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 9 (2008) 352–361 www.elsevier.com/locate/sleep

Original article

Comparison of sleep variables between chronic widespread musculoskeletal pain, insomnia, periodic leg movements syndrome and control subjects in a clinical sleep medicine practice Kazuo Okura a

a,b,c

, Gilles J. Lavigne a,b,*, Nelly Huynh a,b, Christiane Manzini Daniel Fillipini b, Jacques Y. Montplaisir a,b

a,b

,

Faculte´s de me´decine dentaire et de me´decine, Universite´ de Montre´al, CP 6128, succursale Centre-ville, Montre´al, Que., Canada H3C 3J7 b Centre d’e´tude du sommeil, Hoˆpital du Sacre´-Cœur de Montre´al, Que., Canada c Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Received 10 October 2006; received in revised form 3 July 2007; accepted 12 July 2007 Available online 4 September 2007

Abstract Background: Between 50% and 89% of chronic pain patients report unrefreshing sleep. The aim of this retrospective analysis was to compare the sleep of normal subjects with the sleep of a clinical population presenting musculoskeletal chronic widespread pain (CWP), psychophysiological insomnia and restless legs syndrome/periodic limb movements during sleep (RLS/PLMS) in order to identify sleep variables that may explain the poor sleep complaints of CWP patients. Methods: Sleep data from 10 normal subjects and 37 patients (mean age 55 ± 3 yo), matched for age and sex, were retrieved from our sleep data bank. Sub-analysis controlled for the effects of medication. Results: In comparison to normal subjects, sleep duration was shorter in CWP patients ( 71 min; p < 0.01); sleep efficiency was significantly lower in CWP and insomnia patients ( 10.1% and 11.1%, respectively; p < 0.05). CWP and PLMS patients lost one non-rapid eye movement (REM) to REM sleep cycle (p < 0.04). An intermediate level of PLM was observed during the sleep of CWP patients in comparison to normal subjects (8.8/h vs. 2.0/h) and PLMS patients (33/h). Regular use of non-narcotic analgesics did not seem to interfere with sleep variables. Conclusions: The sleep of middle-aged patients with CWP is comparable to that of insomnia patients. The moderate level of PLM during sleep suggests that such sensory motor activity needs to be evaluated in patients suffering from chronic pain. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Sleep duration; Sleep efficiency; Sleep cycle; Chronic pain; Widespread pain

1. Introduction Chronic pain (CP) is reported by 11–29% of the general population [1–5]. Between 50% and 89% of CP patients complain of poor sleep and/or feeling unre*

Corresponding author. Address: Faculte´s de me´decine dentaire et de me´decine, Universite´ de Montre´al, CP 6128, succursale Centre-ville, Montre´al, Que., Canada H3C 3J7. Tel.: +1 514 343 2310; fax: +1 514 343 2233. E-mail address: [email protected] (G.J. Lavigne). 1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2007.07.007

freshed upon awakening [6–12]. In these patient groups the most frequent CP conditions are back pain and rheumatoid and musculoskeletal pain, including temporomandibular myofascial pain and fibromyalgia [6,7,11, 12]. The two last conditions share common symptoms: generalized pain sensitivity, sleep disturbances, fatigue, bowel complaints and headache; interestingly, 1/5 patients with temporomandibular problems present fibromyalgia and over 3/4 patients with fibromyalgia present temporomandibular problems [7,13–15]. Myofascial pain and fibromyalgia are now included under

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the term of widespread pain to describe the generalized diffuse allodynia observed upon digital palpation of specific body sites [16–18]. Recent clinical evidence suggests that pain is a relatively frequent complaint of patients suffering from the restless leg syndrome (RLS) as manifested by periodic limb movements during sleep (PLMS) in the majority of patients [19]. For example, in an international study performed in a primary care setting, 1/5 patients reported pain as a concomitant symptom of RLS [20]. In a genetic study on RLS, pain was reported among RLS-related symptoms by over 60% of cases with a positive family history of RLS, and by 85% of patients with no family history [21]. Furthermore, over 40% of patients with somatoform pain disorder also complain of RLS-related symptoms, a value that rises over 70% if the pain is constant [22]. Furthermore, some evidence suggests that sensory pain-related perception is altered in RLS patients [23–25]. The aim of this retrospective clinical study was to compare age- and gender-matched subjects in order to specify the different sleep variables associated with poor sleep complaints in CWP patients. The present report is based on data drawn from routine medical evaluation in the sleep laboratory. In order to be able to translate our findings to the reality of clinical practice, we did not choose subjects who had withdrawn from medication use, since many CP patients are using medication when physicians see them. In other words, this study is a clinical report that was not planned with the intent of addressing mechanistic issues on the interaction between pain and sleep. 2. Methods Polysomnographic data from a total of 47 subjects (10 normals and 37 patients), matched for age and sex, were retrieved from the sleep clinic data bank according to their diagnostic status at referral (later confirmed during the clinical examination and following one night of polysomnographic recording in our laboratory by two of the co-authors [J.M.; D.F.]). All subjects were Caucasian, French- or English-speaking Canadians living in the Montreal area, an urban milieu. The subject population comprised normal subjects (5 female/5 male) and patients with RLS and PLMS (RLS/PLMS; 5 female/5 male), insomnia (5 female/5 male) and CWP (8 female and 9 male). Subjects were matched for age with a mean of 55 ± 3 years. Note that the number of patients with CWP is higher than in other groups since we elected to further control for the potential effects of medication (e.g., analgesic, antidepressant, muscle relaxant) on sleep variables. Subjects were included or excluded from this retrospective analysis based on the following criteria: all sub-

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jects were seen in our sleep clinic either as a control in a randomized clinical trial or due to a sleep-related problem requiring at least one night of polygraphic sleep evaluation. Subjects were instructed to avoid excessive smoking and caffeine during the day prior to the evaluation but none were requested to modify their usual medication intake since the main goal of the study was to report on the sleep of clinical patients as they are seen by physicians [26]. A group of normal subjects formed the control group with the following criteria for exclusion: pain, sleep, psychiatric or neurological disorders. Patients suspected to have RLS/PLMS had a clear history of leg restlessness or discomfort while awake, spontaneous leg jerks during sleep and met the usual International Restless Legs Syndrome Study Group (IRLSSG) criteria as commonly used by our laboratory [27,28]. All insomnia patients presented psychophysiological insomnia; insomnia was not due to psychiatric problems, drug or substance abuse. A diagnosis of CWP with sleep-related complaints was confirmed upon clinical examination based on the usual criteria: widespread musculoskeletal pain (at least 11 of 18 body sites; for 3 months or more) of at least moderate intensity and present for at least 6 days in the last month and the presence of sleep complaints such as a perception of unrefreshing sleep [17,18,29,30]. The main pain complaints included diffuse musculoskeletal pain at shoulder, lower back, neck or leg levels. Based on a clinical examination and a full night’s investigation in sleep laboratory, we excluded patients with a history of drug or substance abuse, mental health disorder, sleep and/or movement disorders such as mild apnea >10/h of sleep [29], Parkinson’s disease, REM behavior disorder, and sleep bruxism (tooth-grinding) >5 episodes/h sleep, with the exception of the sleep disorders described above (e.g., insomnia, PLMS). Again, since our intention was to compare patient groups referred to the sleep clinic, no attempt was made to discourage patients from taking usual sleep or painrelated medication. The list of medications used by various groups is reported in Table 1. First a comparison was made, for all sleep variables (e.g., sleep duration, efficiency, duration of each sleep stage, PLMS index) between normal subjects and each patient group (see Table 2). CWP pain patients were further subdivided based on the presence of a PLMS index smaller or larger than 5 (see Table 3) [19]. We further compared the effect of non-opioid analgesic, antidepressive and muscle relaxant medications, as described above for CWP patients, on sleep variables (see Tables 4.1–4.3). The polysomnographic recordings included electroencephalograph (EEG) (C3/A2, O2/A1), electrooculograph (EOG), electromyograph (EMG), electrocardiograph (ECG: D-1) and respiratory variables (chest belt, respiratory thermistance, oximetry). All signals were sampled at a frequency of 128 Hz using a commercial hardware

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Table 1 Medication used on regular basis by subject Non-opioid

Normal subjects (n = 10)

RLS/PLMS (n = 10)

Insomnia (n = 10)

CWP (n = 17)

1 (cardio prevention)

0

1 (cardio prevention)

6

0

2

4

3

Muscle relaxant Cyclobenzaprine Clonazepam

0 0

1 1

0 1

2 4

Antidepressant TCA SSRI Others

0 0 0

1 1 2 (trazodone)

2 4 0

Dopaminergic agents (RLS/PLMS) Anti-epileptic (Pain)

0 0

1 (pramipexole) 0

0 0

1 (levodopa) 2 (gabapentin, epival)

Antihypertensive

0

1

1

5

Cholesterol reducers

0

4

1

7

Hormonal therapies

0

3

1

3

Vitamins

0

0

0

4

Analgesic NSAI (non-steroidal anti-inflammatory): aspirin, ibruprofen, acetaminophen, celecoxib, naproxen, nabumetone Hypnotic/Benzodiazepine Zopiclone, temazepam, zolpidem/ativan

Table 2 Demographics and sleep variables of normal subjects, PLMS/RLS, insomnia and chronic widespread pain (CWP) patients Variables

Normal subjects a

PLMS/RLS patients b

Insomnia patients c

CWP patients d

I. Demographics Sex distribution Age

5F; 5M 54.9 ± 3.2

5F; 5M 55.9 ± 3.1

5F; 5M 56.1 ± 3.1

8F; 9M 54.8 ± 2.4

II. Sleep variables Sleep duration [min] Sleep efficiency [%] Sleep cycle Sleep latency [min]** REM latency [min]* Awakenings/h* Micro-arousals/h Sleep stage shifts/h** Stage 1 [%] Stage 2 [%] Stages 3 and 4 [%]** REM [%] PLMS index** % Subject index > 15 [%] Apnea index* Apnea/hypopnea index*

436.5 ± 10.3 91.2 ± 1.5 4.4 ± 0.2 11.2 ± 2.0 87.5 ± 10.6 5.1 ± 0.8 9.6 ± 1.6 33.6 ± 4.2 11.2 ± 1.6 61.9 ± 1.9 7.0 ± 2.6 19.8 ± 1.3 2.0 ± 0.9 (9) 0.0 0.8 ± 0.2 (7) 1.8 ± 0.7 (4)

411.7 ± 12.5 88.1 ± 1.6 3.4 ± 0.3 24.8 ± 10.8 120.4 ± 27.8 5.7 ± 0.9 11.7 ± 1.9 31.6 ± 4.1 12.9 ± 2.2 64.4 ± 2.1 5.8 ± 2.6 16.9 ± 1.3 33.4 ± 3.4 100.0 1.2 ± 0.4 (8) 2.2 ± 1.1 (7)

381.5 ± 11.2 81.1 ± 2.0 4.5 ± 0.4 17.5 ± 2.8 76.7 ± 11.7 6.9 ± 0.8 10.8 ± 0.9 27.3 ± 3.5 13.9 ± 2.0 61.5 ± 2.0 3.3 ± 1.9 21.3 ± 1.8 1.7 ± 0.8 10.0 1.0 ± 0.5 1.6 ± 0.6 (9)

362.0 ± 19.6 80.1 ± 2.8 3.4 ± 0.3 33.4 ± 14.5 109.9 ± 19.6 7.1 ± 0.9 9.1 ± 1.3 32.3 ± 3.2 11.0 ± 1.5 65.8 ± 2.9 5.3 ± 1.3 17.9 ± 1.7 8.8 ± 3.2 17.7 1.2 ± 0.4 (15) 1.7 ± 0.6 (15)

p-value group effect

p-value post-hoc test

0.98 0.01 0.006 0.04 0.51 0.53 0.31 0.58 0.74 0.62 0.58 0.69 0.29 15 [%] Apnea index* Apnea/hypopnea index*

368.5 ± 28.6 79.2 ± 4.2 3.7 ± 0.4 20.8 ± 4.6 83.0 ± 19.0 8.0 ± 1.5 8.4 ± 1.6 36.4 ± 4.8 11.9 ± 2.6 63.5 ± 3.6 5.8 ± 2.1 18.8 ± 2.4 15.7 ± 5.0 33.3 1.0 ± 0.5 (8) 1.8 ± 0.9 (8)

354.8 ± 28.2 81.2 ± 4.1 3.1 ± 0.5 47.7 ± 30.6 140.3 ± 33.9 6.1 ± 1.1 9.9 ± 2.1 28.1 ± 3.8 10.1 ± 1.5 68.4 ± 4.9 4.7 ± 1.8 16.8 ± 2.6 1.0 ± 0.5 0.0 1.4 ± 0.8 (7) 1.7 ± 0.9 (7)

p-value group effect 0.15 0.04 0.74 0.74 0.44 0.87 0.14 0.31 0.59 0.19 0.56 0.43 0.69 0.59 15 [%] Apnea index* Apnea/hypopnea index*

366.9 ± 38.7 82.5 ± 4.3 3.7 ± 0.7 55.2 ± 40.8 80.1 ± 19.5 6.3 ± 1.3 11.1 ± 2.5 26.4 ± 4.8 9.6 ± 2.6 70.9 ± 6.2 2.3 ± 1.3 17.3 ± 3.7 11.0 ± 7.9 16.7 2.6 ± 1.1 (5) 3.6 ± 1.6 (5)

359.4 ± 23.2 78.8 ± 3.8 3.3 ± 0.4 21.5 ± 4.9 126.2 ± 27.8 7.5 ± 1.3 8.0 ± 1.4 35.7 ± 3.9 11.8 ± 1.9 63.0 ± 2.9 7.0 ± 1.8 18.2 ± 1.8 7.5 ± 2.7 18.2 0.5 ± 0.2 (10) 0.8 ± 0.3 (10)

0.87 0.53 0.64 0.42 0.20 0.51 0.31 0.16 0.51 0.29 0.06 0.83 0.99 0.15 0.21

*Applied square root for normalization, **applied logarithm for normalization. Mean ± SEM is presented. Two-sample t-tests were used to compare groups. Bold=significant difference at p value listed. For the PLMS index and apnea index in sleep variables section, the ( ) stands for the number of analyzed subjects.

ings/h, number of micro-arousals/h and of sleep stage shift/h, percent of sleep stage, and the PLMS and sleep apnea index. All data were pooled and averaged for each subject (mean ± standard error of the mean [SEM]). The statistical analysis was performed using SYSTAT (SPSS Soft-

ware, Chicago, USA). Analysis of variance (ANOVA) was carried out on sleep variables for each group. Tukey’s honestly significantly different (HSD) multiple comparisons were performed as a post-hoc analysis. A two-sample t-test was performed as a post-hoc analysis. Statistical significance was accepted at p < 0.05.

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Table 4.2 Demographics and sleep variables of CWP subjects separated by regular use of TCA or SSRI Variables

CWP with TCA/SSRI

CWP without TCA/SSRI

p-value group effect

I. Demographics Sex distribution Age

3F; 3M 54.0 ± 4.9

5F; 6M 55.2 ± 2.8

1.00 0.84

II. Sleep variables Sleep duration [min] Sleep efficiency [%] Sleep cycle Sleep latency [min]** REM latency [min]* Awakenings/h Micro-arousals/h Sleep stage shifts/h Stage 1 [%] Stage 2 [%] Stages 3 and 4 [%] REM [%] PLMS index** % Subject index > 15 [%] Apnea index* Apnea hypopnea index*

378.4 ± 35.0 89.5 ± 2.8 3.0 ± 0.7 61.6 ± 40.1 87.3 ± 24.0 6.3 ± 1.8 7.6 ± 1.8 25.3 ± 4.7 11.5 ± 2.4 66.7 ± 6.5 4.0 ± 2.1 17.9 ± 3.3 15.0 ± 7.6 33.3 0.7 ± 0.3 (6) 0.8 ± 0.4 (6)

353.1 ± 24.3 75.0 ± 3.2 3.6 ± 0.4 18.1 ± 3.6 122.2 ± 27.4 7.5 ± 1.1 9.9 ± 1.7 36.4 ± 3.8 10.8 ± 2.0 65.3 ± 3.1 6.1 ± 1.8 17.8 ± 2.1 5.4 ± 2.4 9.1 1.5 ± 0.7 (9) 2.4 ± 1.0 (9)

0.57 0.004 0.44 0.72 0.36 0.57 0.38 0.09 0.82 0.85 0.45 1.00 0.24 0.37 0.15

*Applied square root for normalization, **applied logarithm for normalization. Mean ± SEM is presented. Two-sample t-tests were used to compare groups. Bold=significant difference at p value listed. For the PLMS index and apnea index in sleep variables section, the ( ) stands for the number of analyzed subjects.

Table 4.3 Demographics and sleep variables of CWP subjects separated by regular use of muscle relaxants Variables

CWP with muscle relaxant

CWP without muscle relaxant

p-value group effect

I. Demographics Sex distribution Age

3F; 3M 58.7 ± 2.6

5F; 6M 52.6 ± 3.3

1.00 0.17

II. Sleep variables Sleep duration [min] Sleep efficiency [%] Sleep cycle* Sleep latency [min]** REM latency [min]* Awakenings/h Micro-arousals/h Sleep stage shifts/h Stage 1 [%] Stage 2 [%] Stages 3 and 4 [%] REM [%] PLMS index** % Subject index > 15 [%] Apnea index* Apnea hypopnea index*

341.7 ± 34.4 76.0 ± 4.6 2.7 ± 0.3 17.8 ± 3.4 145.8 ± 47.8 6.6 ± 1.2 8.4 ± 2.4 33.6 ± 7.6 8.0 ± 2.1 70.7 ± 4.9 6.7 ± 2.9 14.7 ± 1.9 16.7 ± 7.7 33.3 1.3 ± 1.0 (6) 1.5 ± 1.1 (6)

373.2 ± 24.3 82.4 ± 3.6 3.8 ± 0.4 42.0 ± 22.3 90.4 ± 14.7 7.4 ± 1.3 9.5 ± 1.5 31.8 ± 3.0 12.7 ± 1.9 63.1 ± 3.6 4.6 ± 1.4 19.6 ± 2.3 4.4 ± 1.8 9.1 1.1 ± 0.5 (9) 1.9 ± 0.8 (9)

0.47 0.30 0.09 0.86 0.32 0.65 0.70 0.83 0.12 0.24 0.54 0.12 0.13 0.91 0.62

*Applied square root for normalization, **applied logarithm for normalization. Mean ± SEM is presented. Two-sample t-tests were used to compare groups. Bold = significant difference at p value listed. For the PLMS index and apnea index in sleep variables section the ( ) stands for the number of analyzed subjects.

3. Results The list of medications used by various groups is reported in Table 1. In the CWP group, 6 patients out of 17 were taking aspirin, acetaminophen or a non-steroidal anti-inflammatory (NSAI) analgesic on a regular basis; 2 were taking acetaminophen, 2 aspirin, 1 cele-

coxib and 1 naproxen. All patients were asked to avoid opioids one week before the sleep recording; only 2 of the 17 CWP reported using opioids on an irregular basis when the pain was too intense. Among CWP patients, 6/17 were taking antidepressive medications on a regular basis; 2 amitriptyline and 4 one of the following: paroxetine, sertraline, bupropion and venlafax-

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ine. Two patients with CWP were regularly taking cyclobenzaprine and 4 were regularly taking clonazepam as a muscle relaxant. Sleep duration was shorter for all study groups in comparison to normal subjects, although only significantly shorter in the CWP group ( 71 min or 10.9%; p = 0.01; see Table 2). Sleep efficiency was also lower for all groups in comparison to normal subjects, although only significantly lower for insomniac and CWP patients ( 10.1%; p < 0.05 and 11.1%; p = 0.01, respectively; see Table 2). The number of non-REM to REM sleep cycles was lower in RLS/ PLMS and CWP groups in comparison to both normal and insomniac groups (3.4 cycles instead of 4.4 cycles; p = 0.04, see Table 2). As expected, the PLMS index was much more elevated in the PLMS group in comparison to normal subjects (33.4/h of sleep and 2.0/h of sleep, respectively; p < 0.001) and to all other groups (p < 0.001, see Table 2). The CWP group showed a moderate value of PLM index compared to normal subjects and insomnia patients (8.8/h vs. 2.0 and 1.7/h, respectively). In the CWP group, 9 of the 17 subjects had a PLMS index over 5/h of sleep (mean of 15.7 PLM/h of sleep; range = 5.8–50 events/h of sleep; see Table 3). The sub-analysis comparing the 9 CWP with an elevated PLM index to the 10 without PLMS revealed that patients with PLMS were older (59.2 yo vs. 49.8 yo, respectively; p < 0.04) and that none of the other sleep variables were statistically different (e.g., sleep duration was 368.5 min and 354.8 min, respectively, and sleep efficiency 79.2% and 81.2%, respectively; see Table 3). Other sleep variables (sleep latency, awakenings/h, micro-arousals/h, sleep stage shift/h) were not statistically significant between all groups (see Table 2). Furthermore, the index of sleep apnea and apnea/ hypopnea (AHI) did not differ between age- and gender-matched groups (see Table 2). Although two RLS/ PLMS subjects had an AHI of 5.2 and 7.4 and one CWP patient had an AHI of 7.6, all were well below 10 events/h of sleep. Since we observed lower sleep efficiency in CWP patients and less sleep cycles, we controlled for medication effects as seen in Tables 4.1–4.3. Regular use of an NSAI analgesic did not significantly disrupt sleep variables; a trend toward a lower percentage of sleep stages 3 and 4 was noted for the 6/17 patients with CWP taking NSAI medication on a regular basis in comparison with those not taking this type of analgesic (2.3% instead of 7%, respectively; p = 0.06, Table 4.1). Regular use of an antidepressant seemed to normalize the sleep efficiency index in CWP patients (89.5% in patients using an antidepressant vs. 75% in patient not using this medication; p = 0.004; see Table 4.2); other sleep variables were not statistically different, although a trend toward fewer sleep stage shifts was noted in CWP patients on antidepressant medication (p = 0.09). Regular use of a

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muscle relaxant did not reveal any significant effect on the sleep of CWP patients and only a trend was noted towards a reduction in the number of non-REM to REM sleep cycles for patients using a muscle relaxant (from 3.8 to 2.7 cycles for patients without and with medication, respectively; p = 0.09 as seen in Table 4.3). 4. Discussion Sleep duration was significantly shorter in musculoskeletal CWP patients in comparison to normal subjects matched for age (means in mid-50s) and gender; similarly, sleep efficiency was lower in both CWP and insomnia in patients. CWP patients also presented a mild to moderate index of limb movements during sleep, and both CWP and PLMS patients lost one non-REM to REM sleep cycle. Interestingly, regular use of a non-narcotic analgesic, such as NSAI, does not seem to interfere with the sleep of chronic pain patients. There is a certain amount of controversy in the literature regarding the reduction in total sleep time and efficiency in chronic pain patients. Several polygraphic studies have reported that sleep duration and/or efficiency does not differ between control subjects and fibromyalgia, osteoarthritis or rheumatoid arthritis patient groups [34–41]. Interestingly, the value of sleep duration and efficiency reported in those studies was close to our findings and it is important to note that most pain patients in the above studies were younger (30–45 yo range) than in the present report. Moreover, the sleep duration and efficiency values observed in our study are comparable to those of older patients with rheumatoid arthritis, aged in their 60s [42]. The sleep duration of patients in their mid-40s with unidentified chronic pain was also noted to be similar to that of insomnia patients without psychiatric disorders (364.7 and 400 min, respectively) but sleep efficiency was significantly lower in pain patients (74.6% and 89.5%, respectively) [43]. Similarly, pain patients with fibromyalgia and migraines, carpal tunnel syndrome and reflex sympathetic dystrophy presented a lower sleep duration and efficiency than matched medical (e.g., hypertension, chronic obstructive pulmonary disease) patients without pain (362.6 min vs. 431.7 min and 76.8% vs. 90.4%, respectively) [26]. Age is probably an important factor that needs to be evaluated in pain patients complaining of poor sleep quality. Differences between groups may also be explained by lower sleep quality, higher pain intensity and/or dysfunctional pain perception, as suggested by a study based on a questionnaire to assess sleep quality [11,44]. In a population with dominant musculoskeletal pain it was observed, using polygraphy in the sleep laboratory, that good sleepers had 92.4 more minutes of sleep (417 min in good sleepers vs. 324.6 min in poor sleepers; p < 0.001) [12]. Pain intensity may partly

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explain such differences since low back pain patients with low pain intensity reported 49.8 more minutes of sleep than high pain intensity patients (379.8 min vs. 330 min, respectively; p < 0.05) [6]. Similar to our own findings, Drewes and colleagues found that the PLM index during sleep of patients in their mid-50s suffering from rheumatoid arthritis was more than two times higher (10.8 h vs. 4.1 h sleep) in comparison with controls [41]. The presence of PLM in pain patients was also noted in younger and older patients with low back pain and rheumatoid arthritis [6,42]. The mechanism by which PLM during sleep may influence sleep duration and efficiency remains to be investigated since in the rheumatoid population no difference was noted with an age-matched control group [41]. We also noted that both PLMS and CWP patients presented less non-REM to REM cycles in comparison with controls matched for age and gender, which may suggest that both conditions contribute to deregulation in the homeostatic wake and sleep process [45,46]. However, since over 40% of somatoform pain disorder patients also complain of RLS-related symptoms, the assessment of RLS symptoms using a valid, recent questionnaire and actigraphic or polygraphic measurements of PLM frequency during sleep may be indicated for a better understanding of the interaction between RLS/ PLMS, pain and poor sleep quality [22,27,28,47]. As seen in Table 3, age is an important variable that needs to be taken into consideration in sleep studies examining the influence of PLM in CWP patients. An interesting finding of this study, namely the presence of only 3.4 non-REM to REM sleep cycles instead of 4.4, as seen in normal subjects (see Table 2), may also reflect an alteration in sleep stability in CWP and PLMS patients. The distribution of the quantity of sleep cycles in normal subjects seems to follow a bell curve. Most normal subjects have four to five sleep cycles, 45% and 37%, respectively, while few have three sleep cycles (12%) [48]. These results may explain why poor sleep complaints reported by patients with pain may be correlated to a reduction in sleep consolidation. In the present study, all groups except normal subjects were taking their regular medications during the sleep recording session, as has been the case in two other studies on the interaction between sleep and pain [11,26]. Again, our intent was to present sleep variables as seen in the clinic by physicians. We found no difference in the sleep variables of pain patients taking an NSAI analgesic on a regular basis (6 of the 17 patients are taking aspirin, acetaminophen, naproxen or one COX-2, celocoxib) in comparison to those not taking an NSAI. This may be at first surprising since a polygraphic study reported that the sleep of normal young subjects taking aspirin or ibuprofen was of a lower efficiency (less 25 and 42 min, respectively) compared to subjects taking a placebo [49]. By contrast, a recent study failed to rep-

licate such observations; in fact, no difference was found in sleep efficiency, although the ibuprofen doses and subject characteristics were similar [50]. In our report, only 6/17 patients used an NSAI analgesic on a regular basis; the sample size prevents any valid further speculation on the impact of this medication on sleep. It is important to reiterate that we excluded patients taking opioids since it is widely known that such analgesics interfere with sleep variables, thereby causing a reduction in sleep stages 3 and 4 [51,52]. The effect of the other medications, such as hypnotics, may need to be assessed in future studies comparing the sleep of CWP patients with other groups. 4.1. Limitations of study The relationship between sleep and pain in chronic pain has been described as a circular interaction [8,11,53–55]; a day with intense pain influences quality of sleep and a night of poor sleep may lead to complaints of increased pain the following day. Interestingly, it was recently suggested that a night of poor sleep is followed by more variability in pain intensity reports [56]. Pain threshold and tolerance levels are also decreased by sleep deprivation, although some of the variability in pain responses can be explained by the alteration in cognitive function associated with concomitant fatigue [57–62]. Complaints of poor sleep quality are also often confounded by perceptions of unrefreshing sleep, morning fatigue and/or mood changes (e.g., anxiety, depressive thoughts) [9,12,42,53]. One of the limits of our study was the lack of direct assessment of sleep quality, depression, anxiety and fatigue, using questionnaire and pain threshold assessments employing algometry [44,63]. Fatigue remains a dominant complaint in CWP musculoskeletal patients and future studies need to assess its effect on sleep quality [6,17,42,53,64]. Another limitation of the present study is the absence of analysis of sleep laboratory EEG and heart rate variables. Since respiratory variables are important for assessing patients with fibromyalgia [65], we excluded patients with sleep apnea as seen in Table 2. The relevance of EEG and heart rate variability findings is reported for patients with CWP [66–68] and these data will be reported in another paper in which the pain patient population is matched for age, gender and medication use to normal sleepers [53,69]. It is important to reiterate that the debate remains open regarding the specificity of the so-called alpha EEG intrusions and their association with poor sleep in CWP patients [64,70]. Recent reports have found that less than 40% of pain patients present such EEG findings and have questioned their specificity [26,39]. More pertinent to this study is the report that sleep continuity in CP patients is disrupted by frequent sleep stage shifts,

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increased frequency of limb movement and by a high level of phasic-cyclic fluctuations in EEG activity [8,66,71,72]. Among the other EEG findings in fibromyalgia patients is an increase in K alpha activity and a reduction in the number of sleep EEG spindles, suggesting that the sleep of these patients is subject to arousal pressure and lack of consolidation influences, respectively [67,73]. One final limitation of the present study is that we only analyzed data from one night of recording (otherwise the sample size of each patient group would have been too small). We fully recognize that the first-night effect is a phenomenon that cannot be underestimated in assessing sleep variables such as sleep efficiency and duration and number of sleep cycles [74]. The significance of the variables influencing the poor sleep and pain interaction needs to be validated in a prospective sleep laboratory study carried out over more than one night to prevent the so-called first-night effect and to control for the influences of fatigue, medication use on regular basis, and health-related quality of life (such as physical function) since such variables have been recently recognized as being among the most relevant outcomes among patients with CWP–fibromyalgia [17]. Acknowledgements This study was supported by the CIHR, Canada and FRSQ, Que´bec. K Okura was a visiting professor from The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima, Japan. He was also supported by CIHR Pain M2C training grant and by the Louise Edward Foundation, McGill University Pain Research Center. We also thank Pierre H. Rompre´, Francine Guitard, Christiane Manzini, Sylvie Rompre´ and Re´gis Schwab for their assistance in the study.

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