Clinical trial NCT02456532
Conditions: Chronic Insomnia
Sponsor: Henry Ford Health System
Start date: 2015-08-05; Completion date: 2022-02-22
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This proposal will assess risks for transition from therapeutic hypnotic use to abuse in people with insomnia. The investigators will study a hypothesized at-risk sub-population, insomniacs with hyperarousal, and compare two hypnotics, a drug with mood effects, eszopiclone, versus one without mood effects, zolpidem.

Detailed description:
Persons with DSM-V diagnosed insomnia disorder, aged 18-65 yrs, with no other sleep disorders, unstable medical or psychiatric diseases or drug dependency will be entered to the trial. Following a screening NPSG and MSLT, participants will be randomized to zolpidem XR 12.5 mg (n=60), eszopiclone 3 mg (n=60), or placebo (n=50) nightly for 6 months. After 6 months of nightly use, over a 2-week choice period, they were instructed to discontinue hypnotic use, but if necessary, to self-administer either 1, 2, or 3 capsules of their assigned "blinded" medication (zolpidem XR 6.25 mg, 6.25 mg, placebo; eszopiclone 2 mg, 1 mg, placebo as capsules 1, 2 and 3 respectively; or 3 placebos). Nightly sleep at home will be recorded by actigraphy for one week after the screening NPSG and MSLT and before treatment is initiated and actigraphy again during the two week discontinuation.

Arms: arm 1: Intervention: Six months of nightly placebo arm 2: Intervention: Six months of zolpidem cr 12.5 mg nightly use arm 3: Intervention: Six months of eszopiclone 3 mg nightly use
Interventions: intervention 1: placebo intervention 2: Zolpidem CR intervention 3: Eszopiclone
Intervention descriptions: intervention 1: six months of nightly placebo intervention 2: six months of nightly zolpidem intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
RISKS FOR TRANSITION FROM THERAPEUTIC HYPNOTIC  
USE TO ABUSE  
 
Grant No: R01DA038177 
 
Principal Investigator: Timothy Roehrs, PhD 
 
Clinical Trials Registration 
NCT02456532 
 
 
Note: The enclosed protocol was in use unaltered from the first subject entered 
into this NIDA sponsored mechanistic study regarding the risks associated with 
chronic hypnotic use until the last subject was completed 6-2022.  The protocol is 
active during the analysis period which started 6-2022. 
 


 
RISKS FOR TRANSITION FROM THERAPEUTIC HYPNOTIC  
USE TO ABUSE  
(Rev. 1   8/3/2015) 
 
 
 
 
 
Grant No: R01DA038177 
 
Principal Investigator: Timothy Roehrs, PhD 
 
 


 
 
 
 
PROJECT SUMMARY/ABSTRACT 
The acknowledged drugs of choice for the pharmacological treatment of insomnia are the 
benzodiazepine receptor ligand hypnotics (BzRL). Our nighttime studies show that with 
therapeutic doses used either short-term or chronically, the abuse liability of BzRLs in insomnia 
is not seen universally and is relatively low. The data from our last grant, a first-ever study, 
showed the abuse liability of chronic zolpidem use in insomniacs was low. Yet case reports and 
retrospective studies continue to report BzRL dependence and for the majority of these cases 
the abuse developed through initial therapeutic use. In our study some subjects showed an 
increase in dose across time. Understanding the transition from therapeutic use to abuse 
and identifying risk factors, such as specific patient and drug characteristics, is both 
mechanistically and clinically important. 
Our preliminary data have shown that a subset of insomniacs, those insomniacs that have 
signs of hyperarousal as reflected by elevated Multiple Sleep Latency Test (MSLT) scores, 
increased their nightly zolpidem dose across time. BzRLs have differential receptor binding 
affinities and associated anxiolytic or antidepressant properties. Zolpidem has selective alpha 1 
BzRL affinity and little mood activity and thus may show less risk for transition from 
therapeutic use to abuse than another currently frequently prescribed BzRL with less alpha 
subtype selectivity such as eszopiclone. We propose to study the abuse liability of a 
selective (zolpidem) vs nonselective (eszopiclone) hypnotic during chronic use (six 
months) in an at-risk sub-population (insomniacs with hyperarousal shown by elevated 
MSLTs). The proposal is highly innovative as it reflects a paradigm shift in understanding the 
abuse liability of hypnotics. 
In the end, this proposal will generate a unique set of data addressing a number of previously 
clinically important unanswered questions regarding hypnotic abuse by insomniacs (i.e., its 
likelihood as a function of arousal state and specific hypnotic pharmacology, of dose escalation 
over time and change in mood/drug effect ratings over time). It will provide clinicians with 
behavioral indicators of abuse risk. 
 
 


1. INTRODUCTION 
     We thank the reviewers for their careful review of our proposed research project and for the 
recognition of the innovative and clinically significant aspects of this project. We address various 
identified weaknesses in our research plan and indicate in the text by a change in font. 
Two reviewers asked why hyperaroused insomnia is a risk for transition from therapeutic 
BzRL use to abuse and what the underlying mechanism for the transition might be. Many 
theories of addiction hypothesize that stress increases vulnerability to drug abuse (1). Animal 
literature and human neuroimaging studies have identified brain circuits involved in stress that 
include release of CRF from the paraventicular nucleus and NE activation initiated in locus 
coeruleus. This CRF/NE activation also activates dopaminergic brain motivational pathways 
known to be engaged by drugs of abuse including ventral tegmental area and nucleus 
accumbens. So stress co-activates brain stress and reward circuits simultaneously. Thus, at a 
behavioral level stress enhances the positive rewarding properties of drugs with abuse liability. 
Among common physiological stressors is insomnia. In a subset of persons with insomnia in 
our preliminary data we found indications of stress and enhanced abuse liability. Those with 
hyperaroused insomnia as defined by MSLT showed elevated daytime urinary NE and they 
were also those that dose escalated. Previously, we showed such at-risk persons also self-
administered a hypnotic outside of the therapeutic context (i.e. during the day). We also have 
hypothesized that a hypnotic that differentially reduces stress (eszopiclone) associated with 
insomnia will have a higher abuse liability. 
A reviewer questioned the role of anxiety. We addressed anxiety and mood assessment in 
section D6.7 and its analysis in section D8. As to differential pre-existing anxiety, it will be used 
as a covariate in analyses. As to tolerance, it has been shown tolerance does not develop to 
eszopiclone effects over a year (2). 
The rationale for measurement of HPA markers and choice of specific markers was also 
questioned. We will limit assays to urinary NE and salivary cortisol. The rationale for these 
markers is discussed above. Our preliminary data showed NE elevations in our hypothesized at-
risk subset of people with insomnia. The stress and abuse vulnerability literature also suggests 
cortisol elevation. While our preliminary data did not show statistically significant cortisol 
elevation, the more selective inclusion criteria and frequent sampling in this proposal should 
reduce the variability in this measure and enhance our ability to show the predicted differences. 
The study design and subject characteristics were questioned. This is a between group 
design comparing two levels of arousal (MSLT-defined) randomized to three treatments, 
yielding a total of six groups with n=20 per group. We anticipate, based on our previous grant, 
50% of persons with insomnia will qualify for the ≥ 13 min and 40% for the ≤ 11 to > 5 min MSLT 
groups. We have decreased the upper age entry criteria to ≤ 64 yrs to avoid the need to use 
lower doses in those > 65 yrs. Age will not be considered as a variable as our previous grant 
showed no age differences in efficacy or safety. We also will expand the alcohol or substance 
abuse history exclusion from two years to lifetime. We will exclude all Axis I and Axis Il 
psychiatric disorders. We will caution regarding eating prior to capsule ingestions as part of our 
standard medication and sleep hygiene instructions. 
 
1) Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann NY Acad Sci. 2008,1141:105130. 
2) Roth T. Walsh JK, Krystal A, Wessel T, Roehrs TA. An evaluation of the efficacy and safety of 
eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med. 2005;6:487-495. 
 
 


 
2. AIMS 
   The acknowledged drugs of choice for the pharmacological treatment of insomnia are the 
benzodiazepine receptor ligand hypnotics (BzRL). Our nighttime studies show that with 
therapeutic doses used either short-term or chronically, the abuse liability of BzRLs in primary 
insomnia is not seen universally and is relatively low (1-9). The data from our last grant, a first 
ever study, showed the abuse liability of chronic zolpidem use in insomniacs was low. Yet case 
reports and retrospective studies continue to report BzRL dependence and for the majority of 
these cases the abuse developed through initial therapeutic use (10-12). In our last study some 
subjects showed an increase in dose across time (see Section C). Understanding the 
transition from therapeutic use to abuse and identifying risk factors, such as specific 
patient and drug characteristics, is both mechanistically and clinically important. 
 Our preliminary data have shown that a subset of insomniacs, those insomniacs that had 
signs of hyperarousal as reflected by elevated Multiple Sleep Latency Test (MSLT) scores, 
increased their nightly zolpidem dose across time. BzRLs have differential receptor binding 
affinities and associated anxiolytic or antidepressant properties. Zolpidem has selective alpha 1 
BzRL affinity and little mood activity and thus may show less risk for transition from 
therapeutic use to abuse than another currently frequently prescribed BzRL with less alpha 
subtype selectivity such as eszopiclone. We propose to study the abuse liability of a 
selective (zolpidem) vs a nonselective (eszopiclone) hypnotic during chronic use (i.e. six 
months) in an at-risk population (i.e. insomniacs with hyperarousal shown by elevated 
MSLTs). This proposal is designed with these aims and will test the following hypotheses: 
 
2.1. To evaluate hypnotic self-administration by primary insomniacs as a function of their 
daytime MSLT-defined arousal status and the available BzRL hypnotic. 
a. Insomniacs with hyperarousal vs those without will self-administer a hypnotic at 
greater rates.  
b. Insomniacs will more likely self-administer a drug with mood effects (i.e., anxiolytic 
properties, eszopiclone), versus a hypnotic without these mood effects, zolpidem. 
2.2. To evaluate changes in the rate of hypnotic self-administration and subjective effects 
of insomniacs with hyperarousal vs those without during chronic nightly use. 
a. Hyperaroused insomniacs, after six months of nightly use of eszopiclone, will show 
increased rates of self-administration and greater "drug liking” and "euphoria” ratings 
than those using zolpidem nightly. 
2.3. To evaluate the ability to stop using hypnotics when instructed to discontinue use 
after six months of chronic nightly hypnotic use. 
a. Hyperaroused insomniacs will self-administer a greater number of hypnotics during 
discontinuation than non-hyperaroused insomniacs  
b. A greater number of eszopiclone vs zolpidem capsules will be self-administered 
during the discontinuation. 
2.4. To evaluate indices of HPA augmentation as predictors of hypnotic self-
administration. 
a. Levels of urinary catecholamines, specifically norepinephrine, will predict the 
likelihood of self-administration of hypnotics. 
 


3. RESEARCH STRATEGY 
A. Significance 
The acknowledged drugs of choice for the pharmacological treatment of insomnia are the 
benzodiazepine receptor ligand hypnotics (BzRL). However, case reports and cross-sectional 
studies continue to report BzRL dependence and for the majority of cases the dependence 
developed through initial therapeutic use (10-12). We have argued that an important distinction 
in assessing the abuse liability of prescription drugs is differentiating therapy seeking from drug 
seeking behavior (9). This distinction becomes difficult in situations where therapy seeking 
evolves into drug seeking. This path to BzRL dependence, from therapeutic use to drug abuse, 
has been described as "chronic quasi-therapeutic abuse" or "iatrogenic dependence" (13). In a 
previous grant we hypothesized a path to abuse of hypnotics by insomniacs in which chronic 
nighttime BzRL use leads to tolerance development, dose is increased, and rebound insomnia 
occurs making it difficult to discontinue drug use. While demonstrating dependence risk in a 
subset of individuals, the results of that grant did not completely support our hypothesis. We 
showed over twelve months of nightly zolpidem use tolerance for most does not develop (14), 
for most insomniacs dose is not escalated (15), and for most rebound insomnia does not occur 
on discontinuation (16). Importantly in some insomniacs dose was escalated. 
 
Primary insomnia and probably also co-morbid insomnia, is hypothesized to reflect a 24-hr 
state of hyperarousal. This hyperarousal is evident in primary insomniacs' prolonged sleep 
latencies (i.e., about one standard deviation above normals) on the MSLT during the day, 
despite disrupted and shortened nocturnal sleep the previous night (17-19). Evidence also 
suggests that this physiologic hyperarousal is associated with activation of the sympathetic 
nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Insomniacs show 
elevated levels of circulating catecholamines (20), increased metabolic rates (19), increased 
body temperature (21), and altered heart rate variability (22), and pupillometry patterns (23). 
HPA augmentation in insomnia is indicated by elevated levels of nighttime urinary free cortisol 
proportional to the amount of wakefulness during the night (19). An activated SNS and HPA axis 
suggests a central mechanism possibly involving corticotropin releasing factor (CRF) neurons. 
Neuroimaging findings in insomniacs support a hyperarousal hypothesis. Primary insomniacs, 
relative to healthy controls, showed greater cerebral glucose metabolism during sleep, while 
awake, and at the transition from wake to sleep and particularly in brain arousal centers (24). 
Importantly, these studies all compared insomniacs to non-insomniacs rather than assessing 
individual differences among insomniacs in level of hyperarousal. 
 
We confirmed the presence of hyperarousal in some primary insomniacs (about half) as 
defined by the MSLT (25). Further, no previous study had assessed the stability of elevated 
MSLT scores within an individual across time and we found that MSLT elevation in insomnia is 
a stable "trait-like" finding (25). Finally, we found that elevated MSLTs are associated with 
elevated levels of daytime urinary norepinephrine relative to non-elevated MSLTs (see Section 
C). This is a first validation of the construct of hyperarousal in insomnia using two concurrent 
“independent" measures. While the majority of insomniacs in our previous grant did not escalate 
their hypnotic dose, a subset, those among the top third with MSLT elevation did escalate 
hypnotic dose (see Section C). These hyperaroused insomniacs may represent an at-risk 
population for a transition from therapeutic hypnotic use to abuse. 
 
The pharmacology of specific BzRLs may also be important. Our short-term studies used 
triazolam, while our last grant used zolpidem. The present proposal will evaluate an extended 
release formulation of zolpidem and eszopiclone. This change occurs due to a shift in clinical 


practice and our desire to study drugs with differing receptor binding properties, but comparable 
hypnotic efficacy. These two BzRLs have important differential receptor affinities and anxiolytic 
properties. Zolpidem is GABAA receptor selective acting primarily at the alpha 1 receptor, while 
eszopiclone is non-selective acting at both alpha 1 and alpha 3 receptors (26). In ranking BzRLs 
as to abuse liability, the non-receptor selective (i.e., diazepam, triazolam, eszopiclone, 
alprazolam) drugs were ranked higher than those that are more selective (i.e., zolpidem, 
zaleplon) (13). Accompanying the differential receptor selectivity are differences in mood 
effects. Triazolam and alprazolam have anxiolytic and antidepressant properties, as does the 
alpha 1 and 3 BzRL non-benzodiazepine drug, eszopiclone (27). In contrast, zolpidem does not 
have anxiolytic or antidepressant properties, as shown in animal studies and at least one clinical 
study (26, 28). This raises the critical question as to whether zolpidem, being alpha 1 
specific and without anxiolytic properties, has less risk for abuse by insomniacs than a 
non-selective BzRL with anxiolytic properties such as eszopiclone. 
That is not to say that zolpidem is without risk, there are reports of zolpidem abuse (12). 
Daytime studies in healthy normals and drug abusers have shown comparable abuse risk 
between zolpidem and other BzRLs (13, 29–31). Importantly, none of these studies have 
assessed insomniacs or nighttime use. Rather, these studies were carried out in sedative 
abusers and there is no question that both drugs possess sedative effects, but importantly not 
comparable anxiolytic mood effects. We hypothesize hyperaroused insomniacs are an at-risk 
population and in addition that a differential risk between eszopiclone and zolpidem will be 
shown in insomnia populations with nighttime use. To show a differential risk of specific BzRLs 
in hyperaroused insomniacs will further be supportive of our hypothesis that the modulation of 
mood is another therapeutic effect sought by hyperaroused insomniacs. Then a transition to 
abuse occurs over time. This shift to potential abuse will be reflected in dose escalation 
and increased ratings of “drug-liking” and “euphoria” over time. Analyses of case reports 
regarding abuse of BzRLs consistently show dose escalation (10-12). And assessment of 
subjective effects associated with drug administration is a standard approach to assessing the 
abuse liability of a given drug (32). 
Finally, discontinuation of chronic hypnotic use remains an important clinical problem limiting 
the usefulness of hypnotics and also reflects what is termed "iatrogenic dependence” (13). 
While in our last grant we found little evidence of rebound insomnia on discontinuation of 12 
months of nightly zolpidem use (16), clinicians report a return of sleep disturbance on 
discontinuation that leads to a resumption of hypnotic use (33). Importantly, triazolam, a 
nonspecific BzRL was the first drug for which rebound insomnia was described and we were 
able to show dose dependent rebound (1, 2). While rebound is a potential mechanism for 
difficulty stopping medication, it is not a necessary condition for difficulty stopping medication 
use. Difficulty discontinuing medication must be measured directly. Understanding risks for 
discontinuation difficulties as a distinct form of abuse, in addition to likelihood of dose escalation 
and increased ratings of “drug-liking” and "euphoria", is clinically important. The question 
arises as to whether hyperaroused insomniacs and those using a non-selective BzRL 
would encounter greater inability to stop hypnotic use defined by continued use despite 
the instruction to discontinue. 
B. Innovation 
This proposal reflects a paradigm shift in understanding the abuse liability of hypnotics. 
Previous studies have focused on the nighttime characteristics of the sleep of the insomniac, or 
the effectiveness of the hypnotic for a given person, or its discontinuation effects as risk factors 
for abuse. Here we suggest that abuse risk is an attribute of insomnia per se which is seen to a 
greater degree in a subset of insomniacs. We are suggesting that level of 24-hr hyperarousal is 
what places these individuals at greater risk for hypnotic abuse. 


This proposal also focuses on differential mechanisms of action of hypnotics and their relation to 
individual differences in level of arousal as factors contributing to the risk for the often reported 
shift from therapeutic hypnotic use to abuse. For some medications, including BzRLs, 
epidemiological data suggest in many persons with drug abuse problems, the abuse began as 
legitimate therapeutic use. 
  This proposal studies a unique population, drug naïve patients likely to be prescribed these 
drugs for their insomnia. Laboratory studies of hypnotic abuse liability have been traditionally 
conducted in healthy normals or individuals with a sedative drug abuse history. 
This proposal uniquely combines several well established methodologies, human drug abuse 
liability assessment using different measures (i.e., dose escalation, enhanced "drug liking 
euphoria", and inability to stop taking medication) with electrophysiological assessment of 
nocturnal sleep and daytime sleepiness/alertness to better characterize insomnia, nightly 
actigraphic assessment of sleep during chronic use, and concurrent hormone assays. 
  In the end, this proposal will generate a unique set of data addressing a number of previously 
clinically important unanswered questions regarding hypnotic abuse by insomniacs (i.e., 
likelihood as a function of arousal state, of dose escalation over time, and of change in 
mood/drug ratings over time). It will provide clinicians with indicators of abuse risk and begin to 
identify ways for clinicians to recognize the extent of the risk. 
After study completion and identification of subjects demonstrating risks for abuse we propose 
to assess various indicators that clinicians might use to predict the likelihood of transition from 
therapeutic use to abuse. In this proposal we intend to administer a number of questionnaires at 
baseline and during the six month assessment that may predict likelihood of transition (see 
Section D). 
In summary we are 1) comparing insomnia subgroups, 2) comparing hypnotics with different 
binding affinities, 3) using two different paradigms to identify risk, and 4) studying hypnotic naïve 
insomniacs, a population likely to receive a hypnotic prescription and potentially at risk. 
 
  Our previous grant evaluated the efficacy and abuse liability of 12 months nightly use of the 
hypnotic, zolpidem, by primary insomniacs. Our results showed that 1) zolpidem is preferred to 
placebo by insomniacs, but its overall rate of self-administration does not increase over 12 


months of nightly use (8), while the nightly use of a subset is associated with "dose" escalation. 
2) 12 months of nightly zolpidem use does not produce rebound insomnia or withdrawal signs 
and symptoms after chronic use, although 40% of participants showed rebound insomnia on at 
least one of the discontinuation nights (15); 3) relative to placebo zolpidem increases total sleep 
time and this hypnotic efficacy does not diminish over 8 months of nightly use (13); 4) some 
primary insomniacs express hyperarousal, as reflected in elevated MSLT scores relative to a 
control sample from the general population, which is a stable finding suggesting a trait 
characteristic (24), and the most severe insomniacs (i.e., lowest total sleep time) have the 
highest MSLTs, a relation that differs from that in healthy normal sleepers (24) and finally; 5) the 
hyperarousal defined by MSLT in this subset of insomniacs is associated with elevated daytime 
urinary norepinephrine and escalating capsule (both placebo and active drug) self-
administration over time (see Figs 1 and 2 above). 
The implications of these results is extensive in that we have shown with first-ever findings 1) 
chronic zolpidem use leading to abuse is not a general characteristic of the drug producing no 
overall nighttime dose escalation or rebound insomnia, 2) zolpidem remains effective for 8 
months of nightly use, 3) about half of primary insomniacs are hyperaroused as defined by 
MSLT, and the hyperarousal is a reliable and trait like finding, and 5) elevated MSLTs (e.g., 
hyperarousal) are associated with higher concurrent daytime urinary norepinepherine levels and 
increasing drug self-administration. This increase was not differential between zolpidem and 
placebo groups. Thus, the increase was associated with arousal status and not zolpidem (alpha 
1 specific). Consequently, we are proposing a paradigm shift for understanding hypnotic 
abuse, focusing in this proposal on self-administration and subjective effects in an at 
risk sub-population of insomniacs and on drugs with a hypothesized differential 
increased abuse liability, including drug discontinuation difficulty. 
D. Approach 
D.1 Overview 
We propose to study clinical doses of zolpidem CR (6.25 & 12.50 mg) and eszopiclone (2 & 3 
mg) using self-administration methods to further assess hypnotic abuse liability in an at-risk 
population (i.e., insomniacs with the highest MSLTs). This is a sub-population of insomniacs 
that appears to have an enhanced abuse liability risk, defined as escalating dose, subjectively 
by increased “drug liking" and "euphoria", and discontinuation difficulty.  
We have chosen to compare zolpidem CR and eszopicione, two BzRLs that can be matched for 
duration of activity by using the CR preparation of zolpidem. Both of these medications have 
indications for both sleep onset and sleep maintenance difficulties. Eszopiclone binds at alpha 1 
and 3 subunits with alpha 3 subunits known to have anxiolytic effects in insomniacs (27). In 
contrast, zolpidem binds only at alpha 1 and while sedative effects have been shown, it does 
not possess anxiolytic effects (27). Our plan is to study a total of 120 insomniacs (six groups of 
n=20 per group: placebo, zolpidem CR, eszopiclone and two MSLT levels per drug group) over 
the five years (30 per year anticipating about a 30% drop-out rate). 
D.2. Subjects 
The inclusion-exclusion criteria of our last grant will be maintained for this proposal with one 
exception. The major exception will be that primary insomniacs with hyperarousal, defined as a 
MSLT score of ≥ 13 min, which represents the top 50% of insomniacs (25), and those without, 
defined as a MSLT score of ≤ 11 (normal MSLT) and ≥ 5 min on the screening assessment will 
be entered into the study. The ≥ 5 min exclusion is to avoid pathologically sleepy participants. A 
total of 120 insomniacs will be randomized to a placebo, zolpidem CR, or eszopiclone nightly 
treatment for 6 months (n=40 per drug group which includes 20 MSLT ≥ 13 min and 20 with 


MSLTs ≤ 11 min and ≥ 5 min) within each group. 
 
D.2.1 Subject Recruitment and Retention 
Subjects, as previously, will be recruited primarily from two sources, the family practice clinics 
of the Henry Ford Health System, including the system's health maintenance organization, the 
Health Alliance Plan, which is an approximately 500,000 member plan, and public 
advertisements. We have been able with two research assistants to recruit and enter 30 
subjects per year. Our subject retention in a previous grant was higher than expected. Only 32% 
of subject/patients were unable to complete the entire one year study, typically for the study's 
interference with social, family, or job responsibilities. With a 6 month rather than 12 month 
study, conducted at-home rather than in the laboratory, we anticipate we will be able to even 
better retain participants. Compliance in the last grant with the monthly and quarterly clinic and 
sleep laboratory visits was extremely high, 93%, which we attribute to the weekly interactive 
telephone interviewing (IVR) we used. We intend to use a weekly web based questionnaire in 
this grant. Previously, we did not experience any serious adverse events that led to subject loss. 
As was the case in the last study, this study conduct will be monitored by an independent 
DSMB. 
D.2.2. Inclusion Criteria  
1) total n=120, age 21-64 yrs  
2) non-pregnant females who agree to standard birth control for 6 months and males  
3) ≥ 1 insomnia complaints: >30 min sleep latency, < 6 hrs sleep, or non restorative sleep.  
4) meet DSM-V criteria for insomnia disorder (780.52) alone or comorbid with stable medical 
diseases, but psychiatric diseases within the past year will be excluded.  
5) routinely spend > 6 and ≤ 9 hrs time in bed.  
6) have a screening MSLT ≥ 13 min or ≤ 11 min and ≥ 5 min). 
 
D.2.3. Exclusion Criteria  
1) a body mass index >38  
2) acute or unstable illness: conditions making it unsafe for subject to participate, conditions with 
a potential to disturb sleep (i.e. acute pain, respiratory infection), and conditions which could 
interact with the pharmacokinetics or pharmacodynamics of either drug.  
3) chronic illnesses; renal failure, liver disease, seizures, and dementing illnesses.  
4) current or past year psychiatric disease: depression and schizophrenia.  
5) a 2-yr history of alcohol or substance abuse, prestudy positive urine drug screen  
6) previous discontinuation of chronic hypnotic use  
7) consuming >14 standard (1oz) alcoholic drinks/week or caffeine consumption >300 mg/day  
8) smoking during the night (11pm-7am).  
9) medications including anxiolytics, hypnotics. both prescription and OTC, antidepressants, 
anticonvulsants, sedating H1 antihistamines (non-sedating second generation H4 
antihistamines are   allowed), systemic steroids, respiratory stimulants and decongestants, 


prescription and OTC stimulants, prescription and OTC diet aids, herbal preparations, and 
narcotic analgesics. All medications and doses will be documented.  
10) sleep disordered breathing (SDB) and periodic leg movements (PLMs) defined as ≥ 10 
apnea-hypopneas or PLM events associated with EEG arousal per hour of sleep time, or any 
other primary sleep (e.g., restless legs syndrome) or circadian disorder.  
11) sleep efficiency >85% 
D.3. Study Groups 
Qualifying insomniacs, MSLT ≥13 min and MSLT ≤11 min and ≥ 5 min will be randomly 
assigned to one of three groups: placebo, zolpidem CR or eszopiclone. All in the six study 
groups will take their assigned medication at bedtime for six months. For the two-week self-
administration assessments of month 1 and 3 choices will be 0, 1, 2, or 3 of their assigned 
nightly study medication. For the placebo group the choice will be up to three placebos. For the 
two-week discontinuation assessment the choice will be 0, 1, 2, or 3 of their assigned 
medication and dose (see Section D.6.7). 
D.4. Study Drugs 
The drugs will be zolpidem CR 12.50 mg and eszopiclone 3 mg with one exception are the 
indicated clinical doses for both drugs. We are aware of the recent May 2013 FDA advisory 
regarding zolpidem dosing for women, but are concerned that use of a reduced dose of 
zolpidem for women will be associated with reduced hypnotic efficacy and bias our comparative 
data, importantly, the FDA advisory regarding reduced dose was based on a pharmacokinetic 
increase in the AUC for women. To our knowledge no studies have reported a 
pharmacodynamic difference between men and women (34,35). Our own one year zolpidem 
study did not find gender differences on any efficacy or safety measure. Thus, rather than study 
non-equipotent doses, we will use a higher dose than the newly recommended dose for women. 
This will be clearly explained in the informed consent. We will be monitoring via a weekly web 
based questionnaire for morning residual effects. We will designate daytime 
sedation/somnolence as an AE of special interest in reporting to the DSMB. An important side 
effect occurring with eszopiclone (20%) is metallic taste, in secondary sensitivity analyses we 
will account for zolpidem residual effects and eszopiclone metallic taste effects. 
Medications will be prepared by the HFHS research pharmacy, as white capsules regardless 
of drug group. The consent form and the choice forms (see section D.6.7) will explain that 
medication choices may be their nighttime medication or placebo. In the active drug groups the 
first two available capsules will be the low dose of the assigned drug (6.25 mg for zolpidem CR 
and 2 and 1 mg eszopiclone) and the third capsule placebo. This is done to assure that no 
subject will self-administer greater than the clinically indicated dose during the choice phase of 
months 1 and 3. 
D.5. Treatment and Laboratory Assessment Schedule 
   D.5.1 General Schedule 
Subjects qualifying on the pre-study screening will be scheduled for sleep laboratory 
assessment. During this night a clinical polysomnogram (CPSG) will be conducted that includes 
screening for sleep efficiency, sleep disordered breathing (SDB) and periodic leg movements 
(PLMs). This CPSG is followed the next day by a standard clinical Multiple Sleep Latency Test 
(MSLT), conducted according to standard guidelines. Based on the screening MSLT, 
insomniacs with hyperarousal (MSLT ≥ 13 min) and those without (MSLT ≤ 11 and ≥ 5 min) will 
be entered. 
Subjects passing the CPSG screening for sleep efficiency, SDB and PLMs and meeting the 


daytime MSLT criteria will be randomized to begin taking their assigned study medication nightly 
at home after one week of medication free actigraphy monitoring. Subjects will wear actigraphs 
nightly during the six months. Prior to each choice assessment at a clinic visit subjects will be 
instructed regarding the choice or discontinuation procedures. Actigraphic total sleep time will 
be used to assess treatment efficacy (wks 1-2) for zolpidem CR and eszopiclone in comparison 
to placebo. Similarly, in month 3 and 6 differential hypnotic tolerance development can be 
evaluated. Change from the two baseline nights in actigraphic total sleep time in the active drug 
groups relative to placebo will be used as a covariate to correct for possible differential hypnotic 
effects.  
 
D.6 Assessment Procedures 
D.6.1 Sleep and Hypnotic Use Logs 
 
Prior to the clinical interview and entry into the sleep laboratory each prospective subject 
is required to keep a one-week sleep and drug use log. Daily bedtime, latency to sleep, total 
sleep time, number of awakenings, time of arising, hypnotic use, and other drug (both 
prescription and non-prescription) and alcohol use is reported on the log and used in the clinical 
interview. 
D.6.2 Clinical Interview and Diagnosis 
 
The clinical screening conducted by a board-certified sleep specialist, includes a medical 
history and brief physical examination and sleep history to rule out acute and chronic sleep and 
circadian disorders and medical illnesses requiring exclusion. In addition standard laboratory 
blood and urine analyses are done to confirm good physical health. The Structures Clinical 
Interview for DSM-V (SCID-5-RV) will be used to screen for current major psychiatric disease 
and a history of alcohol or substance abuse. During the screening period the following will be 
documented: illicit drug, alcohol, caffeine, nicotine, OTC, and prescribed drug use. Urine 
samples are used to confirm self-reported drug use. Based on all the screening procedures and 
the results of the screening CPSG/MSLT, where the absence of SDB and PLMs is established, 
subjects qualify for our modified DSM V diagnosis of insomnia. The modification is that a 
screening CPSG sleep efficiency (sleep time/time in bed) of ≤ 85% is required. 
D.6.3 Nocturnal Polysomnography and MSLT 
 
All CPSGs and MSLTs will be conducted as described in our previously published 
studies (9). Bedtimes for screening and experimental nights will be established as described 
previously (9). 
D.6.4 Post Sleep Questionnaires 
 
Specified weeks (3,4,7,11,12,18,23,24) throughout the study subjects will complete a 
morning questionnaire. Time to fall asleep, number and duration of awakening, total sleep time, 
and sleep quality are assessed. These results will be used to assess self-rated hypnotic efficacy 
for eszopiclone and zolpidem CR. In addition subjects will be asked to rate their current state of 


alertness and ability to concentrate to assess daytime residual sedation. They will also complete 
drug effects questionnaires during the assessment periods (see section D.6.7). 
 
D.6.5 HPA Hyperactivity Assessments 
 
Urine for catecholamines and salivary cortisol measurements will be collected on the first 
2 days of each of the choice assessments in months 3 and 6. Urine collections done at home 
will be gathered in four 8-hr aliquots while subjects are receiving their appropriate treatment. 
The collection begins with the first void after lights-out on night 1 and continues through night 
and day 2 (i.e., 32 hours total). The subjects will return the four collection vessels to the sleep 
laboratory. After measuring total volume, four 20 ml samples of each aliquot will be frozen at -70 
F until assayed. Assays for epinephrine, norepinephrine, dopamine, dihydroxyphenylalanine 
(DOPA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphylglycol (DHPG) will be 
performed at Warde Laboratories (Ann Arbor, MI) using HPLC. Saliva samples will be taken at 
10am, 12pm, 2pm, and 4pm and assayed for salivary cortisol using RIA (Warde Laboratories, 
Ann Arbor, MI). The third aliquot will be assayed at HFH for urine creatinine to index 
completeness of urine collection. The fourth aliquot will be kept as reserve. The primary 
dependent measure of analysis for HPA hyperactivity will be urinary norepinephrine over the 
whole 32 hrs and each 8 hr collection aliquot, which allows us to assess both sleep-related and 
daytime effects. In our preliminary data norepinephrine levels were elevated in the MSLT-
defined hyperaroused insomniacs and predicted dose escalation (see section C). The 
secondary measures will be the other catecholamines and metabolites listed above.  
D.6.6 Self-administration Assessments 
 
The two week self-administration assessments will be conducted in a very similar 
manner to the previously published self-administration assessment with two changes (15). We 
will use a free choice rather than a forced choice and we will do a 14 night rather than a 4 night 
choice assessment. A free choice procedure is used because it models the clinical situation and 
the number of choice nights is increased to enhance the power to detect predicted differences. 
On each night (at bedtime) of the two week assessment the subjects will be asked to choose 
whether or not they want their medication and will be given the option of taking 0, 1, 2, or 3 
capsules of their medication. For the zolpidem CR group the first two capsules will be 6.25 mg 
zolpidem and a third placebo for a total possible dose of 12.50 mg each night and for the 
eszopiclone group 2mg, 1 mg and placebo for a total possible dose of 3 mg. 
To standardize choice procedures subjects will receive forms on which they are instructed 
about the medication they are receiving and the need to assess effective dosage for them. On 
the form they specify whether or not they want their medication and the number of capsules 
they desire on a given night. As noted above, the consent form and these choice forms will 
specify that the available medications may include their nightly medication or placebo. On 
discontinuation assessments they will be instructed to try to stop using their medication or                                   
reduce the numbers of nights they use it over the next two weeks. The choice will be 0, 1, 2, or 
3 capsules on each of their 14 nights. The available capsules will be their previously 
experienced clinical dose (12.5 mg zolpidem CR or 3 mg eszopiclone). After each two week 
assessment (both choice and the discontinuation weeks) subjects will return their choice forms 
and the opened vs. unopened packages to justify choice forms and capsule usage. Two 
dependent measures for the choice assessments will be the number of medication choices 
made for the 14 nights and the average nightly dose (i.e. number of capsules) when capsule is 
chosen. For discontinuation the measures will be number of nights a capsule is chosen and the 
number of capsules chosen.  


 
D.6.7 Drug Effects/Mood Assessments 
 
In lab office visit will include Profile of Mood States (POMS), Beck Depression Inventory 
II (BDI II), Beck Anxiety Inventory Scale(BAI),  Epworth Sleepiness Scale (ESS) and the 
Insomnia Severity Indes (ISI). Weekly web based questionnaires will include the  Visual Analog 
Scale (VAS) assessments of “drug liking” and “euphorogenic” effect. These will be completed on 
day 1 of each tri-monthly assessment. Drug/mood effects assessments will also be done on the 
mornings after the choice and discontinuation assessments but based on our previous grant 
experience over 4-7 day assessments there may be a reduced “n” as some subjects will display 
no capsule choices. 
D.6.8 Weekly Web Based Monitoring and Monthly Clinic Visits 
Subjects will be monitored on a weekly basis by a web based questionnaire regarding their 
sleep and drug use. In addition to providing weekly self-report efficacy data, this has ensured 
that patients are following the study protocol and it maintains clinical contact. Subjects not 
completing their questionnaire within 24 hrs are then contacted by phone by study staff. At the 
monthly clinic visits the appropriate medication supply is refilled and medication packages 
returned to assess compliance. The sleep logs maintained every night will be checked to assess 
compliance to the sleep schedule. Efficacy and side effects will also be assessed by 
questionnaire at the monthly clinic visit. Additionally, at each monthly visit the BDI II and BAI  
are conducted to monitor any changes in, or emergence of new, physical and psychological 
signs and symptoms, which serves for safety monitoring particularly in the untreated placebo 
group. 
D.7. Outcomes, Comparisons and interpretations 
D.7.1. Chronic Hypnotic Efficacy 
The hypnotic efficacy of zolpidem CR and eszopiclone will be evaluated in comparison to the 
placebo group on the two week actigraphy recordings of months 1, 3, and 6. A difference of 
each drug from placebo on the primary efficacy measure, total sleep time, will confirm the 
expected hypnotic efficacy of each drug. The absence of a difference between drugs will 
suggest they have comparable hypnotic efficacy, secondary analyses will be performed on other 
hypnotic measures like latency to sleep, wake after sleep onset, and number of awakenings. 
These comparisons of efficacy measures on months 1, 3 and 6 are predicted to show no loss of 
efficacy with chronic treatment. It is hypothesized that both drugs will differ from placebo at all 
time points, but not each other. The change from baseline in total sleep time for a given subject 
can be used as a covariate when analyzing self-administration data if efficacy differences 
between hypnotics are found. If loss of efficacy is found we will assess whether it is specific to 
one of the drugs. Further, we will determine whether or not loss of efficacy is predictive of dose 
escalation or discontinuation difficulty. 
D.7.2. Abuse Liability Discontinuation Risks  
The aims of this proposal (aims 1, 2, and 3) are to address the three specific questions. 
What is the abuse liability of hypnotics in hyperaroused vs non-hyperaroused 
insomniacs as operationalized by likelihood of increasing self-administration and 
increased subjective effects assessments? 
Is there differential liability between a hypnotic with alpha 1 receptor selectivity 
and no anxiolytic/mood properties and one with no selectivity (i.e., also binds to 
alpha 3) and known anxiolytic/mood properties? 


What is the discontinuation difficulty as seen in self-administration rates and 
mood effects differentially as a function of the insomniacs’ arousal status and the 
pharmacology of the two hypnotics? 
The primary behavioral risk of abuse measures will be the total number of nights a capsule is 
chosen on the 14 choice nights and the number of capsules chosen on those nights a capsule 
choice is made. An increase in number of active drug choices versus placebo group choices 
over the 14 choice nights from month 1 to 3 will indicate risk of abuse which we hypothesize will 
occur in the hyperaroused insomniacs only (aim 1). A comparison of eszopiclone to zolpidem 
CR in active drug choices will indicate the importance of the pharmacological profile of a given 
drug to its abuse liability with eszopiclone hypothesized to show greater self-administration (aim 
1). Differential effects of the two drugs and the two insomnia groups in the subjective effect 
assessments will be investigated as mediators of these differential abuse liabilities. It can be 
argued that the self-administration of eszopiclone by the hyperaroused insomniacs represents 
therapy seeking for anxiety. However, it is important to remember that all these participants will 
have been screened for anxiety disorders. Also, while self treatment may explain acute effects, 
it would not explain dose escalation across time. The hypothesized change in mood/drug effects 
and self-administration rates across time are the key comparisons in this proposal that will 
reflect increased abuse risk. 
We have hypothesized an interaction of these two main effects (aim 2). An increase in the 
number of nightly active drug choices from month 1 to month 3 will suggest either tolerance 
development, reinforcement of anxiolytic/mood effects, or the learning of new drug effects with 
its use. To differentiate between these possibilities we will look at drug versus placebo effects 
on actigraphy in weeks 1-2 of each month. The absence of a loss of sedative/hypnotic effects 
over the 6 months for each drug will suggest reinforcement of mood effects, or learning of new 
drug effects (i.e., "drug-liking", "euphoric" effects). The various mood and drug-effect 
questionnaire (POMS, VAS, and BAI) measures will reveal subjective effects associated with 
the self-administration of the subjects. Changes in these effects over the 6 months will confirm 
possible reinforcement of mood effects or learning of new drug effects with greater exposure to 
active drugs. Assessment of changes in self-reported drug effects will reveal if new drug effects 
are being learned. Nightly self-administered doses (i.e., number of capsules chosen) over the 2 
choice weeks is the second abuse liability outcome measure and similar interpretations for this 
measure apply. 
Discontinuation difficulty will be reflected in the number of nights over the 14 discontinuation 
nights a capsule is chosen and number of capsules chosen (aim 3). We have hypothesized 
greater difficulty (i.e., more drug choices) as a function of arousal status (“hyperaroused" vs not) 
and pharmacology of the hypnotic (eszopiclone vs zolpidem CR). 
D.7.3 Hormone Levels and Specific Aim 4  
Total 24-hr and 8-hr urinary norepinepherine levels are the dependent measures to address 
specific aim 4. A reduction in norepinepherine levels (24 hr or any 8 hr aliquot), in the zolpidem 
and eszopiclone groups relative to the placebo group will indicate a unique therapeutic effect of 
the hypnotics, correction of the hyperarousal seen in insomnia. However, in our last grant we 
did not find significant drug vs placebo changes in norepinephrine levels, either 24 hr or daytime 
levels. Levels remained high in month 1 and 8 of the last grant for the hyperaroused insomniacs 
vs the non-hyperaroused insomniacs, with no drug vs placebo differences (see section C). This 
proposal will present an opportunity for replicating in an enriched sample of insomniacs with 
elevated MSLTs, this important finding and thereby identify a possible risk marker of abuse 
liability. Importantly, we previously only tested the alpha 1 specific drug zolpidem, while in the 
present proposal we expect to find these effects with eszopiclone differentially from zolpidem. 


We did not find urinary cortisol differences between hyperaroused vs non-hyperaroused 
insomniacs or between drug vs placebo. We did find significant time of day differences in 3 hr 
urinary cortisol aliquots (800-1500 hrs vs 1500-2300 hrs), with the morning aliquot being higher 
than the evening aliquot, a known characteristic of 24-hr cortisol rhythms thereby validating our 
study sample. 
 
 
D.8 Data Analyses  
D.8.1 Analyses  
Hypnotic efficacy will be analyzed as a randomized clinical trial. Since the outcome 
variables are measured on multiple occasions during months 1, 3, and 6, the appropriate 
method for analysis is that of generalized estimating equations (GEE). For example, if the 
outcome is total sleep time a specific model would be written containing terms 
 
 
representing the overall mean (µ), treatment effects (α), occasion effects (β), interactions (γ) 
and error variance (Є). Observations within a subject on multiple occasions are correlated, and 
this correlation structure is accounted for when estimating treatment effects. In addition this 
framework enables us to test for trends in the data over measurement intervals, to incorporate 
changes over months into the model, and to explore interactions between treatment and time. 
Additional covariates, such as age, gender and sleep time, can easily be incorporated into this 
overall framework. The active drug versus placebo group data on weeks 1-2 of month 1, 3, and 
6 will be the data analyzed. The primary efficacy measure will be total steep time. The three 
treatment groups will be a between subject factor and nights and months will be within subject 
factors. Self-reported measures of sleep collected on the post sleep questionnaires and other 
sleep measures will also be analyzed in this manner. We do not anticipate differential 
hyperaroused vs non-hyperaroused effects as our last grant data did not show differential 
hypnotic efficacy as a function of level of arousal. 
For the abuse liability assessment the absolute number of active drug choices (14 total choices 
possible in month 1 and 3) and the total number of nightly capsules chosen (42 total possible 
per subject each month) will be determined. A change score from month 1 to month 3 in these 
two measures will be the outcome measures used to assess abuse liability. The analysis will be 
a two factor between groups design testing drug group and arousal status. We are predicting 
main effects of drug and arousal groups and as well an interaction of these: greater abuse 
liability in hyperaroused insomniacs and with eszopiclone. Hypnotic efficacy can be used as a 
covariate if necessary. Also a set of secondary sensitivity analyses will be done to account for 
possible zolpidem residual effects in women and eszopiclone metallic taste effects. 
The difficulty discontinuing hypnotic use assessment will compare the number of capsule 
choices on the 14 nights, using a two factor between groups design testing drug group and 
arousal status. As in the abuse liability analyses, we are predicting main effects of drug and 
arousal groups and an interaction of these: greater discontinuation difficulty in hyperaroused 
insomniacs and with eszopiclone. 
The morning subjective drug/mood effects collected on the two week efficacy assessments 
(weeks 1-2) for month 1, 3, and 6 will be used to assess drugs/mood effects and their changes 
over time. As noted, while we are assessing these effects during the choice weeks, complete 


data for each subject on choice nights may not be available. Based on our previous experience 
exclusive non self administration may occur and based on our hypothesis the zolpidem group 
should make fewer active drug choices than the eszopiclone group, thereby possibly 
diminishing the available “n” for analyses in the zolpidem group. In the week 1-2 assessments, 
where there should be complete data, we are predicting greater mood effects and drug liking 
effects in hyperaroused insomniacs and with eszopiclone which increases over months reflected 
in change scores from month 1 to 3 and month 1 to 6. 
D.9. Sample Size Justification 
The standard formulas, which are conservative for this situation because of the multiple 
measurement protocol described previously, show that effect sizes of 0.68 or greater are 
detectable for the outcomes in this study including efficacy and subjective measures with three 
subject groups each having a sample size on n=20 and correcting for multiple comparisons. 
Effect sizes considerably greater than this were found in our short-term daytime self 
administration studies (1-7). An effect size of 2.0 differentiated number of active drug choices of 
insomniacs with high MSLTs versus those with low MSLTs (7). The power with n=15 vs 7 per 
group was 0.98. The last grant was designed to detect effect sizes of 0.60 and greater with a 
0.80 power based on our short-term studies. As such, we were prepared to detect a 0.50 
capsule increase in average nightly dose with n=15-20 per group. Such a 0.5 capsule increase 
was found in the placebo group from month 1 to months 4 and 12 in our last grant (8). Here we 
are predicting a differential between group (eszopiclone vs zolpidem CR) increase in our 
outcome variables and we anticipate greater between group variability. Conservatively, to detect 
efficacy, mood and subjective drug effect changes, and importantly self-administration changes, 
we have chosen the upper range of n (n=20) for this project. 
D.10 Future Studies 
Given use of the MSLT to identify at-risk insomniacs is burdensome for patients and clinicians, 
we will assess the various self-report measures of this proposal to develop tools that a clinician 
could use to identify at-risk individuals. For example, if the Epworth Sleepiness Scale (ESS) 
functions in hyperaroused insomniacs as the MSLT, unusually low ESS scores may identify at 
risk hyperaroused insomniacs, or unusually short diary sleep times, given short sleep times are 
associated with high MSLTs, or short actigraphic determined sleep times. Elevated BAI scores 
or consistently elevated POMS Arousal subscale scores may similarly identify hyperaroused 
insomniacs at risk to escalate dose and report increased “drug liking" and “euphoria" over time. 
D.11. Potential Problems/Limitations  
While this is the first study to systematically address individual and drug differences to define 
the risk of clinical hypnotic use evolving into abuse, there are some limitations of this proposal. 
1) We are studying insomniacs without psychiatric co-morbidity limiting the generalizability of 
our results. While many patients in clinical practice have co-morbid psychiatric conditions, 
limiting the study sample avoids the confounding of these co-morbidities in assessing the abuse 
risk of “hyperaroused" insomnia itself.  
2) There are other measures of hyperarousal (e.g., cortisol, FDG, PET, etc) reported in the 
literature and the question is whether our results will generalize to hyperarousal defined with 
such other measures. The literature regarding cortisol is equivocal and in our own data we have 
failed to find cortisol elevations. Use of various neuroimaging methods for this large of a study is 
not feasible. We have chosen elevated MSLT as it is one of the more reliable measures of 
hyperarousal in insomnia and we found it to be stable and to relate to elevated urinary 
norepinephrine levels.  


3) This research will evaluate two FDA approved BzRLs. Other drugs are used “off-label" to 
treat insomnia and will likely have their specific risks. But, we believe it inappropriate to study 
non-approved medications. Thus, this grant will assess abuse risk of "best practice".  
4) We recognize the limitation that we have chosen to study the 12.5 mg zolpidem dose in 
women which may lead to an increased rate of daytime residual effects given the recent FDA 
warning. This may lead to a necessity to reduce dose in some women. But we are concerned 
that use of a reduced dose of zolpidem for women will be associated with reduced hypnotic 
efficacy and thereby bias our comparative assessments. 
4. Human Subjects 
4.1. Ethics of the Proposed Trial 
Questions may be raised about the ethics of placing patients with chronic insomnia on placebo 
or on active drug for the long-term, 6 months in this proposal. In terms of long-term active drug 
use, it should be noted that in the general population a growing percentage of people are using 
hypnotics on a nightly basis long-term and our last grant data suggest the risks associated with 
chronic use (12 months) are low. Next insomnia is a chronic disorder lasting typically for two 
years and it may in fact represent a lifelong predisposition. This same class of drugs, the 
BzRLs, is indicated for the long-term treatment of anxiety disorders. There are no data to 
indicate that this class of drugs is associated with increased rates of side effects in long-term 
use. Throughout the study all patients will be followed medically and their side effects assessed 
carefully. Additionally, at each monthly visit the BDI II will be conducted to assess any changes 
in, or emergence of new physical and psychological signs and symptoms, particularly in the 
untreated placebo group. In our last grant participants were in the study receiving placebo or 
zolpidem for 12 months and no serious adverse events were experienced. This study will be 
shorter and thus with less potential risk. 
A possible risk is addiction, which most of the epidemiological and laboratory data suggest is 
minimal. To minimize this possibility, patients will be screened for a previous history of drug 
abuse or alcoholism, which are the best predictors of a potential addiction to BzRLs. At the end 
of the study every subject will be discontinued from drug and will be drug free. All will be 
returned to their primary care physician to resume their treatment of choice if their insomnia 
continues. In exit interviews they will be given feedback as to the nature of their insomnia, sleep 
hygiene and behavioral treatment instructions, and guidelines regarding their liability of 
dependence to BzRLs, particularly in those that escalate dose and reflect "drug-liking" and 
euphoria in subjective assessments. 
As to placing patients with chronic insomnia on placebo long-term, the majority of patients with 
chronic insomnia (75-90%) receive no treatment. The patients in the placebo group of this 
project will be followed closely medically and assessed for "side effects". If their insomnia of the 
"side effects" require they be discontinued from the study, the double-blind will be broken and 
those on placebo will be sent to their primary care physician to be placed on active drug. Our 
data from the last grant did not show a differential loss of participants from the placebo versus 
active drug group. As with the active drug groups, all will be given feedback as to the nature of 
their insomnia, sleep hygiene and behavioral treatment instructions, and guidelines regarding 
the liability of dependence to BzRLs during exit interviews. 
There may be concerns regarding women in the zolpidem CR group receiving the 12.50 mg 
dose, given the FDA June 2013 advisory. Subjects will be informed on the consent form that 
women, if assigned to the zolpidem group, will receive a zolpidem dose that the FDA recently 
suggested should be lower. Subjects will be monitored weekly via the web based questionnaire 
and face-to-face in monthly clinical visits. They will be asked to report any experienced side 


effects and in women reporting daytime residual effects the nightly dose will be lowered to 6.25 
mg. 
Similarly with regard to the recent FDA guidance regarding eszopiclone and dose titration from 
a starting dose of 1 mg to 3 mg (the upper clinical dose), a fixed dose of 3 mg is being used in 
this study. The dose as a starting dose may produce residual sedation in some patients. AEs of 
residual sedation associated with either zolpidem of eszopiclone will be designated an AE of 
interest and reported to the DSMB. 
4.2. Consent Process and Human Participant Protections  
4.2.1. A total of 120 men and women, aged 21-64 yrs, with primary insomnia, but otherwise 
healthy, will serve as subjects in the experiment. They will be recruited through the outpatient 
clinics of the Henry Ford Health System and newspaper advertisements. Our inclusion 
experience in previous grants reflects the richly diverse participant population we are able to 
recruit. Good physical health will be determined based on a physical examination by one of the 
staff physicians, standard laboratory analyses of blood and urine samples and the Cornell 
Medical index. Each participant will also receive a standardized psychiatric evaluation. 
4.2.2. The data collected from each participant will include standard physiological and 
actigraphic recordings of sleep, self reports of sleep and daytime sleepiness, measures of 
psychological function, records of drug use and alcohol use, and responses to questionnaires 
regarding mood and sleep. 
4.2.3. Subjects will be recruited from the hospital primary care clinics and the community. Each 
subject will sign an informed written consent as approved by the hospital's Institutional Review 
Board. After presenting the subject the written informed consent letter, the subject will have the 
study presented to him/her orally by the investigators or their research assistant. The participant 
then will be asked if he/she has any questions about any part of the protocol. If there are 
questions, further explanations will be offered. Finally, the participants will be asked to explain to 
the interviewer the major experimental manipulations outlined in the study. If it is clear the 
subject still does not understand, she/he will be disqualified from participation. 
4.2.4. Each subject will be instructed regarding the risks associated with zolpidem and 
eszopiclone. They will be cautioned not to eat within 2 hrs prior to consumption of their 
medication and to avoid the use of alcohol within 4 hrs of medication. They will be instructed not 
to drive or operate machinery in the morning if they still feel sleepy and to report such to the 
study coordinator. They will be instructed to maintain a regular sleep schedule and to remain in 
bed for 7-9hrs. 
4.2.5. The equipment and procedures for polysomnographic recording are in standard sleep 
laboratory use and present no potential dangers to the subject. On the first night of the 
recording, some subjects experience slight discomfort due to the attachment of the electrodes 
and the change in sleep environment. However, this is a transient problem which quickly 
disappears with adaptation to the hospital conditions. The at-home actigraphy involves wearing 
a wrist-watch type device and presents no discomfort. The side effects associated with the 
standard hypnotics, zolpidem and eszopiclone, being administered nightly at home involve 
clinical doses and they include most commonly sleepiness, dizziness, lightheadedness, metallic 
taste, difficulty with coordination and uncommonly difficulty concentrating, memory problems, 
and confusion, and rarely hallucinations and loss of personal identity. The risk of privacy 
violations will be managed by housing the consent documents and a code which links the 
participant's name with their unique study identification number in a cabinet in the PIs office. All 
clinical, PSG and MSLT, actigraphic outputs, and questionnaire data collected in the study will 
use the participants study identification number. 


4.2.6. The overall potential risk to the participants is small. All participants will be under 
continuous 24 hour monitoring while in the sleep center. The center where the study will be 
conducted is an outpatient medical clinic of a hospital where 24 hour medical coverage is 
available in the event of adverse effects. When at home, the participants will be monitored 
weekly for any side effects by a web based questionnaire and monthly by clinic visits. To ensure 
confidentiality, subject code numbers will be used to maintain the privacy of all information 
obtained from and about subjects in the study. At no time will a subject's full name or any 
identifying information be made available to anyone not directly involved in the study. 
4.2.7. The risks, as outlined above, to the participants in this study are small. There may be 
direct benefits to the participants in that their insomnia will be improved. The benefits to society 
gained from the information generated by this study will be enormous and far outweigh any 
subject risks. The information to be obtained from this study will provide for a better 
understanding of the efficacy and safety of hypnotics used chronically. The results have a 
potential to change the practice of insomnia treatment. The benefits of this study outweigh the 
study risks. 
4.3. Data Safety Monitoring Plan 
All participants complete a web based questionnaire weekly and they are questioned as to 
unusual events the past week. Monthly participants have a face-to-face clinical visit at which 
time the BDI II will be conducted to assess any changes in, or emergence of new physical and 
psychological signs and symptoms. Again participants are asked about the experience of any 
adverse events. Adverse events reported are monitored by the Pl and it is determined as to any 
event's seriousness and relatedness to the study drug or study procedures. Serious adverse 
events are immediately reported to the local IRB, to the Data Safety Monitoring Board (DSMB), 
and to the NIH funding institute. 
An independent Data Safety Monitoring Board (DSMB) will be established to ensure the 
integrity of the data being collected in this project and to ensure the safety of patient-subjects in 
this study. The DSMB will consist of two Henry Ford Hospital Senior Staff persons and a Wayne 
State University (WSU) School of Medicine person selected for expertise in clinical 
psychopharmacology and human subjects protection. The board will consist of a psychiatrist 
(WSU) with a human subjects protection sub-specialty (WSU, RB chair), a psychiatrist (HFHS) 
with extensive experience in clinical psychopharmacology, and a statistician (HFHS). Quarterly 
reports are submitted to the DSMB members outlining the number of subjects screened, 
number of subjects entered, number of subjects dropping out with their reasons for 
discontinuing, and the number of adverse events and serious adverse events. The DSMB will 
also meet in person on an annual basis to review the study conduct. As with all research 
projects at this institution, all serious adverse events are reported immediately (within 48 hrs) to 
the Human Rights Committee. 
 
 
 
 
 
 
 
 
 


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MEMO 
To the IRB 
 
In reviewing this project and consent please consider several choices that were made: 
 
1.) This project is designed to place some subjects on placebo for six months. The rationale 
for and ethics of doing such is discussed in the Human Subjects section of the grant 
application (pg 17 ff). On the grant review critique, the reviewers recognized this design 
choice and considered it scientifically and ethically justified. 
 
2.) For both drugs a fixed high clinical dose with no gender dose adjustment is being done. 
This choice is also discussed in the Human Subjects section of the grand application (pg 
17 ff). On the grant review critique, the reviewers recognized this design choice and 
considered it scientifically and ethically justified. 
 
 
3.) On the consent form the side effects for zolpidem CR and eszopiclone are not listed 
separately. The various side effects for the most part overlap. But, one side effect is unique 
to eszopiclone, metallic taste. To list that separately with eszopiclone could potentially 
break the double blind.