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Relationship between insomnia and pain in major depressive disorder: A sleep diary and actigraphy study
Sleep Medicine 11 (2010) 752–758
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Original Article
Relationship between insomnia and pain in major depressive disorder: A sleep diary and actigraphy study Ka-Fai Chung *, Kwok-Chu Tso Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
a r t i c l e
i n f o
Article history: Received 26 May 2009 Received in revised form 9 September 2009 Accepted 29 September 2009 Available online 4 February 2010 Keywords: Depression Insomnia Sleep Pain Actigraphy Major depressive disorder
a b s t r a c t Objectives: Insomnia and pain are frequent complaints during the course of a major depressive episode. We analyzed the association between insomnia and pain symptoms using subjective and objective sleep measures. Methods: This is a prospective, naturalistic follow-up study in a university-based psychiatric unit. Ninetyone Chinese patients were enrolled during an acute episode of major depressive disorder (mean age = 48 years, 73 women); 82 of them were reassessed 3 months later using the same assessment on sleep, pain, depressive, and anxiety symptoms. Clinician-rated insomnia symptoms were obtained using the insomnia items of the Hamilton Rating Scale for Depression. Subjective sleep disturbances were assessed using the Insomnia Severity Index (ISI). Detailed sleep pattern was acquired using sleep diary and actigraphy. Pain intensity was evaluated using a verbal rating scale, a visual analog scale, and a multidimensional pain scale. Results: Cross-sectional analyses found that insomnia symptoms and quantitative sleep parameters were related to pain symptoms. The correlations between sleep and pain scores were more significant after 3 months of pharmacotherapy as compared to baseline. After controlling for the severity of anxiety and depression, the ISI total score and actigraphy-derived wake after sleep onset and total sleep time remained significant in predicting pain. Conclusion: This study supports specific role of subjective sleep disturbances and actigraphic measures in predicting pain symptoms in major depressive disorder. Further studies using a micro-longitudinal design are necessary to find out the causal relationship between sleep and pain in depressed patients. Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction Insomnia is a common and key depressive symptom that affects both the course and treatment response for major depressive disorder (MDD). Patients with sleep disturbances have demonstrated significantly worse outcome and more frequent relapses [1]. Recently, there has been a growing interest in the role of sleep on pain processing. Experimental studies have shown that total or partial sleep deprivation enhances pain sensitivity and is associated with pain complaints [2,3]. Epidemiological studies have found a strong correlation between insomnia and chronic pain [4,5]. Results from clinical studies suggest that the relationship between sleep disturbances and pain is likely to be bi-directional [6,7]. Pain symptoms are also frequent complaints in patients with depression. A recent review reported an average 65% co-occur* Corresponding author. Address: Department of Psychiatry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China. Tel.: +852 28554487; fax: +852 28551345. E-mail address: [email protected] (K.-F. Chung). 1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.09.005
rence rate for pain and depression [8]. In a survey of 909 Asian patients treated for an acute episode of MDD, the most common pain complaint was headaches, followed by muscle soreness, neck pain, lower back pain, chest pain, joint pain, and abdominal pain; roughly 45% of patients reported being bothered by headaches ‘‘moderately,” ‘‘quite a bit,” or ‘‘a great deal” over the previous week [9]. The severity of pain complaints in MDD was found to predict a longer time to remission, greater functional impairment, poorer clinical outcome, and higher associated health care costs [10]. A few studies have attempted to find predictors of pain complaints in patients with major depression. Female, younger, and less educated patients were more likely to report pain complaints [9,11,12]. In addition, those with pain complaints were relatively more depressed and anxious and had more medical comorbidity [9,11,12]. While exact mechanisms have not been clarified, there are likely complicated pathways linking sleep disturbances, negative emotion, and pain [8,13]. To date, studies exploring the relative contributions of sleep and depression to pain complaints are scarce. A population based study found that sleep disturbances and depression were independently associated with a low pain
K.-F. Chung, K.-C. Tso / Sleep Medicine 11 (2010) 752–758
threshold [14]. Husain et al., however, showed that the presence of insomnia symptoms was not related to pain complaints during an acute depressive episode when adjusted for sex and severity of depression and general physical health [12]. While the effect of insomnia on pain perception may be over-shadowed by the pervasive low mood associated with a major depressive episode, there had been no study looking at the relationship between sleep and pain after an acute depressive episode. As a local extension of a multi-center study of Asian patients with acute MDD [9], we systematically collected both subjective and objective measures of sleep in order to determine the relative contributions of sleep disturbances, depression, and anxiety to pain complaints during the course of a major depressive episode. We included anxiety as a potential predictor of pain in MDD because recent epidemiological studies found that anxiety disorder had a strong association with chronic pain. The magnitude of the association between anxiety disorder and pain was similar to that of MDD and pain [15,16]. We hypothesize that sleep disturbances are independently associated with pain symptoms in MDD. 2. Methods 2.1. Design This is a multi-center, prospective, non-interventional, observational study of Asian patients with acute MDD [9]. The Hong Kong study was conducted at the Department of Psychiatry of Queen Mary Hospital, a regional teaching hospital. We systematically collected sleep, anxiety, depression, and pain data twice over a 3month period. Baseline assessment was conducted after written informed consent was obtained from the participants. All procedures used in the present study were reviewed and approved by the local Institutional Review Board.
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exact test). The subjects who did not complete the second assessment, however, had significantly longer wake after sleep onset (WASO), lower sleep efficiency (SE) and poorer sleep quality (SQ) by sleep diary, together with longer sleep-onset latency (SOL) by actigraphy at baseline than those who completed the second assessment.
2.3. Measures 2.3.1. Sleep data Clinician-rated insomnia severity was obtained by averaging the three insomnia items of the 17-item Hamilton Rating Scale for Depression (HRSD17) [18]. Self-reported insomnia symptoms and the associated functional impairment were assessed using the 7-item Insomnia Severity Index (ISI) [19]. Higher scores indicated more severe insomnia symptoms and greater distress and impairment. Detailed sleep pattern was obtained using a sleep diary and actigraphy. The subjects were asked to complete a one-week sleep diary at baseline and at 3 months. The diary inquired about bedtime and rising time, from which total time in bed (TIB) was calculated. Subjects were also advised to estimate their SOL, WASO, and TST and rate their SQ using a 4-point scale (‘‘very bad,” ‘‘fairly bad,” ‘‘fairly good,” and ‘‘very good”) [20]. SE was calculated as (TST/ TIB 100%). Actigraphs are watch-like devices that record physical movement by means of an accelerometer-microprocessor link. In this study, actigraphs (Octagonal Basic Motionlogger, Ambulatory Monitoring, Inc. Ardsley, NY) were worn 24 h per day on the non-dominant wrist for 3 days at the baseline and at 3-month assessments. The subjects were asked to press the actigraphy event marker to indicate ‘‘lights out.” We used Zero-Crossing Mode for quantification of wrist movement and ACTION-W 2.0 software to estimate SOL, WASO, TST, and SE using one-minute epoch.
2.2. Subjects Those considered eligible for study entry were either outpatients or inpatients of Chinese ethnicity, aged from 18 to 65 years, with a Diagnostic and Statistical Manual of Mental DisordersFourth Edition (Text Revision) (DSM-IV-TR) diagnosis of a new or first episode of MDD and were prepared to take antidepressant medication. Additional inclusion criteria were as follows: at least moderate on the Clinical Global Impression scale (CGI) for illness severity [17], at least 2 months free of depressive symptoms prior to the onset of the current episode, and able to give informed consent. The diagnosis of MDD was based on clinical interview and supplementary information from appropriate informants. Subjects were excluded if they (1) had any previous or current diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, dementia, or other mental deficiencies; (2) were experiencing a painful condition due to infectious or inflammatory disease, trauma, fracture, cancer, or any identifiable physical illness; or (3) had ongoing substance abuse or dependence. A total of 91 patients were enrolled at the beginning of the study. Treatment was based solely on the usual practice in the provision of care to patients with MDD. Choice of antidepressant medication was naturalistic and based on the treating psychiatrist’s clinical judgment. We tried to contact all patients 3 months after their first assessment. Nine patients could not be contacted or refused a subsequent interview; hence, 82 patients were reassessed using the same set of scales and measurements. We found no significant difference in age, sex distribution, depression, and pain severity at baseline between the respondents who completed the second assessment and those who did not (all P > 0.05, unpaired t or Fisher
2.3.2. Pain measures Numerous instruments have been developed for different qualitative aspects of pain [21]. Experimental and clinical evidence suggests that pain has at least two dimensions: sensory and affective [22,23]. In this study, we used a verbal rating scale (VRS), a visual analog scale (VAS), and the sensory items of a multidimensional pain scale to assess the sensory dimension of pain. The seven pain items of the Somatic Symptom Inventory (SSI) [24] were selected as the VRS in this study. The patients were asked to indicate the severity of muscle soreness, abdominal pain, lower back pain, heart or chest pain, headaches, joint pain, and neck pain for the past week using five descriptors: ‘‘not at all,” ‘‘a little bit,” ‘‘moderately,” ‘‘quite a bit” and ‘‘a great deal.” The VRS pain score was computed as the average of the seven pain items, and the score ranged between 0 and 4. Higher scores indicated more severe pain. The VAS used in this study is a 10-cm line, with the end point 0 for ‘‘no pain” and 10 for ‘‘as severe as I can imagine.” Patients were asked to make a mark on the line that represented their severity of various pains during the past week. The types of pain assessed by the VAS were the same as the VRS pain items. The VAS pain score was computed as the average of the items. The 101-item Multidimensional Affect and Pain Survey (MAPS) has been developed as a gender and ethnoculturally unbiased questionnaire to evaluate the multidimensional aspects of pain [25]. Each of the 101 descriptors of pain was presented in a sentence to clarify its meaning. The patients rated these statements on a response scale from ‘‘not at all” (0) to ‘‘very much so” (5). We selected the somatosensory pain dimension score of the MAPS for further analysis.
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2.3.3. Depressive and anxiety symptoms The HRSD17 was used to assess the severity of depressive and anxiety symptoms [18]. Because the HAMD17 contains a relatively large number of somatic symptoms and insomnia items, we selected the depression and anxiety components of the HAMD17 for further analysis. The depression component includes five items: depressed mood, feeling of guilt, suicide, work and activities, and retardation; while the anxiety component includes agitation, anxiety psychic, anxiety somatic, and hypochondriasis [26]. Higher scores indicated more severe depression or anxiety over the past one week. The self-reported Hospital Anxiety and Depression Scale (HADS) was selected to evaluate the depressive and anxiety symptoms from the patient’s perspective [27]. The HADS depression and anxiety subscales have seven items each and total score ranged from 0 to 21. Higher scores indicated more severe depression or anxiety. All questionnaires were presented in Chinese. We used the Chinese versions of the MAPS and HADS, which are known to be reliable and valid [28,29]. The original English versions of the ISI, SSI, and VAS were translated into Chinese by a bilingual translator. The items and response choices were back-translated into English by another researcher who was blinded to the original version. The back-translation was compared with the original English version and modified until consensus between the investigators was achieved. 2.4. Data analysis All statistical analyses were performed using SPSS 16.0 for Windows. The subjects’ pain, sleep, anxiety and depression scores at baseline were compared with those obtained at 3 months using the paired t-test. The proportion of subjects using anxiolytics, hypnotics analgesics, and different types of antidepressants at baseline and 3 months was compared using the McNemar’s test and the sign test, respectively. Pearson correlation was used to examine the relationship between pain and sleep scores at baseline and at 3-month follow-up and between pain scores and subject variables. Comparison of pain and sleep scores between patients using different types of antidepressants was analyzed using oneway analysis of variance (ANOVA). Stepwise multiple linear regression was used to examine the relationship between pain scores at baseline, pain scores at 3 months and changes in pain score with potential predictors. The potential predictors for baseline pain score were subjects’ demographic, clinical, and baseline sleep, anxiety and depression variables; for pain score at 3-month follow-up, the predictors included demographic, clinical, sleep, anxiety, and depression variables at baseline and at 3 months. The potential predictors for changes in pain score were demographic, clinical, baseline pain, sleep, anxiety and depression variables and changes in severity of sleep, anxiety and depression from baseline to 3-month follow-up. To be included in the linear regression, subject variables had to show a significant bivariate association with pain scores. The potential predictor that had the most significant bivariate association with pain scores was first entered into the regression analyses. The change score in pain, sleep, anxiety and depression was computed as the difference between values at baseline and at 3month follow-up; a positive change score represents an improvement in sleep or a reduction in pain, anxiety and depressive symptoms. 3. Results Table 1 presents the demographic and clinical features of the subjects. Participants had a mean age of 48.3 years and a majority
Table 1 Demographic and clinical features of sample. Variables
Total sample (n = 91) n (%)
Age (years) Female gender Marital status Married/cohabiting Single Divorced/widowed Occupation Managers, administrators, and professionals Associate professionals, clerks and service workers Manual workers Retired Students Unemployed/homemakers Living alone Family monthly income HK$ 5000 or below Number of chronic medical conditions Age of onset of depression, yrs Number of previous depressive episode 0 1 2 3 or above Duration of current depressive episode, wks 2–4 5–8 9 or above
Mean (SD, range) 48.3 (9.5, 20–62)
73 (80.2) 44 (48.4) 23 (25.3) 24 (26.4) 4 (4.4) 13 (14.3) 23 (25.3) 5 (5.5) 1 (1.1) 45 (49.5) 12 (13.2) 36 (39.6) 0.5 (0.8, 0–4) 44.8 (9.7, 18–61) 0.9 (1.0, 0–5) 35 (38.5) 37 (40.7) 13 (14.3) 6 (6.6) 7.1 (4.5, 2–24) 35 (38.5) 36 (39.6) 20 (22.0)
of the subjects were female (80.2%). Most patients (61.5%) had experienced at least one previous episode of MDD. Table 2 presents the types of medication prescribed to the subjects and changes in symptomatology from baseline to 3-month follow-up. About 50% of the subjects were given selective serotonin reuptake inhibitors alone. Concomitant use of more than one antidepressant occurred in 30% of the sample. Around 60% of the subjects were taking hypnotics, and roughly 15% needed analgesics. The proportions of subjects using hypnotics and analgesics at baseline were similar to the extent of use at 3 months (Table 2). The subjects’ pain, anxiety and depression scores at 3 months were significantly lower than those at baseline. Self-reported insomnia symptoms, as measured by the ISI, and most sleep-diary parameters also had significant improvement over the 3-month period; however, no significant changes were observed in any actigraphic measures (Table 2). There was significant correlation between the subjects’ pain scores at baseline and those obtained at 3 months. The Pearson r between baseline and 3-month VRS pain scores, VAS pain scores, and MAPS somatosensory scores was 0.68, 0.76 and 0.62, respectively (all P < 0.01). The correlations between sleep variables at baseline and 3-month follow-up were mostly significant. The Pearson r was 0.43 for the ISI, 0.04–0.67 for sleep-diary parameters and 0.27–0.57 for actigraphy measures. All correlations were statistically significant, except the association between baseline and 3month sleep-diary-derived SQ (Pearson r = 0.04). Table 3 presents the results of correlational analysis between pain scores and subject variables. At baseline, pain scores had small correlations with the ISI total score (Pearson r = 0.24–0.30), sleep-diary-derived SOL, WASO, SE and SQ (Pearson r = 0.21– 0.27), and SOL by actigraphy (Pearson r = 0.22–0.26). After 3 months’ antidepressant treatment, there were higher correlations between pain scores and the ISI total score (Pearson r = 0.49–0.53), while the associations between pain scores, sleep diary data, and actigraphy measures were similar to those obtained at baseline.
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K.-F. Chung, K.-C. Tso / Sleep Medicine 11 (2010) 752–758 Table 2 Pain, sleep, anxiety and depression symptomatology (mean ± SD) and treatment received (N, %) at baseline (N = 91) and 3-month follow-up (N = 82). Baseline
3-month follow-up
Paired t-value
P value
VRS pain VAS pain MAPS somatosensory HADS anxiety HADS-depression HRSD17-total ISI total
2.6 ± 1.1 3.3 ± 2.4 1.9 ± 1.1 11.8 ± 4.3 11.6 ± 4.5 24.3 ± 4.8 18.0 ± 6.1
2.3 ± 1.0 2.8 ± 2.3 1.4 ± 1.1 8.1 ± 5.1 8.3 ± 5.5 10.6 ± 6.5 12.8 ± 7.7
2.77 2.27 4.01 6.53 5.91 16.46 6.17
<0.01 0.03 <0.01 <0.01 <0.01 <0.01 <0.01
Sleep-diary parametersa SOL (min) TST (min) WASO (min) SE (%) Sleep quality
(N = 85) 72.3 ± 65.6 320.6 ± 87.7 52.3 ± 63.1 66.8 ± 20.0 2.2 ± 0.8
(N = 79) 44.6 ± 45.3 378.9 ± 95.9 36.4 ± 48.2 78.2 ± 17.8 2.7 ± 0.7
3.58 4.75 1.65 4.21 4.17
<0.01 <0.01 0.10 <0.01 <0.01
Actigraphy measuresa SOL (min) TST (min) WASO (min) SE (%)
(N = 74) 28.1 ± 24.2 420.9 ± 79.3 38.3 ± 40.4 85.7 ± 12.7
(N = 68) 30.5 ± 36.3 414.8 ± 96.1 35.2 ± 31.3 85.8 ± 11.4
0.68 0.70 1.19 0.08
0.50 0.49 0.24 0.93
Antidepressantsb Selective serotonin reuptake inhibitors Serotonin and noradrenalin reuptake inhibitors Tricyclic antidepressants and others Combination
47 (51.6) 5 (5.5) 11 (12.1) 26 (28.6)
38 (46.3) 6 (7.3) 9 (11.0) 26 (31.7)
18 (19.8) 2 (2.2)
16 (19.5) 3 (3.7)
52 (57.1) 5 (5.5)
41 (50.0) 8 (9.8)
Antipsychotics, lithium and anticonvulsantsb
6 (6.6)
11 (13.4)
0.06
Analgesicsb
15 (16.5)
12 (14.6)
1.00
Anxiolyticsb Benzodiazepines Buspirone Hypnoticsb Benzodiazepine receptor agonists Anti-histamine
0.63
1.00
0.42
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; SE, sleep efficiency; SOL, sleep-onset latency; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. a Difference from total n reflects omission of sleep diary and actigraph assessment in some participants. b Comparing the proportion of subjects using different types of antidepressant by sign test and the proportion of subjects with and without anxiolytic, hypnotic, antipsychotic and mood stabilizer, and analgesic by McNemar’s test.
The use of anxiolytic was unrelated to the severity of pain at baseline and 3-month follow-up (Pearson r = 0.10–0.21, all P > 0.05). There were significant correlations, however, between the use of analgesic and the subjects’ pain scores at baseline and at 3 months and between hypnotics use and the VRS pain score at 3 months (Table 3). One-way ANOVA showed that there was no significant difference between subjects using selective serotonin reuptake inhibitors alone, serotonin and noradrenalin reuptake inhibitors, tricyclic antidepressants and other antidepressants alone, and combination antidepressant therapies in pain and sleep scores at baseline and 3-month follow-up (all P > 0.05). Table 4 shows the results of multiple regressions predicting pain scores at baseline and at 3-month follow-up from subject variables. At baseline, the major predictors for pain scores were the HADS anxiety score and the use of analgesic. The subjects’ ISI total score contributed a small amount of variance in the baseline VAS pain score. Nevertheless, the ISI total score at 3 months was the most significant predictor of the patients’ VRS pain score at 3 months; it was also associated with the 3-month VAS pain score and MAPS somatosensory score. Additionally, actigraphy-derived TST was independently associated with the MAPS somatosensory score at 3 months. The two most significant predictors for changes in pain score from baseline to 3-month follow-up were baseline pain score and anxiety change scores (Table 4). Actigraphic sleep parameters contributed a small amount of variance in changes in pain score. We found that higher baseline WASO by actigraphy was associated with less reduction in pain by VAS from baseline to 3-month follow-up, while increase in actigraphy-derived TST over the 3-month
period was predictive of greater reduction in MAPS somatosensory score. 4. Discussion To our knowledge, this is the first study using sleep diary and actigraphy to examine the relationship between sleep and pain in MDD. The findings support our hypothesis that sleep disturbances are independently associated with pain symptoms in MDD. We found that insomnia symptoms and quantitative sleep parameters correlated to a significant extent with pain scores in patients with an acute episode of MDD and after 3 months of pharmacotherapy for depression. After controlling for anxiety and depression, sleep variables remained associated with pain symptoms and were predictive of the magnitude of pain reduction over the 3-month period. We found that the correlations between sleep disturbances and pain scores were more significant at 3 months as compared to baseline. It is possible that the effects of sleep on pain perception are over-shadowed by the prominent depressive and anxiety symptoms of an acute depressive episode. When the acute symptoms reduce in severity, the impact of insomnia begins to emerge. Previous studies have shown that persistent insomnia in subjects with MDD is associated with poor quality of life, early relapse, and suicidality [30]. Our findings complement the current literature on the significance of insomnia in the course of MDD. Subjective sleep disturbances and actigraphy-derived sleep measures were independently associated with pain symptoms; however, clinician-rated insomnia and sleep-diary parameters
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Table 3 Pearson correlations between demographic, clinical, depression and sleep variables and pain scores at baseline (N = 91) and 3 months (N = 82). Baseline pain scores VRS Age (years) Gender (0 = female, 1 = male) Education (0 = primary or below, 1 = secondary or above) Marital status (0 = single/divorced/widowed, 1 = married/cohabiting) Occupation (0 = unemployed/homemakers/retired/students, 1 = employed) Family income (0 = below HK$ 5000 per month, 1 = others) Living alone (0 = no, 1 = yes) Number of chronic medical conditions Age of onset of depression (years) Number of previous depressive episodes Duration of current depressive episode (weeks) On hypnotics (0 = no, 1 = yes) On analgesics (0 = no, 1 = yes) HADS-depression HADS anxiety HRSD17-depression HRSD17-anxiety HRSD17-insomnia ISI total
VAS
0.01 0.15 0.18 0.09 0.16 0.02 0.16 0.05 0.07 0.29** 0.05 0.05 0.33** 0.28** 0.44** 0.07 0.37** 0.21* 0.24*
3-month follow-up pain scores MAPS
0.01 0.12 0.16 0.03 0.19 0.06 0.18 0.10 0.05 0.31** 0.02 0.005 0.37** 0.24* 0.32** 0.05 0.23* 0.14 0.30**
0.20 0.11 0.12 0.20 0.08 0.11 0.13 0.16 0.23* 0.31** 0.02 0.13 0.40** 0.32** 0.38** 0.15 0.29** 0.17 0.28**
VRS 0.04 0.07 0.11 0.05 0.11 0.03 0.09 0.05 0.05 0.08 0.03 0.23* 0.25* 0.40** 0.54** 0.40** 0.46** 0.46** 0.53**
VAS
MAPS
0.05 0.18 0.16 0.10 0.18 0.07 0.07 0.06 0.10 0.15 0.11 0.20 0.38** 0.41** 0.53** 0.38** 0.54** 0.45** 0.49**
0.11 0.01 0.10 0.10 0.13 0.08 0.08 0.04 0.16 0.07 0.04 0.04 0.36** 0.49** 0.56** 0.45** 0.52** 0.43** 0.51**
Sleep-diary parametersa SOL (min) TST (min) WASO (min) SE (%) Sleep quality (0 = very bad, 3 = very good)
(N = 85) 0.23* 0.18 0.16 0.18 0.23*
0.26* 0.20 0.26* 0.22* 0.21*
0.21 0.13 0.18 0.18 0.27*
(N = 79) 0.22* 0.21 0.18 0.21 0.21
0.15 0.14 0.23* 0.20 0.20
0.30** 0.18 0.16 0.23* 0.33**
Actigraphy measuresa SOL (min) TST (min) WASO (min) SE (%)
(N = 74) 0.26* 0.18 0.02 0.17
0.22 0.13 0.09 0.06
0.22 0.15 0.03 0.10
(N = 68) 0.20 0.25* 0.14 0.20
0.07 0.08 0.16 0.08
0.27* 0.31** 0.25* 0.30*
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; SE, sleep efficiency; SOL, sleep-onset latency; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. a Difference from total n reflects omission of sleep diary and actigraph assessment in some participants. * P < 0.05. ** P < 0.01.
were not significant predictors of the severity of pain and changes in pain severity. Our results seem to suggest that the distress associated with insomnia as captured by the ISI is more important in determining pain symptoms in MDD than insomnia symptoms alone and sleep-diary parameters. The finding that actigraphy measures are independent predictors of pain is intriguing. Although actigraphy only measures movement but not physiologic sleep, previous studies have found superior approximation to polysomnography of actigraphy over sleep diary in people with insomnia [31,32]. We showed that actigraphy measures were more predictive of pain in MDD when compared to sleep-diary parameters. Actigraphy-derived WASO and TST were independently associated with the severity of pain and the degree of pain reduction from baseline to 3 months. Longer WASO at baseline and less of an increase in TST over the 3-month period were predictive of less pain reduction. We observed that sleep variables at baseline were significantly associated with those obtained at 3 months. It was possible that patients with severe sleep disruption and short sleep duration during an acute episode of MDD continued to have a significant sleep problem after 3 months of pharmacotherapy. The subjects’ persistent sleep problem was associated with less pain reduction. The results are consistent with a recent study showing that sleep deprivation in patients with MDD can induce pain symptoms [3]. It is important to note that the correlation analyses of this study restrict our ability to make causal inferences on the relationship between sleep and pain symptoms. For example, pain symptoms may result in short sleep duration rather than reduced sleep time causing pain. Current literature tends to support a bi-directional
relationship between sleep and pain [6,7]. Moreover, insomnia and pain share common pathogenic mechanisms. Several neurotransmitters, neurohormones, and neuroimmunologic factors— such as serotonin, opioids, the hypothalamic–pituitary–adrenal axis, and the autonomic sympatho-adrenal system—have possible roles in both sleep and pain [2,13]. Cognitive-behavioral factors that are common to both insomnia and pain include heightened attention, catastrophizing, muscle tension, and activity avoidance [33,34]. Further studies using a micro-longitudinal design to examine the within-person and day-to-day changes in sleep and pain in MDD are warranted. Anxiety symptoms are common among patients with MDD [35]. We found that the severity of anxiety was associated with pain symptoms in depressed patients; however, depressive features did not play a significant role. Previous studies have shown that a high level of anxiety in depressive disorder is associated with greater severity of illness and functional impairment, chronicity, delayed response to treatment, and an increased risk of suicidality [36–38]. Although many studies have focused on the impact of depressive symptoms on pain in MDD, our findings suggest that when insomnia, anxiety and depression are considered together, depressive symptoms play a less important role in pain perception in MDD. There are certain limitations that should be considered while interpreting our findings. Our sample only included moderately depressed patients in a specialty mental health setting. It is possible that subjects with mild depression and depressed patients in non-specialized centers may have different relationships between sleep and pain symptoms; hence, our findings could not be
K.-F. Chung, K.-C. Tso / Sleep Medicine 11 (2010) 752–758 Table 4 Stepwise multiple regressions predicting pain scores at baseline and 3-month followup and changes in pain scores from demographic, clinical, sleep, anxiety and depressive features. Unstandardized regression coefficients (SEs) Pain scores at baseline Baseline VRS score (R2 = 36.2%) Baseline HADS anxiety (22.6%) On analgesic at baseline (7.7%) Number of previous depression (5.9%)
0.10 (0.03)** 0.73 (0.29)* 0.29 (0.12)*
Baseline VAS score (R2 = 37.9%) Baseline HADS anxiety (17.8%) On analgesic at baseline (10.8%) Baseline ISI total (4.4%) Number of previous depression (4.9%)
0.15 1.91 0.10 0.56
Baseline MAPS score (R2 = 43.7%) Baseline HADS anxiety (22.1%) On analgesic at baseline (10.1%) Age of onset of depression (7.6%) Number of previous depression (3.9%)
0.11 (0.02)** 0.91 (0.24)** 0.03 (0.01)* 0.23 (0.10)*
Pain scores at 3-month follow-up 3-month VRS score (R2 = 46.1%) 3-month ISI total (31.4%) On analgesic at 3 months (7.8%) 3-month HADS anxiety (6.9%) 3-month VAS score (R2 = 54.9%) 3-month HRSD17-anxiety (33.3%) On analgesic at 3 months (13.4%) 3-month ISI total (8.2%) 3-month MAPS score (R2 = 56.1%) 3-month HADS anxiety (26.6%) On analgesic at 3 months (19.2%) 3-month ISI total (6.0%) 3-month TST-actigraphy (4.3%)
(0.06)** (0.58)** (0.04)* (0.22)*
757
In conclusion, we showed that subjective sleep disturbances and actigraphy measures were significantly correlated with pain symptoms in MDD. The findings would support aggressive efforts to identify and treat sleep disturbances in patients with depression and comorbid painful conditions. A recent study found that augmenting antidepressant medication with cognitive-behavioral therapy for insomnia could alleviate both depression and insomnia [41]. Further research will also need to examine the beneficial effects of specific treatment for insomnia in patients with MDD comorbid with insomnia and pain. Conflict of interest Dr. Chung is a member of the advisory board for Eli Lilly and Takeda, and the honoraria is less than US$ 10,000 per year. Dr. Tso has no conflict of interest to declare. Both Drs. Chung and Tso have no personal financial investment to declare. References
**
0.05 (0.02) 0.70 (0.24)** 0.06 (0.02)** 0.47 (0.09)** 2.47 (0.53)** 0.10 (0.03)** 0.05 (0.03)** 1.27 (0.26)** 0.04 (0.02)** 0.002 (0.001)*
Changes in pain score from baseline to 3 months Change score for VRS (R2 = 46.0%) Baseline VRS pain score (26.2%) HADS anxiety change score (19.8%) Change score for VAS (R2 = 30.2%) Baseline VAS pain score (13.5%) HRSD17-anxiety change score (11.7%) Baseline WASO-actigraphy (5.0%)
0.29 (0.08)** 0.22 (0.07)** 0.009 (0.004)*
Change score for MAPS (R2 = 36.1%) Baseline MAPS pain score (16.9%) HADS anxiety change score (14.8%) Change in TST-actigraphy (4.4%)
0.38 (0.10)** 0.07 (0.02)** 0.002 (0.001)*
0.41 (0.06)** 0.08 (0.01)**
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. * P < 0.05. ** P < 0.01.
extrapolated to the mildly depressed patients and subjects in other settings. About 10% of the sample failed to complete the 3-month reassessment and some participants did not take part in the sleep diary and actigraphy assessment. Future studies with larger sample and wider patient population are warranted. We have pointed out that our study design could not be used to establish any causal relationship between sleep and pain symptoms. Experimental studies have shown that selective sleep-stage deprivation produces hyperalgesic changes in healthy subjects [3,39]. Since actigraphy could not examine detailed sleep architecture, the effect of different sleep stages on pain perception in MDD has not been answered and could only be addressed in future studies using polysomnography. Although a consensus report on the research assessment of insomnia recommends a minimum of 3 days of actigraphy [40], we considered that 3 days may be insufficient to include data on variations between weekday and weekend variables.
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Original Article
Relationship between insomnia and pain in major depressive disorder: A sleep diary and actigraphy study Ka-Fai Chung *, Kwok-Chu Tso Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
a r t i c l e
i n f o
Article history: Received 26 May 2009 Received in revised form 9 September 2009 Accepted 29 September 2009 Available online 4 February 2010 Keywords: Depression Insomnia Sleep Pain Actigraphy Major depressive disorder
a b s t r a c t Objectives: Insomnia and pain are frequent complaints during the course of a major depressive episode. We analyzed the association between insomnia and pain symptoms using subjective and objective sleep measures. Methods: This is a prospective, naturalistic follow-up study in a university-based psychiatric unit. Ninetyone Chinese patients were enrolled during an acute episode of major depressive disorder (mean age = 48 years, 73 women); 82 of them were reassessed 3 months later using the same assessment on sleep, pain, depressive, and anxiety symptoms. Clinician-rated insomnia symptoms were obtained using the insomnia items of the Hamilton Rating Scale for Depression. Subjective sleep disturbances were assessed using the Insomnia Severity Index (ISI). Detailed sleep pattern was acquired using sleep diary and actigraphy. Pain intensity was evaluated using a verbal rating scale, a visual analog scale, and a multidimensional pain scale. Results: Cross-sectional analyses found that insomnia symptoms and quantitative sleep parameters were related to pain symptoms. The correlations between sleep and pain scores were more significant after 3 months of pharmacotherapy as compared to baseline. After controlling for the severity of anxiety and depression, the ISI total score and actigraphy-derived wake after sleep onset and total sleep time remained significant in predicting pain. Conclusion: This study supports specific role of subjective sleep disturbances and actigraphic measures in predicting pain symptoms in major depressive disorder. Further studies using a micro-longitudinal design are necessary to find out the causal relationship between sleep and pain in depressed patients. Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction Insomnia is a common and key depressive symptom that affects both the course and treatment response for major depressive disorder (MDD). Patients with sleep disturbances have demonstrated significantly worse outcome and more frequent relapses [1]. Recently, there has been a growing interest in the role of sleep on pain processing. Experimental studies have shown that total or partial sleep deprivation enhances pain sensitivity and is associated with pain complaints [2,3]. Epidemiological studies have found a strong correlation between insomnia and chronic pain [4,5]. Results from clinical studies suggest that the relationship between sleep disturbances and pain is likely to be bi-directional [6,7]. Pain symptoms are also frequent complaints in patients with depression. A recent review reported an average 65% co-occur* Corresponding author. Address: Department of Psychiatry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China. Tel.: +852 28554487; fax: +852 28551345. E-mail address: [email protected] (K.-F. Chung). 1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.09.005
rence rate for pain and depression [8]. In a survey of 909 Asian patients treated for an acute episode of MDD, the most common pain complaint was headaches, followed by muscle soreness, neck pain, lower back pain, chest pain, joint pain, and abdominal pain; roughly 45% of patients reported being bothered by headaches ‘‘moderately,” ‘‘quite a bit,” or ‘‘a great deal” over the previous week [9]. The severity of pain complaints in MDD was found to predict a longer time to remission, greater functional impairment, poorer clinical outcome, and higher associated health care costs [10]. A few studies have attempted to find predictors of pain complaints in patients with major depression. Female, younger, and less educated patients were more likely to report pain complaints [9,11,12]. In addition, those with pain complaints were relatively more depressed and anxious and had more medical comorbidity [9,11,12]. While exact mechanisms have not been clarified, there are likely complicated pathways linking sleep disturbances, negative emotion, and pain [8,13]. To date, studies exploring the relative contributions of sleep and depression to pain complaints are scarce. A population based study found that sleep disturbances and depression were independently associated with a low pain
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threshold [14]. Husain et al., however, showed that the presence of insomnia symptoms was not related to pain complaints during an acute depressive episode when adjusted for sex and severity of depression and general physical health [12]. While the effect of insomnia on pain perception may be over-shadowed by the pervasive low mood associated with a major depressive episode, there had been no study looking at the relationship between sleep and pain after an acute depressive episode. As a local extension of a multi-center study of Asian patients with acute MDD [9], we systematically collected both subjective and objective measures of sleep in order to determine the relative contributions of sleep disturbances, depression, and anxiety to pain complaints during the course of a major depressive episode. We included anxiety as a potential predictor of pain in MDD because recent epidemiological studies found that anxiety disorder had a strong association with chronic pain. The magnitude of the association between anxiety disorder and pain was similar to that of MDD and pain [15,16]. We hypothesize that sleep disturbances are independently associated with pain symptoms in MDD. 2. Methods 2.1. Design This is a multi-center, prospective, non-interventional, observational study of Asian patients with acute MDD [9]. The Hong Kong study was conducted at the Department of Psychiatry of Queen Mary Hospital, a regional teaching hospital. We systematically collected sleep, anxiety, depression, and pain data twice over a 3month period. Baseline assessment was conducted after written informed consent was obtained from the participants. All procedures used in the present study were reviewed and approved by the local Institutional Review Board.
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exact test). The subjects who did not complete the second assessment, however, had significantly longer wake after sleep onset (WASO), lower sleep efficiency (SE) and poorer sleep quality (SQ) by sleep diary, together with longer sleep-onset latency (SOL) by actigraphy at baseline than those who completed the second assessment.
2.3. Measures 2.3.1. Sleep data Clinician-rated insomnia severity was obtained by averaging the three insomnia items of the 17-item Hamilton Rating Scale for Depression (HRSD17) [18]. Self-reported insomnia symptoms and the associated functional impairment were assessed using the 7-item Insomnia Severity Index (ISI) [19]. Higher scores indicated more severe insomnia symptoms and greater distress and impairment. Detailed sleep pattern was obtained using a sleep diary and actigraphy. The subjects were asked to complete a one-week sleep diary at baseline and at 3 months. The diary inquired about bedtime and rising time, from which total time in bed (TIB) was calculated. Subjects were also advised to estimate their SOL, WASO, and TST and rate their SQ using a 4-point scale (‘‘very bad,” ‘‘fairly bad,” ‘‘fairly good,” and ‘‘very good”) [20]. SE was calculated as (TST/ TIB 100%). Actigraphs are watch-like devices that record physical movement by means of an accelerometer-microprocessor link. In this study, actigraphs (Octagonal Basic Motionlogger, Ambulatory Monitoring, Inc. Ardsley, NY) were worn 24 h per day on the non-dominant wrist for 3 days at the baseline and at 3-month assessments. The subjects were asked to press the actigraphy event marker to indicate ‘‘lights out.” We used Zero-Crossing Mode for quantification of wrist movement and ACTION-W 2.0 software to estimate SOL, WASO, TST, and SE using one-minute epoch.
2.2. Subjects Those considered eligible for study entry were either outpatients or inpatients of Chinese ethnicity, aged from 18 to 65 years, with a Diagnostic and Statistical Manual of Mental DisordersFourth Edition (Text Revision) (DSM-IV-TR) diagnosis of a new or first episode of MDD and were prepared to take antidepressant medication. Additional inclusion criteria were as follows: at least moderate on the Clinical Global Impression scale (CGI) for illness severity [17], at least 2 months free of depressive symptoms prior to the onset of the current episode, and able to give informed consent. The diagnosis of MDD was based on clinical interview and supplementary information from appropriate informants. Subjects were excluded if they (1) had any previous or current diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, dementia, or other mental deficiencies; (2) were experiencing a painful condition due to infectious or inflammatory disease, trauma, fracture, cancer, or any identifiable physical illness; or (3) had ongoing substance abuse or dependence. A total of 91 patients were enrolled at the beginning of the study. Treatment was based solely on the usual practice in the provision of care to patients with MDD. Choice of antidepressant medication was naturalistic and based on the treating psychiatrist’s clinical judgment. We tried to contact all patients 3 months after their first assessment. Nine patients could not be contacted or refused a subsequent interview; hence, 82 patients were reassessed using the same set of scales and measurements. We found no significant difference in age, sex distribution, depression, and pain severity at baseline between the respondents who completed the second assessment and those who did not (all P > 0.05, unpaired t or Fisher
2.3.2. Pain measures Numerous instruments have been developed for different qualitative aspects of pain [21]. Experimental and clinical evidence suggests that pain has at least two dimensions: sensory and affective [22,23]. In this study, we used a verbal rating scale (VRS), a visual analog scale (VAS), and the sensory items of a multidimensional pain scale to assess the sensory dimension of pain. The seven pain items of the Somatic Symptom Inventory (SSI) [24] were selected as the VRS in this study. The patients were asked to indicate the severity of muscle soreness, abdominal pain, lower back pain, heart or chest pain, headaches, joint pain, and neck pain for the past week using five descriptors: ‘‘not at all,” ‘‘a little bit,” ‘‘moderately,” ‘‘quite a bit” and ‘‘a great deal.” The VRS pain score was computed as the average of the seven pain items, and the score ranged between 0 and 4. Higher scores indicated more severe pain. The VAS used in this study is a 10-cm line, with the end point 0 for ‘‘no pain” and 10 for ‘‘as severe as I can imagine.” Patients were asked to make a mark on the line that represented their severity of various pains during the past week. The types of pain assessed by the VAS were the same as the VRS pain items. The VAS pain score was computed as the average of the items. The 101-item Multidimensional Affect and Pain Survey (MAPS) has been developed as a gender and ethnoculturally unbiased questionnaire to evaluate the multidimensional aspects of pain [25]. Each of the 101 descriptors of pain was presented in a sentence to clarify its meaning. The patients rated these statements on a response scale from ‘‘not at all” (0) to ‘‘very much so” (5). We selected the somatosensory pain dimension score of the MAPS for further analysis.
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2.3.3. Depressive and anxiety symptoms The HRSD17 was used to assess the severity of depressive and anxiety symptoms [18]. Because the HAMD17 contains a relatively large number of somatic symptoms and insomnia items, we selected the depression and anxiety components of the HAMD17 for further analysis. The depression component includes five items: depressed mood, feeling of guilt, suicide, work and activities, and retardation; while the anxiety component includes agitation, anxiety psychic, anxiety somatic, and hypochondriasis [26]. Higher scores indicated more severe depression or anxiety over the past one week. The self-reported Hospital Anxiety and Depression Scale (HADS) was selected to evaluate the depressive and anxiety symptoms from the patient’s perspective [27]. The HADS depression and anxiety subscales have seven items each and total score ranged from 0 to 21. Higher scores indicated more severe depression or anxiety. All questionnaires were presented in Chinese. We used the Chinese versions of the MAPS and HADS, which are known to be reliable and valid [28,29]. The original English versions of the ISI, SSI, and VAS were translated into Chinese by a bilingual translator. The items and response choices were back-translated into English by another researcher who was blinded to the original version. The back-translation was compared with the original English version and modified until consensus between the investigators was achieved. 2.4. Data analysis All statistical analyses were performed using SPSS 16.0 for Windows. The subjects’ pain, sleep, anxiety and depression scores at baseline were compared with those obtained at 3 months using the paired t-test. The proportion of subjects using anxiolytics, hypnotics analgesics, and different types of antidepressants at baseline and 3 months was compared using the McNemar’s test and the sign test, respectively. Pearson correlation was used to examine the relationship between pain and sleep scores at baseline and at 3-month follow-up and between pain scores and subject variables. Comparison of pain and sleep scores between patients using different types of antidepressants was analyzed using oneway analysis of variance (ANOVA). Stepwise multiple linear regression was used to examine the relationship between pain scores at baseline, pain scores at 3 months and changes in pain score with potential predictors. The potential predictors for baseline pain score were subjects’ demographic, clinical, and baseline sleep, anxiety and depression variables; for pain score at 3-month follow-up, the predictors included demographic, clinical, sleep, anxiety, and depression variables at baseline and at 3 months. The potential predictors for changes in pain score were demographic, clinical, baseline pain, sleep, anxiety and depression variables and changes in severity of sleep, anxiety and depression from baseline to 3-month follow-up. To be included in the linear regression, subject variables had to show a significant bivariate association with pain scores. The potential predictor that had the most significant bivariate association with pain scores was first entered into the regression analyses. The change score in pain, sleep, anxiety and depression was computed as the difference between values at baseline and at 3month follow-up; a positive change score represents an improvement in sleep or a reduction in pain, anxiety and depressive symptoms. 3. Results Table 1 presents the demographic and clinical features of the subjects. Participants had a mean age of 48.3 years and a majority
Table 1 Demographic and clinical features of sample. Variables
Total sample (n = 91) n (%)
Age (years) Female gender Marital status Married/cohabiting Single Divorced/widowed Occupation Managers, administrators, and professionals Associate professionals, clerks and service workers Manual workers Retired Students Unemployed/homemakers Living alone Family monthly income HK$ 5000 or below Number of chronic medical conditions Age of onset of depression, yrs Number of previous depressive episode 0 1 2 3 or above Duration of current depressive episode, wks 2–4 5–8 9 or above
Mean (SD, range) 48.3 (9.5, 20–62)
73 (80.2) 44 (48.4) 23 (25.3) 24 (26.4) 4 (4.4) 13 (14.3) 23 (25.3) 5 (5.5) 1 (1.1) 45 (49.5) 12 (13.2) 36 (39.6) 0.5 (0.8, 0–4) 44.8 (9.7, 18–61) 0.9 (1.0, 0–5) 35 (38.5) 37 (40.7) 13 (14.3) 6 (6.6) 7.1 (4.5, 2–24) 35 (38.5) 36 (39.6) 20 (22.0)
of the subjects were female (80.2%). Most patients (61.5%) had experienced at least one previous episode of MDD. Table 2 presents the types of medication prescribed to the subjects and changes in symptomatology from baseline to 3-month follow-up. About 50% of the subjects were given selective serotonin reuptake inhibitors alone. Concomitant use of more than one antidepressant occurred in 30% of the sample. Around 60% of the subjects were taking hypnotics, and roughly 15% needed analgesics. The proportions of subjects using hypnotics and analgesics at baseline were similar to the extent of use at 3 months (Table 2). The subjects’ pain, anxiety and depression scores at 3 months were significantly lower than those at baseline. Self-reported insomnia symptoms, as measured by the ISI, and most sleep-diary parameters also had significant improvement over the 3-month period; however, no significant changes were observed in any actigraphic measures (Table 2). There was significant correlation between the subjects’ pain scores at baseline and those obtained at 3 months. The Pearson r between baseline and 3-month VRS pain scores, VAS pain scores, and MAPS somatosensory scores was 0.68, 0.76 and 0.62, respectively (all P < 0.01). The correlations between sleep variables at baseline and 3-month follow-up were mostly significant. The Pearson r was 0.43 for the ISI, 0.04–0.67 for sleep-diary parameters and 0.27–0.57 for actigraphy measures. All correlations were statistically significant, except the association between baseline and 3month sleep-diary-derived SQ (Pearson r = 0.04). Table 3 presents the results of correlational analysis between pain scores and subject variables. At baseline, pain scores had small correlations with the ISI total score (Pearson r = 0.24–0.30), sleep-diary-derived SOL, WASO, SE and SQ (Pearson r = 0.21– 0.27), and SOL by actigraphy (Pearson r = 0.22–0.26). After 3 months’ antidepressant treatment, there were higher correlations between pain scores and the ISI total score (Pearson r = 0.49–0.53), while the associations between pain scores, sleep diary data, and actigraphy measures were similar to those obtained at baseline.
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K.-F. Chung, K.-C. Tso / Sleep Medicine 11 (2010) 752–758 Table 2 Pain, sleep, anxiety and depression symptomatology (mean ± SD) and treatment received (N, %) at baseline (N = 91) and 3-month follow-up (N = 82). Baseline
3-month follow-up
Paired t-value
P value
VRS pain VAS pain MAPS somatosensory HADS anxiety HADS-depression HRSD17-total ISI total
2.6 ± 1.1 3.3 ± 2.4 1.9 ± 1.1 11.8 ± 4.3 11.6 ± 4.5 24.3 ± 4.8 18.0 ± 6.1
2.3 ± 1.0 2.8 ± 2.3 1.4 ± 1.1 8.1 ± 5.1 8.3 ± 5.5 10.6 ± 6.5 12.8 ± 7.7
2.77 2.27 4.01 6.53 5.91 16.46 6.17
<0.01 0.03 <0.01 <0.01 <0.01 <0.01 <0.01
Sleep-diary parametersa SOL (min) TST (min) WASO (min) SE (%) Sleep quality
(N = 85) 72.3 ± 65.6 320.6 ± 87.7 52.3 ± 63.1 66.8 ± 20.0 2.2 ± 0.8
(N = 79) 44.6 ± 45.3 378.9 ± 95.9 36.4 ± 48.2 78.2 ± 17.8 2.7 ± 0.7
3.58 4.75 1.65 4.21 4.17
<0.01 <0.01 0.10 <0.01 <0.01
Actigraphy measuresa SOL (min) TST (min) WASO (min) SE (%)
(N = 74) 28.1 ± 24.2 420.9 ± 79.3 38.3 ± 40.4 85.7 ± 12.7
(N = 68) 30.5 ± 36.3 414.8 ± 96.1 35.2 ± 31.3 85.8 ± 11.4
0.68 0.70 1.19 0.08
0.50 0.49 0.24 0.93
Antidepressantsb Selective serotonin reuptake inhibitors Serotonin and noradrenalin reuptake inhibitors Tricyclic antidepressants and others Combination
47 (51.6) 5 (5.5) 11 (12.1) 26 (28.6)
38 (46.3) 6 (7.3) 9 (11.0) 26 (31.7)
18 (19.8) 2 (2.2)
16 (19.5) 3 (3.7)
52 (57.1) 5 (5.5)
41 (50.0) 8 (9.8)
Antipsychotics, lithium and anticonvulsantsb
6 (6.6)
11 (13.4)
0.06
Analgesicsb
15 (16.5)
12 (14.6)
1.00
Anxiolyticsb Benzodiazepines Buspirone Hypnoticsb Benzodiazepine receptor agonists Anti-histamine
0.63
1.00
0.42
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; SE, sleep efficiency; SOL, sleep-onset latency; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. a Difference from total n reflects omission of sleep diary and actigraph assessment in some participants. b Comparing the proportion of subjects using different types of antidepressant by sign test and the proportion of subjects with and without anxiolytic, hypnotic, antipsychotic and mood stabilizer, and analgesic by McNemar’s test.
The use of anxiolytic was unrelated to the severity of pain at baseline and 3-month follow-up (Pearson r = 0.10–0.21, all P > 0.05). There were significant correlations, however, between the use of analgesic and the subjects’ pain scores at baseline and at 3 months and between hypnotics use and the VRS pain score at 3 months (Table 3). One-way ANOVA showed that there was no significant difference between subjects using selective serotonin reuptake inhibitors alone, serotonin and noradrenalin reuptake inhibitors, tricyclic antidepressants and other antidepressants alone, and combination antidepressant therapies in pain and sleep scores at baseline and 3-month follow-up (all P > 0.05). Table 4 shows the results of multiple regressions predicting pain scores at baseline and at 3-month follow-up from subject variables. At baseline, the major predictors for pain scores were the HADS anxiety score and the use of analgesic. The subjects’ ISI total score contributed a small amount of variance in the baseline VAS pain score. Nevertheless, the ISI total score at 3 months was the most significant predictor of the patients’ VRS pain score at 3 months; it was also associated with the 3-month VAS pain score and MAPS somatosensory score. Additionally, actigraphy-derived TST was independently associated with the MAPS somatosensory score at 3 months. The two most significant predictors for changes in pain score from baseline to 3-month follow-up were baseline pain score and anxiety change scores (Table 4). Actigraphic sleep parameters contributed a small amount of variance in changes in pain score. We found that higher baseline WASO by actigraphy was associated with less reduction in pain by VAS from baseline to 3-month follow-up, while increase in actigraphy-derived TST over the 3-month
period was predictive of greater reduction in MAPS somatosensory score. 4. Discussion To our knowledge, this is the first study using sleep diary and actigraphy to examine the relationship between sleep and pain in MDD. The findings support our hypothesis that sleep disturbances are independently associated with pain symptoms in MDD. We found that insomnia symptoms and quantitative sleep parameters correlated to a significant extent with pain scores in patients with an acute episode of MDD and after 3 months of pharmacotherapy for depression. After controlling for anxiety and depression, sleep variables remained associated with pain symptoms and were predictive of the magnitude of pain reduction over the 3-month period. We found that the correlations between sleep disturbances and pain scores were more significant at 3 months as compared to baseline. It is possible that the effects of sleep on pain perception are over-shadowed by the prominent depressive and anxiety symptoms of an acute depressive episode. When the acute symptoms reduce in severity, the impact of insomnia begins to emerge. Previous studies have shown that persistent insomnia in subjects with MDD is associated with poor quality of life, early relapse, and suicidality [30]. Our findings complement the current literature on the significance of insomnia in the course of MDD. Subjective sleep disturbances and actigraphy-derived sleep measures were independently associated with pain symptoms; however, clinician-rated insomnia and sleep-diary parameters
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Table 3 Pearson correlations between demographic, clinical, depression and sleep variables and pain scores at baseline (N = 91) and 3 months (N = 82). Baseline pain scores VRS Age (years) Gender (0 = female, 1 = male) Education (0 = primary or below, 1 = secondary or above) Marital status (0 = single/divorced/widowed, 1 = married/cohabiting) Occupation (0 = unemployed/homemakers/retired/students, 1 = employed) Family income (0 = below HK$ 5000 per month, 1 = others) Living alone (0 = no, 1 = yes) Number of chronic medical conditions Age of onset of depression (years) Number of previous depressive episodes Duration of current depressive episode (weeks) On hypnotics (0 = no, 1 = yes) On analgesics (0 = no, 1 = yes) HADS-depression HADS anxiety HRSD17-depression HRSD17-anxiety HRSD17-insomnia ISI total
VAS
0.01 0.15 0.18 0.09 0.16 0.02 0.16 0.05 0.07 0.29** 0.05 0.05 0.33** 0.28** 0.44** 0.07 0.37** 0.21* 0.24*
3-month follow-up pain scores MAPS
0.01 0.12 0.16 0.03 0.19 0.06 0.18 0.10 0.05 0.31** 0.02 0.005 0.37** 0.24* 0.32** 0.05 0.23* 0.14 0.30**
0.20 0.11 0.12 0.20 0.08 0.11 0.13 0.16 0.23* 0.31** 0.02 0.13 0.40** 0.32** 0.38** 0.15 0.29** 0.17 0.28**
VRS 0.04 0.07 0.11 0.05 0.11 0.03 0.09 0.05 0.05 0.08 0.03 0.23* 0.25* 0.40** 0.54** 0.40** 0.46** 0.46** 0.53**
VAS
MAPS
0.05 0.18 0.16 0.10 0.18 0.07 0.07 0.06 0.10 0.15 0.11 0.20 0.38** 0.41** 0.53** 0.38** 0.54** 0.45** 0.49**
0.11 0.01 0.10 0.10 0.13 0.08 0.08 0.04 0.16 0.07 0.04 0.04 0.36** 0.49** 0.56** 0.45** 0.52** 0.43** 0.51**
Sleep-diary parametersa SOL (min) TST (min) WASO (min) SE (%) Sleep quality (0 = very bad, 3 = very good)
(N = 85) 0.23* 0.18 0.16 0.18 0.23*
0.26* 0.20 0.26* 0.22* 0.21*
0.21 0.13 0.18 0.18 0.27*
(N = 79) 0.22* 0.21 0.18 0.21 0.21
0.15 0.14 0.23* 0.20 0.20
0.30** 0.18 0.16 0.23* 0.33**
Actigraphy measuresa SOL (min) TST (min) WASO (min) SE (%)
(N = 74) 0.26* 0.18 0.02 0.17
0.22 0.13 0.09 0.06
0.22 0.15 0.03 0.10
(N = 68) 0.20 0.25* 0.14 0.20
0.07 0.08 0.16 0.08
0.27* 0.31** 0.25* 0.30*
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; SE, sleep efficiency; SOL, sleep-onset latency; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. a Difference from total n reflects omission of sleep diary and actigraph assessment in some participants. * P < 0.05. ** P < 0.01.
were not significant predictors of the severity of pain and changes in pain severity. Our results seem to suggest that the distress associated with insomnia as captured by the ISI is more important in determining pain symptoms in MDD than insomnia symptoms alone and sleep-diary parameters. The finding that actigraphy measures are independent predictors of pain is intriguing. Although actigraphy only measures movement but not physiologic sleep, previous studies have found superior approximation to polysomnography of actigraphy over sleep diary in people with insomnia [31,32]. We showed that actigraphy measures were more predictive of pain in MDD when compared to sleep-diary parameters. Actigraphy-derived WASO and TST were independently associated with the severity of pain and the degree of pain reduction from baseline to 3 months. Longer WASO at baseline and less of an increase in TST over the 3-month period were predictive of less pain reduction. We observed that sleep variables at baseline were significantly associated with those obtained at 3 months. It was possible that patients with severe sleep disruption and short sleep duration during an acute episode of MDD continued to have a significant sleep problem after 3 months of pharmacotherapy. The subjects’ persistent sleep problem was associated with less pain reduction. The results are consistent with a recent study showing that sleep deprivation in patients with MDD can induce pain symptoms [3]. It is important to note that the correlation analyses of this study restrict our ability to make causal inferences on the relationship between sleep and pain symptoms. For example, pain symptoms may result in short sleep duration rather than reduced sleep time causing pain. Current literature tends to support a bi-directional
relationship between sleep and pain [6,7]. Moreover, insomnia and pain share common pathogenic mechanisms. Several neurotransmitters, neurohormones, and neuroimmunologic factors— such as serotonin, opioids, the hypothalamic–pituitary–adrenal axis, and the autonomic sympatho-adrenal system—have possible roles in both sleep and pain [2,13]. Cognitive-behavioral factors that are common to both insomnia and pain include heightened attention, catastrophizing, muscle tension, and activity avoidance [33,34]. Further studies using a micro-longitudinal design to examine the within-person and day-to-day changes in sleep and pain in MDD are warranted. Anxiety symptoms are common among patients with MDD [35]. We found that the severity of anxiety was associated with pain symptoms in depressed patients; however, depressive features did not play a significant role. Previous studies have shown that a high level of anxiety in depressive disorder is associated with greater severity of illness and functional impairment, chronicity, delayed response to treatment, and an increased risk of suicidality [36–38]. Although many studies have focused on the impact of depressive symptoms on pain in MDD, our findings suggest that when insomnia, anxiety and depression are considered together, depressive symptoms play a less important role in pain perception in MDD. There are certain limitations that should be considered while interpreting our findings. Our sample only included moderately depressed patients in a specialty mental health setting. It is possible that subjects with mild depression and depressed patients in non-specialized centers may have different relationships between sleep and pain symptoms; hence, our findings could not be
K.-F. Chung, K.-C. Tso / Sleep Medicine 11 (2010) 752–758 Table 4 Stepwise multiple regressions predicting pain scores at baseline and 3-month followup and changes in pain scores from demographic, clinical, sleep, anxiety and depressive features. Unstandardized regression coefficients (SEs) Pain scores at baseline Baseline VRS score (R2 = 36.2%) Baseline HADS anxiety (22.6%) On analgesic at baseline (7.7%) Number of previous depression (5.9%)
0.10 (0.03)** 0.73 (0.29)* 0.29 (0.12)*
Baseline VAS score (R2 = 37.9%) Baseline HADS anxiety (17.8%) On analgesic at baseline (10.8%) Baseline ISI total (4.4%) Number of previous depression (4.9%)
0.15 1.91 0.10 0.56
Baseline MAPS score (R2 = 43.7%) Baseline HADS anxiety (22.1%) On analgesic at baseline (10.1%) Age of onset of depression (7.6%) Number of previous depression (3.9%)
0.11 (0.02)** 0.91 (0.24)** 0.03 (0.01)* 0.23 (0.10)*
Pain scores at 3-month follow-up 3-month VRS score (R2 = 46.1%) 3-month ISI total (31.4%) On analgesic at 3 months (7.8%) 3-month HADS anxiety (6.9%) 3-month VAS score (R2 = 54.9%) 3-month HRSD17-anxiety (33.3%) On analgesic at 3 months (13.4%) 3-month ISI total (8.2%) 3-month MAPS score (R2 = 56.1%) 3-month HADS anxiety (26.6%) On analgesic at 3 months (19.2%) 3-month ISI total (6.0%) 3-month TST-actigraphy (4.3%)
(0.06)** (0.58)** (0.04)* (0.22)*
757
In conclusion, we showed that subjective sleep disturbances and actigraphy measures were significantly correlated with pain symptoms in MDD. The findings would support aggressive efforts to identify and treat sleep disturbances in patients with depression and comorbid painful conditions. A recent study found that augmenting antidepressant medication with cognitive-behavioral therapy for insomnia could alleviate both depression and insomnia [41]. Further research will also need to examine the beneficial effects of specific treatment for insomnia in patients with MDD comorbid with insomnia and pain. Conflict of interest Dr. Chung is a member of the advisory board for Eli Lilly and Takeda, and the honoraria is less than US$ 10,000 per year. Dr. Tso has no conflict of interest to declare. Both Drs. Chung and Tso have no personal financial investment to declare. References
**
0.05 (0.02) 0.70 (0.24)** 0.06 (0.02)** 0.47 (0.09)** 2.47 (0.53)** 0.10 (0.03)** 0.05 (0.03)** 1.27 (0.26)** 0.04 (0.02)** 0.002 (0.001)*
Changes in pain score from baseline to 3 months Change score for VRS (R2 = 46.0%) Baseline VRS pain score (26.2%) HADS anxiety change score (19.8%) Change score for VAS (R2 = 30.2%) Baseline VAS pain score (13.5%) HRSD17-anxiety change score (11.7%) Baseline WASO-actigraphy (5.0%)
0.29 (0.08)** 0.22 (0.07)** 0.009 (0.004)*
Change score for MAPS (R2 = 36.1%) Baseline MAPS pain score (16.9%) HADS anxiety change score (14.8%) Change in TST-actigraphy (4.4%)
0.38 (0.10)** 0.07 (0.02)** 0.002 (0.001)*
0.41 (0.06)** 0.08 (0.01)**
HADS, Hospital Anxiety and Depression Scale; HRSD17, 17-item Hamilton Rating Scale for Depression; ISI, Insomnia Severity Index; MAPS, Multidimensional Affect and Pain Survey; TST, total sleep time; WASO, wake after sleep onset; VAS, visual analog scale; VRS, verbal rating scale. * P < 0.05. ** P < 0.01.
extrapolated to the mildly depressed patients and subjects in other settings. About 10% of the sample failed to complete the 3-month reassessment and some participants did not take part in the sleep diary and actigraphy assessment. Future studies with larger sample and wider patient population are warranted. We have pointed out that our study design could not be used to establish any causal relationship between sleep and pain symptoms. Experimental studies have shown that selective sleep-stage deprivation produces hyperalgesic changes in healthy subjects [3,39]. Since actigraphy could not examine detailed sleep architecture, the effect of different sleep stages on pain perception in MDD has not been answered and could only be addressed in future studies using polysomnography. Although a consensus report on the research assessment of insomnia recommends a minimum of 3 days of actigraphy [40], we considered that 3 days may be insufficient to include data on variations between weekday and weekend variables.
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