Clinical trial NCT02684136
Conditions: Insomnia Fibromyalgia
Keywords: insomnia fibromyalgia polysomnography pain management
Sponsor: Henry Ford Health System
Start date: 2016-02-01; Completion date: 2018-07-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will compare sleep, pain and daytime sleepiness/fatigue in people with insomnia co-morbid with fibromyalgia while treated short-term with suvorexant 20 mg versus placebo.

Detailed description:
It has now become clear that the relation of sleep and pain is bidirectional; acute and chronic pain is associated with disturbed sleep and disturbed sleep enhances pain. Experimental studies have shown that reduced and fragmented sleep in pain-free normals increases their pain sensitivity and daily self-report studies in chronic pain patients have shown a poor night of sleep is followed by enhanced next-day pain. In mediation analyses of large clinical data sets it is found that the sleep-pain side of the bidirectional relation, as opposed to the pain-sleep side, accounts for the greater variance. These data then would suggest that improving sleep in chronic pain disorders should attenuate daytime pain.

Most of the drugs used to treat chronic pain facilitate inhibitory central nervous system mechanisms as their primary mechanism of action. Suvorexant, recently approved by the FDA for the treatment of insomnia characterized by difficulties with sleep onset and sleep maintenance, has a unique mechanism of action. Suvorexant is a selective antagonist for orexin receptors (OX1R and OX2R). Orexins are considered to be involved in arousal and maintenance of the waking state.

As such, suvorexant may provide unique clinical benefit as a treatment in chronic pain conditions with co-morbid insomnia, and specifically for fibromyalgia with its putative central hyperarousal and hypersensitization. Thus, this project proposes to study objective and clinical measures of sleep, pain, and daytime sleepiness and fatigue in patients with fibromyalgia and co-morbid insomnia while treated short-term with suvorexant 20 mg versus placebo.

Those qualifying will receive suvorexant 20 mg and placebo for each of 9 nights in a cross over design with 7 nights of washout between treatments. Overnight sleep recordings (PSGs) will be collected on nights 7 and 8 of each crossover treatment arm to determine objective sleep measures. During the day following night 7 in each arm, a Multiple Sleep Latency Test (MSLT) at 1000, 1200, 1400, and 1600 hr will be conducted and nociceptive sensitivity \[finger withdrawal latency (FWL)\] testing to a radiant heat stimulus (1100 and 1500 hr) will be conducted on day 1 and day 8. Self-reported mood and pain indices will also be completed prior to each FWL test.

Primary outcomes to be measured include PSG sleep efficacy and FWL response on both conditions (suvorexant 20 mg versus placebo).

Arms: arm 1: 9 nights of 20 mg suvorexant arm 2: 9 nights placebo
Interventions: intervention 1: suvorexant intervention 2: placebo
Intervention descriptions: intervention 1: suvorexant 20 mg taken before sleep intervention 2: placebo taken before sleep

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
A double-blind, cross-over, study to compare the hypnotic, daytime 
sleepiness/fatigue, and pain effects of nighttime administration of 
suvorexant 20 mg versus placebo in patients with fibromyalgia and 
comorbid insomnia. 
 
NCT #02684136 
 
 
 
 
Henry Ford Health System 
Sleep Disorders & Research Center 
 
Timothy A. Roehrs PhD, Thomas Roth PhD 
Henry Ford Hospital 
2799 W, Grand Blvd, CFP-3 
Detroit, MI 48202 
313-916-5177 
313-916-5167 
troehrs1@hfhs.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version 3.1 (12-10-15) 
 


2.1 Objectives and Hypotheses 
2.1.1 The primary objectives of this proposed study in persons with fibromyalgia and co-
morbid insomnia are: 
1) to assess the effect of suvorexant 20 mg versus placebo on polysomnographic (PSG) 
measures of sleep. 
2)  to assess the effect of suvorexant 20 mg versus placebo on next day measures of 
sleepiness/fatigue. 
3) to assess the effect of suvorexant 20 mg versus placebo on next day measures of 
nociception and pain. 
     2.1.2 The clinical hypotheses to be tested are: 
1) relative to placebo suvorexant 20 mg will increase PSG sleep efficiency and reduce 
sleep latency and wake after sleep onset in persons with fibromyalgia and comorbid 
insomnia. 
2) relative to placebo suvorexant 20 mg will reduce self-reported next-day pain and 
nociceptive sensitivity as measured by Finger Withdrawal Testing (FWT) in persons with 
fibromyalgia and comorbid insomnia. 
3) relative to placebo suvorexant 20 mg will reduce self-reported next-day fatigue and 
normalize Multiple Sleep Latency Test (MSLT) scores in persons with fibromyalgia and 
comorbid insomnia. 
 
2.2  Background and Rationale 
 
Typically insomnia is co-morbid with various medical and psychiatric disorders and 
among the disorders frequently co-morbid with insomnia are the various chronic pain disorders. 
A prevalent musculoskeletal chronic pain disorder is fibromyalgia in which pain is widespread 
and not specifically localized (1).  Its etiology is unknown, although a prominent hypothesis 
suggests the pain is associated with enhanced central nervous system sensitization shown over 
all sense modalities (2).  Between 60-80% of fibromyalgia patients complain of sleep 
disturbance, which most typically is a sleep maintenance problem, a complaint which has been 
confirmed with polysomnography (PSG).  Another important persisting symptom in fibromyalgia 
is daytime sleepiness and fatigue, which may relate to the disturbed sleep of fibromyalgia or the 
underlying pathophysiology of the disorder, putative pro-inflammatory cytokine activation. 
 
The PSG studies in fibromyalgia, dating to as early as 1975, have consistently reported 
reduced total sleep time relative to age-matched controls, primarily due to increased wake time 
after sleep onset (WASO) (3).  However, despite having reduced nocturnal sleep compared to 


age-matched healthy controls and reporting elevated levels of daytime sleepiness and fatigue 
like patients with rheumatoid arthritis, patients with fibromyalgia show elevated daytime arousal 
on an objective measure of daytime sleepiness/alertness, the Multiple Sleep Latency Test 
(MSLT) (4).  Elevated MSLT latencies, despite shorter total sleep times, have also been seen in 
people with primary insomnia, which is consistent with the sensory hypersensitization model of 
fibromyalgia (2). 
 
It has now become clear that the relation of sleep and pain is bidirectional; acute and 
chronic pain are associated with disturbed sleep and shortened and disturbed sleep enhances 
pain.  Experimental studies have shown that reduced and fragmented sleep in pain-free normals 
increases their pain sensitivity and daily self-report studies in chronic pain patients have shown 
a poor night of sleep is followed by enhanced next-day pain (3).  In mediation analyses of large 
clinical data sets it is found that the sleep-pain side of the bidirectional relation, as opposed to 
the pain-sleep side, accounts for the greater variance (5).  These data then would suggest that 
improving sleep in chronic pain disorders should attenuate daytime pain.  
 
Drugs from a number of different drug classes have been assessed as treatments in 
chronic pain disorders including analgesics, antidepressants, antiepileptics, and hypnotics.  In 
many of these studies pain is the major study focus and if sleep is measured, it is a secondary 
outcome and typically only measured by self-report.  Further, rarely are patients in these studies 
specifically included for the presence of co-morbid insomnia and degree of sleep disturbance.   
 
While analgesics, antidepressants, and antiepileptics are typically used and studied in 
chronic pain disorders, only a few studies have assessed hypnotics and with quite mixed 
results.  In fibromyalgia patients zolpidem (6), but not zopiclone (7), improved some of the sleep 
measures, but neither drug improved pain.  Triazolam improved sleep and pain in patients with 
rheumatoid arthritis (8), whereas zopiclone only improved pain (9).  A large (N=153) study of 
eszopiclone, the S isomer of zopiclone, assessed its sleep and pain effects in patients with 
insomnia co-morbid with rheumatoid arthritis (10).  Eszopiclone compared to placebo improved 
self-reported measures of sleep and most all of the pain measures.  Hospitalized patients with 
mucositis associated with chemotherapy for hematologic malignancies were randomized to 2 
nights of eszopiclone or placebo (11).  Pain scores throughout the day were improved with 
eszopiclone and patients reported increased sleep time and fewer awakenings. 
 
Most of the drugs used to treat chronic pain facilitate inhibitory CNS mechanisms as 
their primary mechanism of action.  Suvorexant, recently approved by the FDA for the treatment 
of insomnia characterized by difficulties with sleep onset and sleep maintenance, has a unique 
mechanism of action.  Suvorexant is a selective antagonist for orexin receptors (OX1R and 


OX2R) (12).  Orexins are considered to be involved in arousal and maintenance of the waking 
state. In support of this view, findings have shown that orexin neurons send dense projections to 
brain arousal areas including the locus coeruleus, tuberomammillary nucleus, and the basal 
forebrain cholinergic system (13).  In PSG studies in healthy men, suvorexant 10 mg increased 
sleep efficiency and reduced WASO (14) and in patients with primary insomnia it increased 
sleep efficiency by reducing latency to persistent sleep (10 min of continuous sleep) and WASO 
(15). 
 
As such, suvorexant may provide unique clinical benefit as a treatment in chronic pain 
conditions with co-morbid insomnia, and specifically for fibromyalgia with its putative central 
hyperarousal and hypersensization.  Thus, this project proposes to study objective and clinical 
measures of sleep, pain, and daytime sleepiness and fatigue in patients with fibromyalgia and 
co-morbid insomnia while treated short-term with suvorexant 20 mg versus placebo. 
 
 
2.3 Study Design 
 
The study will be conducted as a double blind, placebo controlled, trial using a repeated 
measures design.  Patients with fibromyalgia and co-morbid insomnia (n=30) will be treated for 
9 nights each with suvorexant 20 mg and placebo with the order of treatments counterbalanced.  
The study will be registered on clinicaltrials.gov  
 
2.4 Study Flowchart 
 
Patients with fibromyalgia and co morbid insomnia will be recruited from the HFHS 
hospitals and clinics and from patient support groups in Metro Detroit.  In our most recent study 
of fibromyalgia we were able to recruit 20 patients over a period of twelve months.  Patients will 
be assessed clinically for fibromyalgia and insomnia using American College of Rheumatology 
(ARC) (16) and Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (17) criteria, 
respectively.  They will be screened by PSG for other primary sleep disorders and a sleep 
efficiency (sleep time/bedtime) of < 85%. 
 
2.4.1 Inclusion Criteria 
o 
Women with good psychiatric and stable physical health. 
o 
Aged between 21 and 65 yrs old. 
o 
Having a customary bedtime of 12 midnight or earlier, having at least 6 to 8 hrs in bed on 
average. 
o 
Meeting the American College of Rheumatology criteria for fibromyalgia. 
o 
Having wide spread pain, which includes pain in all four quadrants; including symptoms 
and/or complaints of fatigue, waking non-refreshed and cognitive symptoms. 
o 
Current average pain severity score > 4 on the Brief Pain Inventory at screening. 
o 
Meeting the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, criteria for 
insomnia and additionally with a sleep efficiency of < 85% on a screening PSG. 


 
  
 
2.4.2 Exclusion Criteria 
o 
Pain symptoms (unrelated to fibromyalgia) that could interfere with the interpretation of 
outcome measures; regional pain syndromes (eg. back, neck ); multiple surgeries; pain from 
a traumatic injury; a confirmed current or previous diagnosis of rheumatoid arthritis, or similar 
disorders, inflammatory arthritis, or other autoimmune disease, osteoarthritis, tendonitis, 
unstable medical or psychiatric disorders. 
o 
Any condition that could confound assessment of sleep, including depression (scoring 14 > 
on the Hamilton Depression Rating Scale (HAM-D), anxiety (scoring 24> on the Hamilton 
Anxiety Rating Scale (HAM-A), other psychiatric disorders, chronic medical conditions (e.g. 
liver disease, heart failure) or uncontrolled medical conditions. 
o 
Consuming >14 alcoholic beverages per week (and/or >5 or > 4 drinks per single occasion 
for males and females, respectively) and >300mg of caffeine per day. 
o 
The inability to discontinue, hypnotics or antidepressants.  
o 
Substance abuse within the last 2 years and/or a failed urine drug screen; 
o 
Primary sleep disorders, including narcolepsy, or circadian rhythm sleep disorder, excluding 
insomnia; 
o 
Respiratory disturbances [apnea hypopnea index] or periodic limb movement arousal index 
greater than 10 per hour of sleep. 
o 
Having a history of frostbite and/or Raynaud's syndrome. 
o 
Current pregnancy or breast-feeding. 
 
While patients will be told to discontinue hypnotic use, they will be allowed use of pain 
medications throughout the study to be recorded in a daily diary, as long as they are using a 
stable dose on a regular basis.  The one exception will be that sedating tricyclic antidepressant 
use will be excluded.  Patients will be asked to discontinue their antidepressant or hypnotic use 
two weeks before entering the study protocol. 
 
Those qualifying will receive suvorexant 20 mg and placebo for each of 9 nights in a 
cross over design with 7 nights of washout between treatments.  PSGs will be collected on 
nights 7 and 8 of each crossover treatment arm.  During day 8 of each treatment a MSLT (1000, 
1200, 1400, and 1600 hr) will be done, and on days 1 and 8 nociceptive sensitivity [finger 
withdrawal latency (FWL)] testing to a radiant heat stimulus (1100 and 1500 hr) will be 
conducted.  On days 1 and 8 self-reported mood and pain indices will also be completed prior to 
each nociceptive sensitivity test.   
 
2.5 Study Procedures 
 
2.5.1 Polysomnography (PSG)   
For each PSG night, participants will arrive 2 hours prior to their reported bedtime to 
complete check-in procedures and undergo electrode placement for standard 8-hr PSGs (18). 
Bedtimes will be determined using the participant’s self-reported normal sleep schedule with 


time in bed fixed to 8 hrs.  For the screening PSG, central and occipital electro-encephalogram 
(EEG) leads (C3-A2 and O2-A1) will be placed to measure EEG activity and left and right 
horizontal electroculograms (EOG) will be used to measure eye movements.  A V5 
electrocardiogram (ECG) lead and a sub-mental electromyogram (EMG) lead will be placed. 
Airflow (by pressure transducer), body position via video recording, thoracic and abdominal 
excursion (inductance plethysmography), oxygen saturation (finger pulse oximetry), leg 
movement (with electrode over left anterior tibialis muscle), and sound will also be recorded.  
For the study nights 8 and 9 the 8-hr PSGs will consist of continuous monitoring of two channels 
of EEG (C3-A2 and O2-A1), left and right EOGs, submental EMG and V5 ECG.  
All recordings will be scored in 30 second epochs for standard sleep stages according to 
the standards of Rechtschaffen & Kales (18). Scoring will be done by technicians with 
established intra-laboratory scoring concordance and verified by review of the PI or CoI.  
Respiratory events and periodic leg movement events will be scored according to established 
AASM published criteria (19).  Based on the screening PSG, patients with respiratory or periodic 
leg movement event indices of > 10 will be excluded.  
 
2.5.2 Daytime Sleepiness/Alertness (MSLT)  
Each test of the MSLT will be conducted according to the standard research MSLT 
protocol (20). Participants will be placed in bed in quiet, darkened rooms and instructed to close 
their eyes, relax, and fall asleep. Each test is concluded after 20 minutes of continuous wake or 
after three continuous 30s epochs of stage one sleep, or one epoch of any other sleep stage.  
Latency to sleep onset will be scored as min to the first epoch of sleep or 20 min if sleep did not 
occur. The latencies for the 4 tests are averaged to generate a single latency value.   
 
2.5.3 Nociceptive Sensitivity (FWL) 
 
A radiant heat method will be used to assess nociceptive sensitivity (21).  Participants are 
seated in a comfortable chair at a desk with their hand resting on top of a metal box housing the 
heat source. The pad of the index finger (fingerprint whorl) is centered over a 3-mm hole 


through which the heat radiates. The heat source is a 100-watt projection bulb, located 10 mm 
from the finger.  A potentiometer controls the amount of current delivered to the light bulb, 
thereby varying heat intensity. On each trial, participants are instructed to place their index 
finger on the hole through which the heat source radiates and to withdraw their index finger 
when they first began to feel pain. Once finger withdrawal occurs, a photocell (mounted on a 
post located above the finger) detects the light (from the bulb underneath) and stops a digital 
timer connected to the circuit.  Both index fingers are tested and the heat intensities are 
adjusted on each trial such that five different heat intensities (ranging from 83.4 to 101.6 
degrees Fahrenheit, measured at steady-state after 10-sec duration) are presented in a 
randomized order. The FWL from left and right index fingers are averaged. The primary 
dependent measure is mean FWL (to a resolution of 0.01 sec) for each of the 5 heat intensities. 
Patients initially will undergo a training session to familiarize themselves with the nociceptive 
testing equipment and procedures.  The threshold at which a finger withdrawal response is 
elicited for each participant is established. The threshold radiant heat intensity is defined as the 
intensity that produces FWL of <21 sec.   
As to the validity of the radiant heat method, our studies have shown FWL is systematically 
related to stimulus intensity (greater intensity = shorter FWL), basal level of sleepiness/alertness 
(greater sleepiness = shorter FWL), and codeine versus placebo (codeine = longer FWL) (21).  
Importantly, in healthy normals without sleep disturbance reducing sleep time by as little as 2 
hrs reduces FWL and increasing sleep time by as little as 1 hr increases FWL (22,23).  Further, 
in patients with moderate to severe obstructive sleep apnea (OSA) treated with Continuous 
Positive Airway Pressure (CPAP), thereby eliminating the OSA and consolidating sleep, FWL is 
increased and when the CPAP is discontinued for two nights FWL is again reduced (24). 
2.5.4 Morning Self-reported Sleep and Previous Day Pain Assessment 
Each morning after arising participants will complete a brief questionnaire regarding the 
previous night’s sleep and the previous day’s pain.  The Red Cap questionnaires will be 


accessed over the internet by participants’ using their own password protected login 
identification credential with a daily time-limited completion interval (before 12 noon each day).  
The questionnaire will query regarding latency to fall asleep, wake time after falling asleep, total 
sleep time, pain disruption of sleep and alertness after awakening in the morning.  Daytime pain 
the previous day will be assessed using the Short-Form McGill Pain Questionnaire (28).        
2.5.5 Safety Monitoring 
Each participant will complete the Columbia Suicidality Scale at screening and on study day 
1 and 8.  Additionally the Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety 
Rating Scale (HAM-A) will also be completed on those days.  The rating scales will be 
administered between the first and second nociceptive sensitivity testing (at approximately 1130 
hr) on each day.  Changes on any of these scales from the scores established at the baseline 
will be reported as AEs (see below).  On day three of each of the treatment periods the 
patient/subjects will be contacted by phone to determine whether they are experiencing AEs. 
2.6 Study Duration 
 
It is estimated that the study can be completed within 18 months and that data analysis 
and paper preparation can be completed in an additional six months.  
 
2,7  Statistical Procedures and Sample Size Justification 
 
2.7.1 Statistics 
 
The primary PSG efficacy variables will be sleep efficiency and WASO computed as a 
mean of nights 7 and 8.  The secondary PSG measures will include nocturnal sleep latencies 
and sleep stages.  The primary daytime measures will be the MSLT scores from day 8 and the 
FWL test results (the average of the am and pm tests) from day 1 and day 8.  Secondary 
daytime measures will include the in-lab self-ratings of sleepiness/fatigue and pain.  Another set 
of secondary measures will be the morning ratings of sleep and previous day’s pain collected on 
the internet administered questionnaires during each 9 day treatment condition.  The in-lab 
sleep, daytime sleepiness/fatigue, and pain data for each dependent variable of the two 9 day 
conditions will be compared using two factor MANOVAs with drug (suvorexant vs placebo) and 
days (7 and 8) as the two repeated factors.  The internet questionnaire data will be treated 
similarly using drug and days as two repeated measures.  In addition we will conduct path 


analyses to determine the degree to which the change in nociceptive sensitivity is mediated 
directly by suvorexant and indirectly by suvorexant’s effect on sleep.  
   
 
2.7.2 Sample Size 
 
Our estimates of necessary sample size and the associated powers are presented in 
Appendix A.  The sample sizes and associated powers are presented for each of the primary 
outcome measures.  Given these assessments, we have chosen to recruit 30 patients.   
 
2.8 Drug Supply Requirements 
 
Nine nights each of suvorexant 20 mg and matching placebo will be required for each 
participant with the total study sample being 30.  (270 suvorexant 20 mg and 270 placebo).  In 
addition accounting for a 10% dropout rate we anticipate a total need for 300 20 mg suvorexant 
and 300 placebos 
  
2.9 Adverse Event Reporting 
 
Adverse events (AE) will be collected and reported to the study sponsor and the HFHS 
IRB as blinded events quarterly.  Serious adverse events (SAEs) will be reported as unblinded 
events to the study sponsor, the HFHS IRB and the FDA.  SAEs will be reported within 48 hrs of 
becoming aware of the event.  Initial reports will be followed by reports of the resolution of the 
SAE. 
 
2.10 References 
1) Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary 
diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 
2010;62:600-610. 
  
2)  Ynus, M. B.  Fibromyalgia and overlapping disorders: The unifying concept of central 
sensitivity syndromes. Seminars in Arthritis and Rheumatology, 2007;36:339-356. 
 
3) Roehrs T, Roth T.  Pain and sleep.  In: Babson KA, Feldner MT (eds).  Sleep and Affect.  
New York: Elsevier, 2015, pp 377-397. 
 
4) Roehrs T, Diederichs C, Gillis M, Burger AJ, Stout RA, Lumley MA, Roth T.  Nocturnal sleep, 
daytime sleepiness and fatigue in fibromyalgia patients compared to rheumatoid arthritis 
patients and healthy controls: A preliminary study.  Sleep Med 2013;14:109-115. 
 
5) Russel,I. J., Crofford, L. J., Leon, T., Cappelleri, J. C., Bushmakin, A. G., Whalen, E., Barrett, 
J. A., & Sadosky, A.  The effects of pregabalin on sleep disturbance symptoms among 
individuals with fibromyalgia syndrome.  Sleep Med 2009;10:604-610. 
 


6)  Moldofsky H, Lue FA, Mously C, Roth-Schechter B, Reynolds, WJ.  The effect of zolpidem in 
patients with fibromyalgia: a dose ranging, double-blind, placebo controlled, modified crossover 
study.  J Rheumatol 1996; 23:529-533. 
 
7) Gronbald, M., Nykanen, J., & Konttinen, Y.  Effect of zolpiclone on sleep quality, morning 
stiffness, widespread tenderness and pain and general discomfort in primary fibromyalgia 
patients.  A double-blind randomized trial.  Clin Rheumat 1993;12:186-191. 
 
8) Walsh, J. K., Muehlbach, M. J., Lauter, S. A., Hilliker, A., & Schweitzer, P. K. Effects of 
triazolam on sleep, daytime sleepiness, and morning stiffness in patients with rheumatoid 
arthritis.  J Rheumat 1996;23:245–252 
 
9) Drewes, A. M., Bjerregard, K., & Taaghold, S. J. Zopiclone as night medication in rheumatoid 
arthritis.  Scan J Rheumat 1998;27:180-187. 
 
10) Roth, T., Lankford, A., Bhadra, P., Whalen, E., & Resnick, E. M.  Effect of pregabalin on 
sleep in patients with fibromyalgia and sleep maintenance disturbance: A randomized, placebo-
controlled, 2-way crossover polysomnography study.  Arthritis Care Res 2012;62:597-606. 
 
11) Dimsdale, J. E., Ball, E. D., Carrier, E., Wallace, M., Holman, P., Mulroney, C., Shaikh, F., & 
Natarajan, L..  Effect of eszopiclone on sleep, fatigue, and pain in patients with musocitis 
associated with hematologic malignancies.  Support Care Cancer 2011;19:2015-2020. 
 
12) Hoyer D, Jacobson LH.  Orexin in sleep, addiction and more: Is the perfect insomnia drug at 
hand.  Neuropeptides 2013;47:477-488. 
 
13) Harris GC, Aston-Jones G.  Arousal and reward: a dichotomy in orexin function.  TINS 
2006;29:571-577. 
 
14). Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, 
Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM.  Effects of suvorexant, an orexin 
receptor antagonist, on sleep parameters as measujred by polysomnography in healthy men.  
Sleep 2013;36:259-267. 
 
15) Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T. Michelson 
D.  Orexin receptor antagonism for treatment of insomnia.  Neurology 2012;79:2265-2274. 
 
16) Wolfe F. Fibromyalgia. Rheum Dis Clin North Am. 1990;16:681-698. 
 
17) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 
Fifth Ed. (DSM-5), Washington DC: American Psychiatric Association, 2013.  
  
18) Rechtschaffen A, Kales A, eds. A manual of standardized terminology, techniques and 
scoring system for sleep stages of human subjects. Los Angeles, CA: UCLA Brain Information 
Service/Brain Research Institute, 1968. 
 
19) Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM, Marcus CL, Vaughn BV. The 
AASM manual for the scoring of sleep and associated events. Darien, IL: American Academy of 
Sleep Medicine, 2014. 
 


20) Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. (1986).  
Guidelines for the Multiple Sleep Latency Test (MSLT):  A standard measure of sleepiness.  
Sleep, 1986;9:519-524. 
 
21) Chhangani BS, Roehrs TA, Harris EJ, Hyde M, Drake C, Hudgel DW, Roth T.  Pain 
sensitivity in sleepy pain-free normals.  Sleep 2009;32:1011-1017. 
 
22) Roehrs, T. A., Hyde, M., Blaisdell, B., Greenwald, M., & Roth T. Sleep loss and REM sleep 
loss are hyperalgesic. Sleep 2006; 29:145-151. 
 
23) Roehrs TA, Harris E, Randall S, Roth T. Pain sensitivity and recovery from mild chronic 
sleep loss. Sleep 2012;35:1602-1608. 
 
24) Khalid I, Roehrs TA, Hudgel DW, Roth T.  Continuous positive airway pressure in severe 
obstructive sleep apnea reduced pain sensitivity.  Sleep 2011;34:1687-1691. 
 
25) Okura K, Lavigne GJ, Huynh N, Manzini C, Fillipini D, Montplaisir JY.  Comparison of sleep 
variables between chronic widespread musculoskeletal pain, insomnia, periodic leg movements 
syndrome and control subjects in a clinical sleep medicine practice.  Sleep Medicine 
2008;9:352-361. 
 
26) Hindmarch I, Dawson J, Stanley N.  A double-blind study in healthy volunteers to assess the 
effects on sleep of pregabalin compared with alprazolam and placebo.  Sleep 2005;28:187-193. 
 
27) Stout R, Burger A, Villareal A, Gillis M, Lumley M, Roehrs T, Roth T.  Objective sleepiness 
following sleep restriction in rheumatoid arthristis and fibromyalgia.  Sleep 2007;30:A323 (ab). 
 
28) Hawker GA, Mian S, Kendzerske T, French M.  Measures of adult pain.  Arth Care & Res 
2011;63:S240-S252. 
 
 
2.12 Publication Plan 
 
The PI and CoI will be responsible for analyses and paper preparation.  The paper will 
submitted to the study sponsor Merck for approval prior to submission for publication. 
 
 
 
 


APPENDIX A 
 
Sample Size and Power Estimates 
 
All estimates based on two-tailed tests with alpha set at 0.05 
 
Nocturnal Polysomnographic (NPSG) Sleep Efficiency (SE) 
 
Based on a SE increase of 8% versus placebo with 20 mg suvorexant in primary insomnia 
(Herring et al, Neurology 2012;79:2265-2273). 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 
8.000 
Standard Deviation of Difference : 12.800 
Effect Size 
: 
0.625 
ALPHA 
: 
0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
 
 
 
 
 
Based on a SE increase of 6% versus placebo with 10 mg zolpidem in primary insomnia 
(Randall et al, Sleep 2012;35:1551-1557). 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 6.000 
Standard Deviation of Difference : 9.000 
Effect Size 
: 0.667 
ALPHA 
: 0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
  
 
 
 
 
 
Sample Size
(Per Cell) 
POWER 
20 
0.755 
21 
0.778 
22 
0.798 
23 
0.817 
24 
0.834 
25 
0.850 
26 
0.865 
27 
0.878 
28 
0.890 
29 
0.901 
30 
0.911 
Sample Size
(Per Cell) 
POWER
20 
0.807 
21 
0.828 
22 
0.846 
23 
0.863 
24 
0.878 
25 
0.892 
26 
0.904 
27 
0.915 
28 
0.925 
29 
0.934 
30 
0.942 


Sample Size and Power Estimates 
 
All estimates based on two-tailed tests with alpha set at 0.05 
 
Nocturnal Polysomnographic (NPSG) Wake after Sleep Onset (WASO) 
 
Based on a WASO reduction of 25 min versus placebo with 20 mg suvorexant in primary 
insomnia (Herring et al, Neurology 2012;79:2265-2273). 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 25.000 
Standard Deviation of Difference : 45.000 
Effect Size 
: 
0.556 
ALPHA 
: 
0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
 
 
 
 
   
 
Based on a WASO reduction of 20 min versus placebo with 10 mg zolpidem in primary insomnia 
(Randall et al, Sleep 2012;35:1551-1557). 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 20.000 
Standard Deviation of Difference : 43.000 
Effect Size 
: 
0.465 
ALPHA 
: 
0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
Sample Size
(Per Cell) 
POWER 
20 
0.655 
21 
0.678 
22 
0.700 
23 
0.721 
24 
0.741 
25 
0.760 
26 
0.777 
27 
0.794 
28 
0.809 
29 
0.823 
30 
0.837 
Sample Size
(Per Cell) 
POWER
20 
0.506 
21 
0.527 
22 
0.548 
23 
0.569 
24 
0.588 
25 
0.607 
26 
0.625 
27 
0.643 
28 
0.660 
29 
0.677 
30 
0.692 


Sample Size and Power Estimates 
 
All estimates based on two-tailed tests with alpha set at 0.05 
 
Multiple Sleep Latency Test (MSLT) 
 
Based on reduction in MSLT in Fibromyalgia patients following 1 night of 4 hrs time in bed (i.e. 
reflects sensitivity of MSLT to sleep time manipulations) relative to their baseline “hyperaroused” 
MSLT (Roehrs et al, J Psychosom Res 2015:79:27-31) 
 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 4.300 
Standard Deviation of Difference : 4.800 
Effect Size 
: 0.896 
ALPHA 
: 0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
 
 
 
 
Based on increase in MSLT in “sleepy” volunteers after 4 nights of 1 hr increased sleep per 
night (Roehrs et al, Sleep 2012;35:1667-1672) 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 4.500 
Standard Deviation of Difference : 3.800 
Effect Size 
: 1.184 
ALPHA 
: 0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
Sample Size
(Per Cell) 
POWER 
20 
0.967 
21 
0.974 
22 
0.979 
23 
0.984 
24 
0.987 
25 
0.990 
26 
0.992 
27 
0.994 
28 
0.995 
29 
0.996 
30 
0.997 
Sample Size
(Per Cell) 
POWER 
20 
0.999 
21 
0.999 
22 
1.000 
23 
1.000 
24 
1.000 
25 
1.000 
26 
1.000 
27 
1.000 
28 
1.000 
29 
1.000 
30 
1.000 


Finger Withdrawal Latency (FWL) 
 
Based on increase in FWL (i.e. reduction in pain sensitivity) in “sleepy” volunteers after 4 nights 
of 1 hr increased sleep per night (Roehrs et al, Sleep 2012;35:1667-1672 
 
 
Paired t-test with Alternative 'not equal' 
 
 
Expected Difference 
: 2.600 
Standard Deviation of Difference : 2.500 
Effect Size 
: 1.040 
ALPHA 
: 0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
 
 
 
 
Estimating greater variability in a Fibromyalgia sample 
 
Paired t-test with Alternative 'not equal' 
 
Expected Difference 
: 2.600 
Standard Deviation of Difference : 3.500 
Effect Size 
: 0.743 
ALPHA 
: 0.050 
Sample Size: Low 
: 
20 
Sample Size: High 
: 
30 
Increment 
: 
1 
 
 
   
 
 
 
 
 
Sample Size
(Per Cell) 
POWER 
20 
0.993 
21 
0.995 
22 
0.996 
23 
0.997 
24 
0.998 
25 
0.999 
26 
0.999 
27 
0.999 
28 
1.000 
29 
1.000 
30 
1.000 
Sample Size
(Per Cell) 
POWER
20 
0.883 
21 
0.899 
22 
0.913 
23 
0.926 
24 
0.936 
25 
0.945 
26 
0.953 
27 
0.960 
28 
0.966 
29 
0.971 
30 
0.976