Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to the history of sleep medicines?
There are a variety of sleep medicines. I am going to refer to what are commonly described as hypnotics or sleeping pills. Sleeping pills have been around for a long time. In the 50’s, 60’s and 70’s, most patients who were using pills for insomnia were using barbiturates, which have a number of problems in terms of dependence, and tolerance develops very rapidly. Nevertheless, there were not too many other options.
In the 1970’s, benzodiazepines were introduced. These were things like Dalmane and Halcion. They had advantages over the barbiturates in that tolerance didn’t develop as rapidly and dependence and abuse was not as problematic. They did have their own problems though. For example, some people felt that rebound insomnia was a big issue and that there was at least some psychological dependence. The drugs not only sedated you to help you sleep, but they basically shut down most of your brain so to speak.
Then came the non-benzodiazepines, which have been around since the early ‘90’s. They have been the predominant type of drug used recently. Very recently there has been a low dose doxylamine that has been approved for the treatment of insomnia.
Most of the people who use hypnotic medications now are using the Z drugs, such as Zolpidem and Zaleplon and Zopiclone. Most people feel that those medications work very well, they are relatively safe, but they don’t work for everybody. There is also a potential concern over substance abuse. Those drugs typically aren’t used for people who have substance abuse histories.
One of the reasons sleep researchers are excited about Merck’s new compound (suvorexant) is that it operates in the brain totally differently to the drugs that we have now. Concerns about abuse don’t seem to be a problem with suvorexant.
How many people take sleep medicines?
Roughly, about 5% of the US population in any given year are taking a prescription medicine. It is probably around 3% for people who are 20 to 30 years old. It is probably around 6-10% in individuals above 65.
Perhaps the most important issue is how many people with significant sleep difficulties are not taking any prescription medication and might benefit from it. Myself and Dr. Ron Kessler and others have published a series of papers fairly recently and it appears that at the current time about 20% of the US population have a diagnosable insomnia disorder. Many of those people could probably benefit from treatment and many of those people are not being treated because either they or their physicians have some concerns over the available options.
How are sleep medicines currently developed?
There are FDA guidelines that pharmaceutical companies use as a template when they are developing sleep medications. There is some early basic research that indicates for one reason or the other that a chemical might be good to test for the promotion of sleep. Then early studies are done in humans to demonstrate that the chemical is safe for humans to use, and also to get some idea of what doses of that medication should be used.
Then, assuming that the drug is safe and is tolerated by humans, other studies are performed, such as Phase II and Phase III studies, which gradually test the medication in a small number of people, to make sure what doses should be used. Then studies are expanded to a larger number of individuals to get enough exposure to human patients with insomnia to be confident that:
- the drug works well, i.e. it is efficacious
- it is safe and any infrequent side effects are detected if they would occur
How important is testing the safety of potential new sleep medicines?
It is very important. Just from an efficacy standpoint, the medications that are on the market now help the vast majority of people that want to take them. The advances will come with improved safety: medications that come without the sleep related abnormal behaviors, e.g. some people get up in the middle of the night and drive a car, or get up in the middle of the night and eat and are not aware of what they are doing.
A lot of the medications available today are for patients that are older and some have mild cognitive impairment. They can dull their cognition a little bit and cause balance problems or potential falls. That’s where the advantages will occur in my opinion: to find medications that are effective and are even more safe.
Merck have recently been testing their investigational medicine for insomnia known as suvorexant. They have demonstrated that no withdrawal symptoms emerged. What kinds of withdrawal symptoms are possible with sleep medicines?
Withdrawal symptoms are highly dependent on the dose of the medications that are being used and to some extent the duration for which the medication is used. The extreme case would be if you took benzodiazepines or barbiturates at a high dose, when you stopped the medication not only would your sleep problem return but it might get much worse. Also, you may be nervous or anxious during the day. These effects may lead the person to go back on the medication and may be even increase the dose even further.
The better term in my opinion is discontinuation effects because the term withdrawal symptoms connotates that the person was dependent or addicted to the drug and they are withdrawing from. It is not necessary for the person to be addicted or to have physiological dependence to have some discontinuation effects.
One of the exciting things about the recent studies that we presented in Europe on suvorexant was that when the primary insomnia patients took suvorexant for a year and then half of the patients, without their knowledge, were changed to placebo and half maintained on suvorexant every night for a couple more months, insomnia returned in the people who were abruptly switched to placebo, but they did not have any consistent indication that they were troubled in any other ways. There weren’t a lot of anxiety symptoms. We gave them the Tyrer Benzodiazepine Withdrawal Questionnaire (a questionnaire used to record the symptoms patients experience when they stop taking medication) to rate their anxiety levels. So it appears that suvorexant, at the doses that are going to be potentially marketed, has no concerns over discontinuation effects.
How important is it to demonstrate that new medicines do not cause withdrawal symptoms?
I think it is very important because even though some of the medications available previously did not have a lot of withdrawal/discontinuation effects, they typically have not been tested for a long period of use, like a year, they are usually tested for much shorter periods like 2 months or 3 months
Perhaps the most important reason to demonstrate safety is that in the minds of patients and many prescribing physicians, the discontinuation effects or the concerns about them can often lead to no treatment. The physician may have had a bad experience of withdrawal/discontinuation symptoms in a patient given sleeping pills in the past, and this can affect their decision over how they treat individuals with insomnia.
The more evidence we have that a medication is safe, the more likely a physician is to feel comfortable treating patients with it.
What other research does Merck need to carry out on their investigational medicine suvorexant, before it can be available to patients?
To my knowledge they’ve conducted a sufficient number of studies to be able to send a new drug application to the Food and Drugs Administration (FDA) in the very near future. Then it will be the FDA’s responsibility to judge the data that is submitted to them and they will decide whether any further studies are necessary.
What other types of sleep medicines are in the pipeline?
Unfortunately, there are virtually none. Also the ones that are in the pipeline are only in very early stages. They are either in pre-clinical work – drugs tested in animals or very early, like Phase I studies. To my knowledge there are a couple of other orexin antagonists, which is the class that suvorexant is in. I believe there are some melatonin-modulating drugs that are potentially in development. Right now there is nothing to my knowledge that is imminent.
How do you think the future of sleep medicines will develop?
I think that it is unclear. I think the discovery of orexin in the brain is still relatively recent, probably around 15 years ago. So once those basic science findings are made, then a few years later there usually is a determination of whether a certain brain system can be modulated in a certain way to help any conditions.
I think there is a lot of basic science work going on trying to find molecules that might dampen the alert of histamine and others to modulate the orexin system. But other than that it is going to be basic neuroscience that will come up with the next potential pathway for something that might help people with sleep problems.
Do you have any plans for further research into this area?
Well in terms of the pharmacologic treatment of insomnia I am anxious to work more with suvorexant and some other research projects that may be forthcoming if the medicine is approved by the FDA. I am interested in all potential treatments of insomnia, but personally right now I don’t have any specific plans.
Would you like to make any further comments?
I think with respect to suvorexant it is important for there to be a distinction made that the way that medication works is through orexin antagonism: it dampens the orexin signaling in the brain. Almost all of the available medicines work on the GABA system in the brain which is not as specific to sleep.
GABA is a major inhibitory neurotransmitter in the brain and if you enhance its activity it is very difficult to do that for sleep only and not influence memory for example. We feel that this new medication and new mechanism of action that physicians and patients need to understand that difference.
About James K. Walsh
James K. Walsh is Executive Director and Senior Scientist of the Sleep Medicine and Research Center at St. Luke’s Hospital in St. Louis, Visiting Professor in the Department of Psychiatry at Stanford University, and Adjunct Professor of Psychology at Saint Louis University. Dr. Walsh received his doctorate in experimental psychology from Saint Louis University in 1978.
Since 1975 Dr. Walsh has authored over one hundred-ninety scientific manuscripts and chapters. His primary research interests include insomnia, clinical pharmacology, shift work, and the relationship of sleep and behavior. He is an Associate Editor of Sleep.
From 2005 to 2012 Dr. Walsh served on the Sleep Research Society board of directors (president, 2010-11). He was a member of the Board of Directors of the American Academy of Sleep Medicine (AASM) from 1984 to 1993 (president, 1991-92) and the National Sleep Foundation (NSF) from 1997-2009 (chairman, 2001-5).
From 1994 to 1997 he was a member of the Sleep Disorders Research Advisory Board for the National Center for Sleep Disorders Research at the National Institutes of Health.
Awards received include the AASM’s 1995 Nathaniel Kleitman Award for Distinguished Service, the Lewis University Alumni Achievement Award in Psychology in 1994, the AASM’s Senator Mark Hatfield Public Policy Award in 998, and the NSF’s Lifetime Achievement Award in 2006.