions, clearly diminished over time, whereas atrophy increases over time, and perhaps T1 burden of disease increases over time, as well. So the disease changes over time. Many relapses early. A lot of gadolinium-enhancing lesions early, and less late.
We know that early treatment matters. There's nothing that matters more than mortality. And this is a long-term follow-up over 20 years from the original pivotal interferon beta-1b trial, looking at outcomes of the patients from the original trial. And looked at time from pivotal trial randomization to death over 21 years, or time from clinical symptom onset—which is then a little bit longer, because many of the patients were not newly diagnosed—and looked at the 250 mcg dose versus placebo, or the 50 mcg dose versus placebo in both those outcomes, and found that in fact mortality was less in those individuals who, during the pivotal first 2 years of the trial, received drug as opposed to placebo.
After the trial was over, of course, patients went many different ways and went on multiple different medications. But just being on the active drug at either dose for the first 2 years of this trial compared to placebo was 20 years later associated with an outcome of less mortality. So early treatment does matter in a very profound way.
So what about comparison trials of the new and emerging agents? And there are a variety of them listed here, and I'm just going to show you a few of them. I'll just mention as well that there are some that are not yet published.
So this is the TRANSFORMS trial. This is just the first year of data, the first 350 days, and the main outcomes being adjusted annualized relapse rate from baseline [to] 12 months, showing a significant benefit of fingolimod compared to interferon beta-1a. And then similarly, the time to first relapse was significantly prolonged for patients treated with fingolimod versus interferon beta-1a intramuscular.
The CONFIRM trial, which was published last year in The New England Journal of Medicine by Bob Fox et al., was the phase 3 study of dimethyl fumarate in relapsing MS, comparing two different doses of that to placebo, and then as a fourth arm, glatiramer acetate; these patients were not blinded.
All of the numbers here are compared to placebo, and all of them were significantly better than placebo, with the exception, interestingly, of the confirmed EDSS progression at 12 weeks, which was not significant for any of these different medications.
This is the CARE-MS I trial looking at alemtuzumab versus interferon beta-1a subcutaneous in patients who had never been on other medications. CARE-MS II was the same study, almost identically achieved, but in patients who had previously been on other medications, many of whom had already been on interferon.
The data was very similar for the two. This is from CARE-MS I. And the annualized relapse rate, the T2 lesions, new [gadolinium-enhancing T1] lesions at 24 months and, perhaps most importantly, change in brain parenchymal fraction—year 1, year 2, and combined over years 0 to 2—were all substantially better in the alemtuzumab-treated group compared to the interferon beta-1a-treated group.
In the CARE-MS II data, very similar outcome. But in addition, they looked at the mean change in the EDSS score, and notably the alemtuzumab group had a lowering of their mean EDSS compared to a slight increase in the EDSS in the interferon beta-1a group at 2 years.
The number of patients who had sustained reduction of disability at 6 months was substantially higher in the patients treated with alemtuzumab compared to those with interferon, and there was a 42% reduction in sustained accumulation of disability confirmed over 6 months, and that also was statistically significant. So this was notable, because this was one of the few studies where they actually looked at whether or not patients may have improved while they were taking one of these medications.
This is the first part, just the 6 months, the primary outcome measure in the ocrelizumab versus placebo versus interferon beta-1a trial, showing the mean number of gadolinium-enhancing lesions. And by 8 weeks, and certainly by 12 weeks, essentially the likelihood of having a new gadolinium-enhancing lesion goes to essentially zero in the ocrelizumab group. In addition, 18 months after the last dosage—because this study was extended out many more months—that number essentially stays at zero.
There is no data I'm aware of that has compared natalizumab to any of the medications that are currently available or which might become available over the course of the next several years. There is, however, an interesting observational study being done called TOP. And it's looking at a very large number of patients, almost 4,000, primarily if not exclusively in Europe, all of whom are taking [natalizumab]. And they have some data comparing those patients who were treatment-naïve, about 9% of the population, and the rest of the population, 91%, who had previously tried other medications.
And when they compared the treatment-naïve patients with those who were previously treated, the annualized relapse rate dropped dramatically for both groups, and there was no difference there. But the probability of a relapse by year 3 was less in the patients who were treatment-naïve. The EDSS was lower over time in the treatment-naïve group. And this increased the longer the patients were followed.
And the risk of EDSS improvement was 30% versus 20% in the previously treated group, suggesting, as was seen in the alemtuzumab study that I just mentioned a moment ago, that perhaps patients can actually improve.