Insomnia and Osteoarthritis Study

Study Overview
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Brief Summary
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This research is being done to evaluate the effects of a sleeping pill (eszopiclone, Lunesta)in patients with arthritis of the knee who also suffer from chronic insomnia. This study will test whether Lunesta improves sleep, pain sensitivity, and daytime symptoms in patients with knee pain.

Official Title
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The Efficacy of Eszopiclone (Lunesta) for Chronic Insomnia Associated With Osteoarthritis.

Conditions
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Osteoarthritis, Insomnia

Intervention / Treatment
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* Drug: Placebo
* Drug: Eszopiclone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-64 Diagnosed with and under physicians care for osteoarthritis of the knee according to American College of Rheumatology Criteria with radiographic evidence demonstrating at least grade 1 osteoarthritis (OA) Report at least typical arthritic pain>4 out of 10 (0=no pain, 10=the most extreme pain imaginable) Meet Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and International Classification of Sleep Disorders, Revised definition (ICSD-R) criteria for either primary (psychophysiologic) insomnia or insomnia secondary to osteoarthritis Insomnia symptoms must include problems with middle of the night awakenings Insomnia symptom duration > 6 months Baseline, 2-week, sleep diary average wake after sleep onset time >30 minutes Baseline self-reported total sleep time < 6.5 hours per night Patients taking NSAID therapy for pain must be on a stable dose for a period of at least one month prior to initiating the study Exclusion Criteria: Intrinsic sleep disorders other than insomnia (sleep apnea, periodic limb movement disorder, etc) Significant rheumatologic or chronic pain disorders other than osteoarthritis of the knee, including fibromyalgia or the complaint of widespread pain impacting 4 quadrants, complex regional pain syndrome, post herpetic neuralgia, etc) Major medical disease (including, hepatic impairment, chronic obstructive pulmonary disease/compromised respiratory function, cancer, dementia, diabetes, congestive heart failure, cerebrovascular disease, raynaud's syndrome) Active major psychiatric disorders (including dementia or cognitive impairment) and history of schizophrenia or bipolar I disorder History of serious suicide attempt; 6) history of alcohol or substance (including prescription medications) abuse Pregnancy or plans to become pregnant within 6 months Intraarticular steroid injection within the past month Regular (>3 days/week) use of antidepressants, antipsychotics, and mood stabilizers, within the past two months Regular (> 3/week) use of myorelaxants, narcotics, sedative hypnotics, and anticonvulsants within the past one month Unwilling or unable to discontinue all use of the medications listed in #10 for two weeks prior to starting the study Unwilling or unable to discontinue all centrally acting agents and all analgesic usage within 24 hours of pain testing sessions Refusal to provide consent to contact patient's physician to establish diagnosis and obtain medical record information Regular tobacco or nicotine use Heavy caffeine use [(>2 cups of coffee/day (equivalent) History of previous allergic reaction or severe side effects to sedative hypnotics Use of potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, troleandomycin, ritonavir, nelfinavir) In addition, subjects will undergo in-laboratory blood tests prior to receiving drug and will be excluded from further participation if they exhibit: a) positive pregnancy test, b) positive toxicology (benzodiazepine, opioids, Tetrahydrocannabinol (THC), alcohol, and stimulants), c) abnormal liver enzyme panel

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eszopiclone<br>Eszopiclone 3mg capsules, once daily at bedtime for 12 weeks | Drug: Eszopiclone<br>* 3mg capsule, once daily at bedtime<br>|
| Placebo Comparator: Placebo<br>3mg placebo capsule, once daily at bedtime for 12 weeks | Drug: Placebo<br>* 3mg placebo capsule, once daily at bedtime<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wake After Sleep Onset (WASO) | Total minutes of wakefulness recorded after sleep onset. (Recorded in Daily Sleep Diary) WASO= time awake in the middle of the night, not counting SL or time in bed after awakening. Recorded in minutes | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Time in Bed | Total time in bed, in minutes | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Sleep Latency (SL) | Sleep Latency: time taken to fall asleep, in minutes (as recorded in daily sleep diary) | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Number of Awakenings | As recorded in daily sleep diary | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Total Sleep Time (TST) | minutes spent asleep as recorded in daily sleep diary | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Sleep Efficiency (SE) | [(TST/ TIB)X 100], (%) as recorded in daily sleep diary | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Sleep Quality (SQ) | As recorded in daily sleep diary. Visual analog scales (VAS) Sleep Quality Ratings 0-100, 0= extremely poor sleep quality, (shallow and unrefreshing) and 100=excellent sleep quality (deep and refreshing) | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| WASO as Assessed by Actigraphy | Subjects wore a Mini Mitter Actiwatch for two continuous weeks at each assessment periods to provide an objective index compared to the assessments made by daily sleep journal. Device is lightweight and worn on non-dominant wrist and contains and omni-directional accelerometer. The accelerometer records the occurrence and degree of motion with a minimal resultant force of .01g. Data are stored as activity counts within a specified epoch. WASO recorded by device = total minutes of wakefulness after sleep onset, in minutes. | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| TST as Assessed by Actigraphy | Subjects wore a Mini Mitter Actiwatch for two continuous weeks at each assessment periods to provide an objective index compared to the assessments made by daily sleep journal. Device is lightweight and worn on non-dominant wrist and contains and omni-directional accelerometer. The accelerometer records the occurrence and degree of motion with a minimal resultant force of .01g. Data are stored as activity counts within a specified epoch. TST recorded by device = total minutes spent asleep | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Sleep Efficiency as Assessed by Actigraphy | Subjects wore a Mini Mitter Actiwatch for two continuous weeks at each assessment periods to provide an objective index compared to the assessments made by daily sleep journal. Device is lightweight and worn on non-dominant wrist and contains and omni-directional accelerometer. The accelerometer records the occurrence and degree of motion with a minimal resultant force of .01g. Data are stored as activity counts within a specified epoch. Sleep efficiency is the index of sleep percentage recorded, equal to total sleep time divided by the time in bed X 100 = X%. | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Sleep Latency as Assessed by Actigraphy | Subjects wore a Mini Mitter Actiwatch for two continuous weeks at each assessment periods to provide an objective index compared to the assessments made by daily sleep journal. Device is lightweight and worn on non-dominant wrist and contains and omni-directional accelerometer. The accelerometer records the occurrence and degree of motion with a minimal resultant force of .01g. Data are stored as activity counts within a specified epoch. Sleep latency is the time taken to fall asleep, or equal to lights out- sleep onset (sleep onset: time when sleep is first scored after lights out, first scorable epoch). | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Insomnia Severity Index (ISI) Mean Total Scores | The ISI is made up of 7 questions, each possible of earning a score of 0-4, making the total range 0-28, where 0 indicates no severity/no problem with sleep and therefore no insomnia, or 28, being very severe with the highest level of insomnia | Mean of baseline, 6 week follow-up, and 12 week follow-up | 
| Diffuse Noxious Inhibitory Control (DNIC) Index Scores | PPTh:a somedic algometer's 1cm2 rubber probe was placed over muscle belly, with pressure increasing steadily at constant rate (30kPA/Sec), until subject indicated that s/he first felt pain. PPTh ratings were obtained on right brachioradialis & right trapezius in a random order (average was taken from both areas at each time point). During each cold pressor task, participants immersed contralateral hand (left) up to wrist, in a circulating cold water bath maintained at 4°C. 20 seconds after commencing hand immersion, PPTh was re-assessed on either right brachioradialis or right trapezius (the same site as baseline assessment). After PPTh assessment, participants removed hands from water. DNIC was measured as the % change in PPTh during cold pressor, relative to baseline PPTh [i.e., (mean PPTh during cold pressor / mean PPTh prior to cold pressor)*100]. Increase in PPTh during cold pressor (i.e., percentage scores above 100) reflects normal functioning of pain-inhibitory processes. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Temporal Summation (TS) | TS :maximum windup pain rating - first windup pain rating (0-100). Contact heat stimuli at non tissue damaging temperatures were delivered using computer driven, peltier-element-based stimulator (Medoc, TSA II), with a 9 cm2 probe applied to left forearm. In order to assess temporal summation, three sequences of 10 heat pulses each (with stimulus temperatures of 46 degrees C, 48 degrees C, and 50 degrees C, in random order) were applied to left dorsal forearm. The thermode remains in fixed position during administration of 10 heat pulses that constitute a sequence. Within each sequence, successive thermal pulses at a given temperature are delivered for a duration of approximately 0.5 sec each, with a 2.5-sec inter-pulse interval. The rate of rise & fall of the thermode temp. is set at the device max .of 10 degrees C / S. Subjects verbally rate the perceived intensity of each thermal pulse on a 0-100 rating scale & may terminate the procedure at any time.100=max tolerable intensity | Mean of baseline, 6 week follow-up and 12 week follow-up at 46, 48, and 50 degrees C | 
| Mean Level of Pain Experienced Throughout the Day | Assessed using a Daily Pain Diary with a scale 0-100, 0 being no pain, 100 being the most severe/intense | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Pain as Assessed by the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) Pain Severity Subscale | The WOMAC is a quality of scale life made up of three domains, pain, stiffness, and disability which each comprising of 5, 2, and 7 questions, respectively. A VAS was used for each subscale. Pain was assessed on a scale of 0-100, with 0 being absolutely no pain and 100 being maximum pain. | Mean of baseline, 6 week follow-up and 12 week follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heat Pain Threshold | Contact heat stimuli at non tissue damaging temperatures were delivered using computer driven, peltier-element-based stimulator (Medoc, TSA II), with a 9 cm2 probe applied to the left forearm. The thermode was affixed snugly via Velcro straps to ensure even skin contact and repositioned to an adjacent site after each trial to minimize sensitizationHPTh was assessed on the left ventral forearm using an ascending method of limits paradigm; from a non-painful 32°C baseline, the temperature was steadily increased at 0.5°C/sec. Two trials of heat pain threshold were conducted. Averages of both trials are presented from respective time point below. Subjects push a button when the stimulus first feels painful The temperature (degrees Celsius) at the time button is pushed is automatically recorded. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Heat Pain Tolerance (HPTOL) | Contact heat stimuli at non tissue damaging temperatures were delivered using computer driven, peltier-element-based stimulator (Medoc, TSA II), with a 9 cm2 probe applied to the left forearm. The thermode was affixed snugly via Velcro straps to ensure even skin contact and repositioned to an adjacent site after each trial to minimize sensitization. HPTOL was assessed on the left ventral forearm using an ascending method of limits paradigm; from a non-painful 32°C baseline, the temperature was steadily increased at 0.5°C/sec. Two trials of HPTOL were conducted. An average of both trials at each respective time point is presented below. Subjects push a button when the stimulus becomes intolerable. The temperature (degrees Celsius) at the time button is pushed to terminate the stimulation is automatically recorded. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Pressure Pain Threshold | A Somedic algometer was used to assess pressure pain threshold (PPTh) similar to previous studies. The algometer's 1cm2 rubber probe was placed over the muscle belly, with the pressure increased steadily at a constant rate (30kPA/Sec), until the subject indicated that s/he first felt pain. PPTh was assessed 2 times each, bilaterally, at (in a randomized order) the masseter muscle trapezius muscle, and at the proximal third of the brachioradialis muscle (forearm). The scores from each location were averaged for each participant at that respective time point. The same site was never stimulated consecutively. At least 90 s were maintained between successive stimuli | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Quality of Life as Assessed by the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) Disability Subscale | The WOMAC is a quality of scale life made up of three domains, pain, stiffness, and disability which each comprising of 5, 2, and 7 questions, respectively. A VAS was used for each subscale. Disability was assessed on a VAS of 0-100, with 0 being absolutely no disability and 100 being maximum disability. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Quality of Life as Assessed by the Short Form-36 (SF-36) Physical Health Component Summary | The SF-36 is a broad, well normed measure of quality of life, comprised of 36 questions aggregated into 8 domains/dimensions. The Physical Component Summary was used here as a global index of physical health functioning. Scale 0-100, with 0 being worst functional level, 100 being the best. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Quality of Life as Assessed by the Short Form-36 (SF-36) Mental Health Component Summary | The SF-36 is a broad, well normed measure of quality of life, comprised of 36 questions aggregated into 8 domains/dimensions. The Mental Component Summary was used here as a global index of mental health functioning. Scale 0-100, with 0 being worst functional level, 100 being the best. | Mean of baseline, 6 week follow-up and 12 week follow-up | 
| Joint Stiffness as Assessed by the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) Joint Stiffness Subscale | The WOMAC is a quality of scale life made up of three domains, pain, stiffness, and disability which each comprising of 5, 2, and 7 questions, respectively. A VAS was used for each subscale. Joint Stiffness was assessed on a VAS scale of 0-20, with 0 being no joint stiffness, and 20 being maximum stiffness. | Mean of baseline, 6 week follow-up and 12 week follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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eszopiclone, insomnia