Hypnotics for Insomnia: An Expert Interview With Milton K. Erman
Hypnotics for Insomnia: An Expert Interview With Milton K. Erman
Editor's Note:
Although insomnia affects tens of millions of people in the United States and can seriously affect their functioning, it is often poorly managed. To find out more about pharmacologic options in the treatment of insomnia, Elizabeth Saenger, PhD, Site Editor/Program Director of Medscape Psychiatry & Mental Health, interviewed Milton K. Erman, MD, Clinical Professor of Psychiatry in the Department of Psychiatry at the University of California at San Diego and President of Pacific Sleep Medicine Services in San Diego.
Medscape: I've heard about modified-release formulations in hypnotic therapy for insomnia. Why were modified-release formulations developed to treat insomnia?
Dr. Erman: Insomnia is a condition that is different from many other conditions that psychiatrists treat. As psychiatrists, we're often treating conditions that are affecting people when they're awake, and ideally we'd like to have a fairly uniform level of coverage for the day if we're dealing with a depression, a psychotic disorder, anxiety disorder, etc.
Insomnia, as a symptom, by definition is somewhat time-limited. It occurs during the night in association with the desire to sleep and the ability to sleep. So medications that we might give, that we would be happy with during the day to have a uniform level of coverage over a 24-hour period, aren't really appropriate for treatment of insomnia.
The medications that we've had have been helpful in many ways. We went from very long half-life agents and very long-duration agents, such as flurazepam, or Dalmane, to shorter half-life agents that were effective, like triazolam, or Halcion. But triazolam had its own problems, perhaps on the basis of potency, perhaps on the basis of the dosages that were being used.
We then moved on to the benzodiazepine agonist receptors that are not benzodiazepines, the newer agents like zolpidem (Ambien) and zaleplon (Sonata). And these were also a step forward. Zolpidem and zaleplon had short half-lives and therefore were capable of promoting sleep and promoting sleep initiation, but didn't have an adequate duration to sustain sleep through the night.
And here's the paradox: Any medication that promotes sleep is great, but when we want to wake up in the morning, we don't want residual sedation. So the ideal circumstance here would be an agent that had an immediate onset, sustained itself, and then had an immediate offset. And that can't be accomplished.
The newest agent that has come out, eszopiclone (Lunesta), has a longer half-life and therefore a longer duration of action. It does increase sleep duration and improve sleep maintenance during the latter hours of the night. But this drug, because it has a longer duration of action, will lead to some tendency to residual sedation the next day for some patients.
So the goal in developing the modified-release formulations was to be able to take the advantages that were present inherently in these shorter half-life agents that were very good for sleep initiation and to try to modify them in ways that allowed for improved maintenance of sleep through the night -- better sleep on a continuing basis through the night. It can be argued that the ideal medication really would be one that had an extremely short half-life -- a half-life of, say, minutes, but that was continuously released over the night in some fashion so that you get a square wave. A square wave would be ideal.
Medscape: What is a square wave?
Dr. Erman: The square wave that we would see in pharmacokinetics would be a compound that almost magically had an immediate onset of action. Now, there may be problems with this as well. If we talk about drugs that have an immediate onset, we're talking about effects of things like snorting cocaine or smoking crack cocaine. That has an immediate onset.
We'd like to have a fairly rapid peak, though, because we'd like to have the onset of the action be fairly quick. We'd like to have patients know that when they take a medication, it's going to work fairly quickly.
The notion, then, would be that the square wave would be a sustained level of action. If we can argue that there is some theoretical point at which a drug has sedative properties but does not lead to any other side effects, no confusion, no balance problems, no memory issues... If we could sustain the effect at just that level -- and also at a level close to the point where a person is very easily aroused -- we'd have the ideal square wave.
One of the other concerns that people have about medications is, "What's the effect of a medication? Is it going to make my patients hard to arouse if they need to respond to an emergency or to a problem?" So we don't want a drug that is so sedating that it knocks people out, literally, to a degree that they can't respond if they need to.
So, in the idealized, unrealistic world, that square wave would be simultaneously just at a point where it is promoting sedation, but close enough to the point where people are easily aroused so that they would have no residual sedation. It would sustain them right at that point, up to the point where they would like to get up or shortly before that.
If an agent is promoting sleep at 6:59, that may be perceived by patients to be a great effect if they have to get up at 7:00. But if they still are having residual effects at 7:01 or 7:10, that now is a side effect, because they are less alert than they would like to be, than they would need to be; it's interfering with function.
So, in this very ideal world, the square wave would sustain effect up to or close to the point where the person wants to be fully aware and alert and functional in the daytime. And that would be the advantage of these modified-release formulations -- that they more closely approximate that type of pattern.
So, if you had an agent, for argument's sake, that had a 10-minute half-life, but you could give it in a way that it was going to be released continuously for -- pick your poison -- 5, 6, 7 hours, all of a sudden you have this ideal medication. Practically, that's very hard to do.
And so what is happening now is that companies are working to modify the release formats of their agents and play with the dosing a little bit in order to try to sustain the effects over the course of the night. I can go into some specifics now about that.
Medscape: Please do.
Dr. Erman: There are 2 agents that have been submitted for FDA approval that involve modified-release formulations. One is an already approved agent, zolpidem. The other is indiplon, which is an agent that has been submitted for approval and which is a close relative, really, of an already-existing agent, zaleplon.
Both of these, really, are agents with short half-lives; they're very similar: the zaleplon/indiplon model, sort of a 1-hour half-life; the zolpidem, more like 2.5 hours. And what has been done with both of these agents is to use a pulsatile release, typically a first initial dosing with a second dose later on; that helps the agent approximate the square wave.
The most information on this has been released on the zolpidem modified-release formulation. But because the first dose is somewhere in the range of 7.5 mg, the Cmax, the maximum concentration that is reached within the first several hours of administration, is lower than the total maximum that would have been reached with the standard 10-mg dose for adults. A second pulse then is released somewhat later for a total dose of 12.5 mg.
So what you have is a circumstance where the area under the curve is greater. There is more total dose of medication available. The Cmax is lower so that, if you were going to worry about the tendency for there to be side effects on the basis of the maximal effect that would be present, based on the higher concentration, that's going to be reduced. And the modified release does extend the duration of action of the drug so that there is substantially and significantly better maintenance of sleep through the middle hours of the night The formulation has also been shown to be free of residual sedation the next day.
There has been less reported and released publicly about the modified-release indiplon formulation. This uses a similar sort of model with a very short half-life agent and a modified-release formulation to extend the duration of action to not only promote sleep onset, shortening the latency of the sleep onset and improving the perception of capacity to fall asleep quickly, but also to extend the sedative effect throughout the middle hours of the night and provide a longer duration of action.
Medscape: Is there a typical patient type that benefits most from the modified-release version?
Dr. Erman: I think most practitioners find that the agents we have available for treatment these days are pretty good overall and, certainly, are advantageous relative to the agents we had had previously in several areas. Those advantages include the lower risk for abuse that these drugs typically have. They're not agents that people party with or get high from or have anxiolytic or muscle-relaxant effects from, which may reduce the tendencies for abuse. They're also quite safe in terms of overdosage and have very minimal effects on respiratory suppression, so these are very good drugs.
If there is a deficiency that is perceived with at least some patients, it would be the report of, "This medication puts me to sleep, but I wake up 4, 5, 6 hours later." And, for some patients, it might be, "I wake up 6 or 7 hours later." There are some patients who are looking for a duration of action that, to a certain degree, might even be considered a little bit unreasonable, but that's what they're looking for. So I think the limitation that we have to this point relates to the report from some patients, and the perception from some patients, that the duration of action of the drug is inadequate.
The typical ideal patient here, I guess, would be someone who has been taking zolpidem, to use an available drug, and says, "This drug works very well for me. It helps me to fall asleep, but 5, 6 hours later I find myself waking up." Now we can certainly try to approach that from a perspective of behavioral therapies, which would be quite good. We can work with this patient and say, "Look, if you wake up, we want you to work on relaxation strategies, avoiding clock-watching, all of these things," and we may have some success with that.
But patients may wake up as well for physiologic reasons. They may have pain or discomfort. They may have nocturia. They may have breathing problems that aren't problematic in terms of sustaining sleep with one of these medications, but it's enough to wake them up when the effect of the medication wears off. So, for these types of patients, having an agent that's going to provide that longer duration of action will, we hope, allow them to get more sleep and, as a consequence, to be more functional and feel better the next day.
Beyond that, actually, as we talk about the impact of improved sleep, we have increasing data that people who are sleeping better are doing better in terms of overall function, psychiatric function. We know that sleep deprivation is not the same thing as insomnia, so we have to be careful here. But conceptually, when we're talking about people who are getting inadequate sleep, we can certainly try to extrapolate a bit from some of the sleep-deprivation literature. People who aren't getting adequate sleep have changes in their metabolism, in their dietary intake and choices, in their demands for higher-caloric foods. And so we would hope that we can help people to have improved health overall by helping to improve the quality of sleep they're getting, the number of hours of sleep that they're getting.
Medscape: Are there any differences between the 2 drugs that you mentioned, zolpidem, modified-release, and indiplon, modified-release?
Dr. Erman: Yes, they are different. Certainly they're different compounds chemically. Both of them are non-benzodiazepine compounds by structure, but compounds that work through the same receptor pathway, the GABAA receptor complex, the benzodiazepine receptor system in this GABAA complex. They are both somewhat receptor-selective in terms of the alpha-1 receptor subtype.
The biggest difference between them is going to be the half-life, which is ultrashort for the indiplon and short for the zolpidem. And so the release patterns are going to have to be different between the two.
And I should add that it's a combination of effects as well. In the pharmacokinetics in these agents, dose plays a role as well. Obviously, when we think sort of simplistically about half-life issues and say a drug has a half-life of 2 hours, we have to appreciate that if we double the dose we're doubling the half-life.
So there are various ways of trying to get or keep the dose within an appropriate therapeutic window. And you can work with combinations of dose and changing the release patterns or changing the time when second or third pulses are given as a way of trying to lead to a functional outcome.
Medscape: So when the person wakes up, you want to be at the bottom of the square wave, so you have no side effects.
Dr. Erman: Ideally, yes. And, in the real world, obviously, we want drug levels at a low enough level that they are not interfering with function, that they're not promoting measurable sedation or measurable impact on function or impairment of performance -- and there are various ways of doing this.
There are objective measures that are done, and these were done as part of the studies that have been done with these agents, looking at things like the digit symbol substitution test, DSST, and finding that there are no signs of any measurable impact. It's okay to have it there, but we also appreciate that the higher the blood level, the more likely there are to be residual effects that could be measured and could impair performance and function.
Medscape: And what are the drawbacks of these medications?
Dr. Erman: All of the existing agents, with the exception of zaleplon, which has a very short half-life and short duration of action, carry a statement that says, "Take these when you have the capacity for a full night in bed." So what we're recognizing is that we've been playing this kind of game of "We want the duration to be long enough to sustain sleep." What happens if it's a night where you get into bed late and you're only going to have 5 or 6 hours to spend? You've got a problem, because the existing agents (really, with the exception of zaleplon) don't allow you to take a medication.
Anyone who has a shorter time in bed is more likely to have carryover effect. So, as we improve the duration of action and reduce the probability that the patient is going to wake (from their perception, too early), the tradeoff is, what if someone has a shorter time in bed? Or if they need to wake up earlier because there's a call and they have to get up. So we have to be aware here that, as we promote the longer duration of action and more sedation from these drugs, there is somewhat of a tradeoff. If we extend this sedative effect a little bit through the night and if people have to wake up early or have a shorter night, they're more likely to have some residual sedation.
Medscape: Is there anything you would like to add?
Dr. Erman: Yes. I guess I would say that I think the availability of these new drugs provides additional tools for physicians to use. And that as we have more arrows in our quiver, more tools in our armamentarium, we have more options to treat patients. I think we are starting to take sleep a bit more seriously, understand that by treating these types of sleep problems, we may be able to improve function for patients. It's to our advantage to have new agents that are safe and effective and give us greater leverage in trying to help our patients deal with the increasing stresses of modern life.
Editor's Note:
Although insomnia affects tens of millions of people in the United States and can seriously affect their functioning, it is often poorly managed. To find out more about pharmacologic options in the treatment of insomnia, Elizabeth Saenger, PhD, Site Editor/Program Director of Medscape Psychiatry & Mental Health, interviewed Milton K. Erman, MD, Clinical Professor of Psychiatry in the Department of Psychiatry at the University of California at San Diego and President of Pacific Sleep Medicine Services in San Diego.
Medscape: I've heard about modified-release formulations in hypnotic therapy for insomnia. Why were modified-release formulations developed to treat insomnia?
Dr. Erman: Insomnia is a condition that is different from many other conditions that psychiatrists treat. As psychiatrists, we're often treating conditions that are affecting people when they're awake, and ideally we'd like to have a fairly uniform level of coverage for the day if we're dealing with a depression, a psychotic disorder, anxiety disorder, etc.
Insomnia, as a symptom, by definition is somewhat time-limited. It occurs during the night in association with the desire to sleep and the ability to sleep. So medications that we might give, that we would be happy with during the day to have a uniform level of coverage over a 24-hour period, aren't really appropriate for treatment of insomnia.
The medications that we've had have been helpful in many ways. We went from very long half-life agents and very long-duration agents, such as flurazepam, or Dalmane, to shorter half-life agents that were effective, like triazolam, or Halcion. But triazolam had its own problems, perhaps on the basis of potency, perhaps on the basis of the dosages that were being used.
We then moved on to the benzodiazepine agonist receptors that are not benzodiazepines, the newer agents like zolpidem (Ambien) and zaleplon (Sonata). And these were also a step forward. Zolpidem and zaleplon had short half-lives and therefore were capable of promoting sleep and promoting sleep initiation, but didn't have an adequate duration to sustain sleep through the night.
And here's the paradox: Any medication that promotes sleep is great, but when we want to wake up in the morning, we don't want residual sedation. So the ideal circumstance here would be an agent that had an immediate onset, sustained itself, and then had an immediate offset. And that can't be accomplished.
The newest agent that has come out, eszopiclone (Lunesta), has a longer half-life and therefore a longer duration of action. It does increase sleep duration and improve sleep maintenance during the latter hours of the night. But this drug, because it has a longer duration of action, will lead to some tendency to residual sedation the next day for some patients.
So the goal in developing the modified-release formulations was to be able to take the advantages that were present inherently in these shorter half-life agents that were very good for sleep initiation and to try to modify them in ways that allowed for improved maintenance of sleep through the night -- better sleep on a continuing basis through the night. It can be argued that the ideal medication really would be one that had an extremely short half-life -- a half-life of, say, minutes, but that was continuously released over the night in some fashion so that you get a square wave. A square wave would be ideal.
Medscape: What is a square wave?
Dr. Erman: The square wave that we would see in pharmacokinetics would be a compound that almost magically had an immediate onset of action. Now, there may be problems with this as well. If we talk about drugs that have an immediate onset, we're talking about effects of things like snorting cocaine or smoking crack cocaine. That has an immediate onset.
We'd like to have a fairly rapid peak, though, because we'd like to have the onset of the action be fairly quick. We'd like to have patients know that when they take a medication, it's going to work fairly quickly.
The notion, then, would be that the square wave would be a sustained level of action. If we can argue that there is some theoretical point at which a drug has sedative properties but does not lead to any other side effects, no confusion, no balance problems, no memory issues... If we could sustain the effect at just that level -- and also at a level close to the point where a person is very easily aroused -- we'd have the ideal square wave.
One of the other concerns that people have about medications is, "What's the effect of a medication? Is it going to make my patients hard to arouse if they need to respond to an emergency or to a problem?" So we don't want a drug that is so sedating that it knocks people out, literally, to a degree that they can't respond if they need to.
So, in the idealized, unrealistic world, that square wave would be simultaneously just at a point where it is promoting sedation, but close enough to the point where people are easily aroused so that they would have no residual sedation. It would sustain them right at that point, up to the point where they would like to get up or shortly before that.
If an agent is promoting sleep at 6:59, that may be perceived by patients to be a great effect if they have to get up at 7:00. But if they still are having residual effects at 7:01 or 7:10, that now is a side effect, because they are less alert than they would like to be, than they would need to be; it's interfering with function.
So, in this very ideal world, the square wave would sustain effect up to or close to the point where the person wants to be fully aware and alert and functional in the daytime. And that would be the advantage of these modified-release formulations -- that they more closely approximate that type of pattern.
So, if you had an agent, for argument's sake, that had a 10-minute half-life, but you could give it in a way that it was going to be released continuously for -- pick your poison -- 5, 6, 7 hours, all of a sudden you have this ideal medication. Practically, that's very hard to do.
And so what is happening now is that companies are working to modify the release formats of their agents and play with the dosing a little bit in order to try to sustain the effects over the course of the night. I can go into some specifics now about that.
Medscape: Please do.
Dr. Erman: There are 2 agents that have been submitted for FDA approval that involve modified-release formulations. One is an already approved agent, zolpidem. The other is indiplon, which is an agent that has been submitted for approval and which is a close relative, really, of an already-existing agent, zaleplon.
Both of these, really, are agents with short half-lives; they're very similar: the zaleplon/indiplon model, sort of a 1-hour half-life; the zolpidem, more like 2.5 hours. And what has been done with both of these agents is to use a pulsatile release, typically a first initial dosing with a second dose later on; that helps the agent approximate the square wave.
The most information on this has been released on the zolpidem modified-release formulation. But because the first dose is somewhere in the range of 7.5 mg, the Cmax, the maximum concentration that is reached within the first several hours of administration, is lower than the total maximum that would have been reached with the standard 10-mg dose for adults. A second pulse then is released somewhat later for a total dose of 12.5 mg.
So what you have is a circumstance where the area under the curve is greater. There is more total dose of medication available. The Cmax is lower so that, if you were going to worry about the tendency for there to be side effects on the basis of the maximal effect that would be present, based on the higher concentration, that's going to be reduced. And the modified release does extend the duration of action of the drug so that there is substantially and significantly better maintenance of sleep through the middle hours of the night The formulation has also been shown to be free of residual sedation the next day.
There has been less reported and released publicly about the modified-release indiplon formulation. This uses a similar sort of model with a very short half-life agent and a modified-release formulation to extend the duration of action to not only promote sleep onset, shortening the latency of the sleep onset and improving the perception of capacity to fall asleep quickly, but also to extend the sedative effect throughout the middle hours of the night and provide a longer duration of action.
Medscape: Is there a typical patient type that benefits most from the modified-release version?
Dr. Erman: I think most practitioners find that the agents we have available for treatment these days are pretty good overall and, certainly, are advantageous relative to the agents we had had previously in several areas. Those advantages include the lower risk for abuse that these drugs typically have. They're not agents that people party with or get high from or have anxiolytic or muscle-relaxant effects from, which may reduce the tendencies for abuse. They're also quite safe in terms of overdosage and have very minimal effects on respiratory suppression, so these are very good drugs.
If there is a deficiency that is perceived with at least some patients, it would be the report of, "This medication puts me to sleep, but I wake up 4, 5, 6 hours later." And, for some patients, it might be, "I wake up 6 or 7 hours later." There are some patients who are looking for a duration of action that, to a certain degree, might even be considered a little bit unreasonable, but that's what they're looking for. So I think the limitation that we have to this point relates to the report from some patients, and the perception from some patients, that the duration of action of the drug is inadequate.
The typical ideal patient here, I guess, would be someone who has been taking zolpidem, to use an available drug, and says, "This drug works very well for me. It helps me to fall asleep, but 5, 6 hours later I find myself waking up." Now we can certainly try to approach that from a perspective of behavioral therapies, which would be quite good. We can work with this patient and say, "Look, if you wake up, we want you to work on relaxation strategies, avoiding clock-watching, all of these things," and we may have some success with that.
But patients may wake up as well for physiologic reasons. They may have pain or discomfort. They may have nocturia. They may have breathing problems that aren't problematic in terms of sustaining sleep with one of these medications, but it's enough to wake them up when the effect of the medication wears off. So, for these types of patients, having an agent that's going to provide that longer duration of action will, we hope, allow them to get more sleep and, as a consequence, to be more functional and feel better the next day.
Beyond that, actually, as we talk about the impact of improved sleep, we have increasing data that people who are sleeping better are doing better in terms of overall function, psychiatric function. We know that sleep deprivation is not the same thing as insomnia, so we have to be careful here. But conceptually, when we're talking about people who are getting inadequate sleep, we can certainly try to extrapolate a bit from some of the sleep-deprivation literature. People who aren't getting adequate sleep have changes in their metabolism, in their dietary intake and choices, in their demands for higher-caloric foods. And so we would hope that we can help people to have improved health overall by helping to improve the quality of sleep they're getting, the number of hours of sleep that they're getting.
Medscape: Are there any differences between the 2 drugs that you mentioned, zolpidem, modified-release, and indiplon, modified-release?
Dr. Erman: Yes, they are different. Certainly they're different compounds chemically. Both of them are non-benzodiazepine compounds by structure, but compounds that work through the same receptor pathway, the GABAA receptor complex, the benzodiazepine receptor system in this GABAA complex. They are both somewhat receptor-selective in terms of the alpha-1 receptor subtype.
The biggest difference between them is going to be the half-life, which is ultrashort for the indiplon and short for the zolpidem. And so the release patterns are going to have to be different between the two.
And I should add that it's a combination of effects as well. In the pharmacokinetics in these agents, dose plays a role as well. Obviously, when we think sort of simplistically about half-life issues and say a drug has a half-life of 2 hours, we have to appreciate that if we double the dose we're doubling the half-life.
So there are various ways of trying to get or keep the dose within an appropriate therapeutic window. And you can work with combinations of dose and changing the release patterns or changing the time when second or third pulses are given as a way of trying to lead to a functional outcome.
Medscape: So when the person wakes up, you want to be at the bottom of the square wave, so you have no side effects.
Dr. Erman: Ideally, yes. And, in the real world, obviously, we want drug levels at a low enough level that they are not interfering with function, that they're not promoting measurable sedation or measurable impact on function or impairment of performance -- and there are various ways of doing this.
There are objective measures that are done, and these were done as part of the studies that have been done with these agents, looking at things like the digit symbol substitution test, DSST, and finding that there are no signs of any measurable impact. It's okay to have it there, but we also appreciate that the higher the blood level, the more likely there are to be residual effects that could be measured and could impair performance and function.
Medscape: And what are the drawbacks of these medications?
Dr. Erman: All of the existing agents, with the exception of zaleplon, which has a very short half-life and short duration of action, carry a statement that says, "Take these when you have the capacity for a full night in bed." So what we're recognizing is that we've been playing this kind of game of "We want the duration to be long enough to sustain sleep." What happens if it's a night where you get into bed late and you're only going to have 5 or 6 hours to spend? You've got a problem, because the existing agents (really, with the exception of zaleplon) don't allow you to take a medication.
Anyone who has a shorter time in bed is more likely to have carryover effect. So, as we improve the duration of action and reduce the probability that the patient is going to wake (from their perception, too early), the tradeoff is, what if someone has a shorter time in bed? Or if they need to wake up earlier because there's a call and they have to get up. So we have to be aware here that, as we promote the longer duration of action and more sedation from these drugs, there is somewhat of a tradeoff. If we extend this sedative effect a little bit through the night and if people have to wake up early or have a shorter night, they're more likely to have some residual sedation.
Medscape: Is there anything you would like to add?
Dr. Erman: Yes. I guess I would say that I think the availability of these new drugs provides additional tools for physicians to use. And that as we have more arrows in our quiver, more tools in our armamentarium, we have more options to treat patients. I think we are starting to take sleep a bit more seriously, understand that by treating these types of sleep problems, we may be able to improve function for patients. It's to our advantage to have new agents that are safe and effective and give us greater leverage in trying to help our patients deal with the increasing stresses of modern life.
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