Abstract
Background and aims
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is challenging to live with, often accompanied by pervasive fatigue and pain, accompanied by decreased quality of life (QoL) as well as anxiety and/or depression. Associations between higher pain, lower QoL and higher anxiety and depression have been shown in patients with various chronic pain disorders. Few studies have however examined such associations in a sample of patients with ME/CFS. The aims of the current study were to examine the impact of pain levels and compare levels of pain, health related QoL, anxiety and depression between patients with ME/CFS and healthy controls. In addition, the study aimed and to examine these relationships within the patient group only.
Methods
This is a cross-sectional questionnaire based study comparing 87 well-diagnosed patients with ME/CFS with 94 healthy controls. The De Paul Symptom Questionnaire (DSQ), the Medical Outcomes Study Short-Form Surveys (SF-36) and the Hospital Anxiety and Depression Scale (HADS) were used to examine and compare pain, physical function, QoL, anxiety and depression in patients and healthy controls. Further the pain variables were divided into pain total, pain intensity and a pain frequency score for analyses of the above mentioned variables within the patient group only.
Results
Significantly higher levels of pain, anxiety and depression, and lower levels of QoL were found in the patient group compared with healthy controls. For the patient group alone, pain was significantly associated with lower QoL in terms of physical functioning, bodily pain, general health functioning, vitality and social functioning capacity. In this patient sample, only frequency of joint pain showed significant difference in psychological variables such as depression and anxiety – depression combined.
Conclusions
ME/CFS patients differ significantly from healthy controls in pain, health related QoL, anxiety and depression. Pain is significantly associated with reduced QoL and overall a lower level of functioning. The relation between pain and anxiety and depression appears less clear.
Implications
Pain is for many ME/CFS patients associated with reduced physical functioning and reduced QoL. A thorough pain assessment can therefore be essential for clinicians, and subsequent medical pain treatment combined with good pain coping skills may increase functioning level and QoL for these patients. The link between joint pain and psychological factors should also be focused in clinical practice in terms of mapping and counseling. Pain should be further examined to understand the importance it may have for functioning level as reduced function is a main criteria when diagnosing the patients.
1 Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are frequently accompanied by discomfort as well as psychological or physical challenges. In order to fulfill the Canadian Consensus Criteria (CCC [1]) for a ME/CFS diagnosis, physical and mental fatigue aggravated by minimal exercise and a significant reduction of pre-morbid activity or functioning level are required. In addition, cognitive impairment, sleep problems, irregularities in neurological, symptoms from immunological, endocrine, and autonomic systems and/or pain are characteristic features of ME/CFS. People from all levels of society are affected and there is considerable variations in illness severity [2], [3]. Prevalence of ME/CFS is estimated to 0.23% worldwide and of these approximately two thirds are female that also appear more severely ill than men [4], [5], [6].
1.1 Pain in ME/CFS
As fatigue is usually the main challenge in ME/CFS, less knowledge exist on the impact of pain or factors that impact the experience and report of pain in ME/CFS. Presence of pain is required to meet the CCC [1] and pain may be experienced in muscles, head, stomach, and/or joints and be widespread or migratory in nature [1]. In CCC there is however hardly any specification of the pain symptom such as intensity, frequency or fluctuations of the required symptoms, indicating possible large variations in pain reports between the patients. Clinical similarities exist between ME/CFS, fibromyalgia syndrome (FM) and myofascial pain syndrome, with estimated co-morbidity of 20%–75% [7], [8]. Physical functioning is used as an indicator of illness severity and varies widely within the ME/CFS patient group [2]. A few studies have found that having both CFS and FM associates with more extended symptoms and functional impairment than CFS patients without FM [9], [10]. A recent study using Institute of Medicine (IOM) criteria [11] showed that ME/CFS patients with additional FM had the largest reduction in physical capacity [12]. Another study examining adolescents with CFS showed significant impact of pain and found headache to be most common, followed by pain in muscles, joints and abdomen [13].
1.2 Pain, quality of life and psychological well-being
Pain and psychological factors have rarely been studied together in adults with ME/CFS. Distress is among the most potent and robust indicators of a transition from acute to chronic pain in general [14], [15], [16], [17], [18]. Negative psychological states can impact illness experiences and symptom reports and relate to retreat and avoidance behavior [19], [20]. Anxiety and catastrophic thoughts have been linked to intense pain [21]. Compared with pain-free controls, patients with pain have reported higher negative affect [22], [23] and significantly higher levels of depression and health related anxiety [24].
Prospective studies suggest premorbid psychological dysfunction as a risk factor for later development of various chronic pain conditions [16], [25], [26]. While depression has predicted pain in some studies, pain has predicted depression in others [27]. Reviews have shown a variety of chronic pain conditions such as chronic pelvic pain [28], fibromyalgia [29], [30], low-back pain [31] and rheumatoid arthritis [14], [32], [33], [34], [35] to be associated with increased risk of clinically significant mood or anxiety symptoms [15], [16], [32], [36], [37].
A link between depression, increased fatigue and reduced level of functioning are identified in CFS patients [37]. Similarly, high depression is associated with more widespread pain [38] and higher pain intensity [39]. Depression are shown as main predictors for pain in patients with CFS [40] and a recent study showed anxiety (42.2%) and depression (33.3%) to be common in CFS [41].
Not enough is known about pain experiences, possible associations between pain, functioning and psychological factors in patients diagnosed with ME/CFS. The current study aims to investigate these relationships and the impact of various pain variables in a cohort of ME/CFS patients and healthy controls. It was hypothesized that (a) the studied factors would differ between patients and healthy controls and (b) there would be an association between pain as independent variable and functioning levels, and psychological variables such anxiety and depression as dependent variables in the total sample as well as in the patient group only.
2 Materials and methods
This cross-sectional study sought to examine pain symptoms, quality of life (QoL), anxiety and depression as well as other associated factors in 87 ME/CFS patients, and to compare findings with 94 healthy controls. The current study was conducted in three parts. First, demographic variables, health related QoL and psychological factors including anxiety and depression were compared between patients and healthy controls. Second, the relationships between pain, QoL, anxiety and depression were examined in the total sample. Third, different dimensions of pain, QoL, anxiety and depression were studied in the patient group only.
2.1 Participants
Participants (n=181) were patients with ME/CFS (n=87; 48%) and healthy controls (n=94; 52%). Patients enrolled at ME/CFS outpatient or inpatient clinics at a major hospital for evaluation between March 2013 and June 2016, were recruited. Healthy controls were recruited among first time blood donors at the same hospital during the same time period and they were asked about study participation during their first consultation. Patients with a confirmed ME/CFS diagnosis (CCC1) were asked to participate in the study during their second consultation by a physician.
This is a sample of convenience from a biobank/thematic register continuously sampling data. From March 2013 to June 2016 all the patients that fulfilled the CFS/ME criteria were asked to participate in the data sampling in the biobank/thematic register. A total of 168 patients were contacted. Of these, 64 did not want to participate, mainly because they felt too ill. Seventeen of those who agreed to participate and made an appointment did not show up for their appointment. The final number of participants (i.e. 87 patient and 94 controls) reflect the number of participants available and included at the point the analyses were started. All participants had to be between 18 and 65 years old and fluent in the Norwegian language. The participants were informed about the purposes of the present study and the biobank study and they signed a written informed consent form before inclusion. Outcome measurements were completed by pen and paper at home. To prevent missing data in the quetionnaires, a research nurse ensured that the participants filled out the whole form. The study and all data collection, including Biobank sampling and thematic register, were approved by the Institutional Review Board at Oslo University Hospital (ref: 2011/8355) and the Norwegian Regional Ethical Committee (ref REK 2011/473, and REK South-East, ref: 2017/375).
2.2 ME/CFS assessment and diagnosis
The CCC, [1] was applied as case definition in the current study. The CCC requires a substantial reduction from premorbid functioning, and to be diagnosed the patients must have experienced problems with fatigue or energy for 6 months or more. In addition, patients must report symptoms from different symptom domains such as sleep dysfunction, pain, neurocognitive dysfunction, autonomic dysfunction, neuroendocrine dysfunction or immune dysfunction.
According to the CCC criteria, morbid obesity, lifelong fatigue (e.g. not of newer origin), medical conditions or major psychological conditions that could cause fatigue, will exclude a ME/CFS diagnosis. In the current study, to consider whether other somatic conditions might explain the patient`s symptoms, an extended examination was conducted by a physician and an array of blood tests examined. A clinical psychological interview was also carried out to rule out psychiatric diagnoses.
2.3 Outcome measures
The De Paul Symptom Questionnaire (DSQ) is a 100 items standardized self-report symptom questionnaire originally developed in order to meet the need for more reliable diagnostic screening assessment for ME/CFS for research purpose [42]. The DSQ assesses information on onset, duration and contains questions on self-reported functioning level classified as very severely or severely ill (i.e. bedridden and housebound), as moderately ill (only do light housework, but not work part-time) or as mild degree of the illness (working part-time or full-time, but with no energy left for anything else). The DSQ is developed from a CFS questionnaire with good inter-rater and test-retest reliability able to distinguish between CFS, Major Depressive Disorders and healthy controls [43]. DSQ is found to be a valid tool with acceptable convergent and discriminant validity [44], test- retest reliability [45], sufficient to classify ME/CFS within the CCC [46], having excellent internal reliability and able to differentiate between patients and controls [47]. The DSQ symptom part has two dimensions for each symptom – frequency and intensity – with scales from zero to four. Participants rate each symptom’s frequency and intensity over the past 6 months on a 5-point Likert scale (i.e. 0=none of the time, 1=a little of the time, 2=about half the time, 3=most of the time, and 4=all of the time). Pain variables: There are six various pain symptoms or sites in DSQ; muscle, joint, eye, chest, stomach and head. Three different pain variables were computed: a total pain score (Pain Total) including both the frequency and the intensity for each of the six pain sites were computes. In addition one frequency variable containing the frequency score (Pain Frequency) for each pain site as well as one intensity variable including the intensity scores (Pain Intensity) from each pain site were also computed. The Medical Outcomes Study Short-Form 36 Surveys (SF-36) is a self-report questionnaire on health related QoL and functional status related to health [48]. The SF-36 comprises eight subscales: Physical functioning, role physical (role limitations due to physical health problems), Bodily pain, General health perceptions, Role emotional (role limitations due to emotional problems), Social functioning, Vitality and Mental health. The scores for each subscale ranges from 0 to 100 and higher scores indicate better functioning, except from the bodily pain scale where lower scores indicate more pain. SF-36 is frequently used to assess disability associated with chronic somatic illness and generally demonstrates adequate validity and test-retest reliability across applications [49].
The Hospital Anxiety and Depression Scale (HADS) was originally designed for identifying and screening for anxiety and depression in patients with somatic diseases. It is widely used within medical practice in somatic as well as psychiatric patient groups [50]. Participants are asked to rate their emotions for the last week on a 14-items questionnaire with scale scores from zero to three. The HADS has two seven-item subscales for measuring cognitive and emotional aspects of depression and anxiety, respectively. The HADS is a valid and efficient screening instrument for anxiety and depression [38], [51], [52]. One study suggested the cut-off on depression score (a possible clinical case) in HADS to be 8–9 in CFS populations because of HADS’s tendency to underestimate depression, and not 9–10 as suggested for the general population [53]. A cut-off on 8–9 is also applied for the anxiety score on HADS because of patients’ reported tendency to underreport anxiety [54].
2.4 Statistical analyses
SPSS (SPSS Inc. Released 2009, PASW Statistics for Windows, Version 21.0. Chicago: SPSS Inc.) was used for all statistical analyses. Descriptive statistics were conducted for demographics. Independent sample t-tests were performed to explore the differences between patients (ME/CFS group) and healthy controls. Multivariate analyses were performed with the use of hierarchical regression analyses to examine relationships between the different pain variables one by one (main independent variables) predicting levels of the eight QoL variables and the sum scores of the three HADS variables (main dependent variables). Due to significant age differences between patients and controls the regression analyses also controlled for age. A power analysis with a significance level 0.05, expected mean on physical function (SF-36) on 33.10 (SD21), with 80% chance to detect a difference on at least five on the SF-36 scale (from 0 to 100), indicated that a sample on around 30 participants would be sufficient to compare subgroups within the patient population. A standard p-value of <0.05 was used for all statistical analyses.
3 Results
A total of 181 participants with 87 patients and 94 healthy controls completed the measurements on pain, health related QoL, anxiety and depression. Demographic variables are presented in Table 1. Age was significantly different between the groups, t (142.5)=5.08, p<0.001) with the patients older than the healthy controls. Age was therefore included in all regression analyses. The healthy controls also had a significantly higher educational level than the patient group, but not to the same extent of correlation as age. No significant differences were found for gender and marital status. Self-reported functioning level based on questions from the DSQ revealed that 26% of the patients could be classified as very severely or severely ill, 45% as moderately ill and 29% as having a mild degree of the illness.
Comparison between ME/CFS patients and HC on demographics, quality of life, anxiety and depression (n=181).
| ME/CFS patients n=87 |
HC n=94 |
Sig. | |
|---|---|---|---|
| M(SD) | M(SD) | ||
| Age | 36.02 (11.60) | 28.64 (7.30) | a |
| Gender | n (%) | n (%) | |
| Male | 17 (18.500) | 28 (30) | |
| Female | 70 (80.5) | 66 (70) | |
| Education | a | ||
| 10 years or less | 14 (16) | 1 (1) | |
| Between 10 and 13/14 years | 36 (41.40) | 31 (33) | |
| College or University (14–16/17 years) | 26 (30) | 34 (37.40) | |
| University degree (>17 years) | 10 (11.50) | 25(26.60) | |
| Pain | M (SD) | M (SD) | Sig (CI) |
| Pain total | 24.2 (8.90) | 5.97 (4.74) | a[16.98–21.29] |
| SF-36 | M (SD) | M (SD) | Sig (CI) |
| Physical functioning | 46.67 (21.98) | 98.66 (4.67) | a[−61.82, −52.15) |
| Role physical | 4.65 (14.09) | 94.89 (15.45) | a[−94.61, −85.87] |
| Bodily pain | 38.01 (24.43) | 90.04 (17.34) | a[−58.31, −45.76] |
| General health functioning | 28.32 (16.97) | 85.5 (16.79) | a[−62.16, −52.21] |
| Vitality | 23.33 (15.27) | 67.81 (14.36) | a[−48.84, −40.12] |
| Social functioning | 27.87 (24.09) | 92.2 (15.74) | a[−70.37, −58.29] |
| Role emotional | 78.68 (36.84) | 87.81 (28.14) | |
| Mental health functioning | 70.33 (15.24) | 81.72 (12.72) | a[−15.58, −7.19] |
| Psychosocial variables | M (SD, %) | M (SD, %) | Sig (CI) |
| HADS anxiety | 6.31 (3.80, 37) | 4.26 (3.50, 15) | a[0.973, 3.13] |
| HADS depression | 5.33 (3.60, 27.60) | 1.2 (2.00, 4.30) | a[3.28, 5.01] |
| HADS anxiety-depression | 11.60 (6.30, 49.40) | 5.47 (5.10, 11,) | a[4.41, 7.84] |
-
a p<0.001. ME/CFS=myalgic encephalomyelitis/chronic fatigue syndrome; HC=healthy controls; HADS=Hospital Anxiety and Depression Scale; CI=confidence interval; Sig=significance; M=mean; SD=standard deviation.
3.1 ME/CFS vs. healthy controls on quality of life and pain
There were significant differences between patients and healthy controls in health related QoL (SF-36), as shown in Table 1. Significant differences between the two groups were found for all subscales in SF-36 except for the Role Emotional subscale. There were also large differences between patients with ME/CFS and healthy controls in the pain reports (DSQ) on all the six pain sites.
The ME/CFS group had significantly higher scores compared with healthy controls on anxiety t (176)=3.75, p<0.001, depression t (177)=9.45, p<0.001 and on the total HADS scores t (175)=7.05, p<0.001 (see Table 1). Further examination of the HADS revealed that among the patients 37% were above the cut-off for clinical case on anxiety and that 27.6% had a depression level above the clinical cut-off. For the total HADS, 49.4% of the patients had a cut-off indicating a clinical case. In the healthy control group, 15% met the cut-off criteria for anxiety, 4.3% for depression and 11% for the total HADS score.
3.2 ME/CFS and healthy controls related to pain, quality of life, anxiety and depression
As seen in Table 2, there were significant associations in the total sample (patients and healthy controls). Between Pain total (i.e. pain intensity and pain frequency combined), QoL (physical functioning, role physical, bodily pain, general health functioning, vitality, social functioning, role emotional, mental health functioning), anxiety, depression and anxiety-depression combined (all p<0.001). This supports the notion that pain is a significant factor, with significant impact on QoL and psychological well-being.
Hierarchical regression analyses in ME/CFS patients and healthy controls (n=181): Pain total, quality of life, anxiety and depression.
| Pain total |
Pain total controlling for age |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R2 | ΔR2 | t | β | p-Value | R2 | ΔR2 | t | β | p-Value | |
| Quality of life (SF-36) | ||||||||||
| Physical functioning | 0.63 | 0.63 | −16.9 | −0.79 | <0.001 | 0.65 | 0.54 | −15.80 | −2.12 | <0.001 |
| Role physical | 0.66 | 0.66 | −17.78 | −0.81 | <0.001 | 0.68 | 0.54 | −16.70 | −0.77 | <0.001 |
| Bodily pain | 0.73 | 0.73 | −21.36 | −0.87 | <0.001 | 0.73 | 0.69 | −20.73 | −0.86 | <0.001 |
| General health functioning | 0.62 | 0.62 | −16.42 | −0.79 | <0.001 | 0.62 | 0.56 | −15.61 | −0.78 | <0.001 |
| Vitality | 0.57 | 0.57 | −14.91 | −0.76 | <0.001 | 0.57 | 0.52 | −14.23 | −0.75 | <0.001 |
| Social functioning | 0.60 | 0.60 | −15.70 | −0.77 | <0.001 | 0.60 | 0.53 | −14.82 | −0.75 | <0.001 |
| Role emotional | 0.04 | 0.04 | −2.50 | −0.19 | <0.001 | 0.05 | 0.04 | −2.76 | −0.22 | <0.001 |
| Mental health functioning | 0.12 | 0.16 | −5.57 | −0.39 | <0.001 | 0.16 | 0.16 | −5.64 | −0.42 | <0.001 |
| Hospital Anxiety and Depression Scale (HADS) | ||||||||||
| HADS anxiety | 0.12 | 0.12 | 4.64 | 0.34 | <0.001 | 0.14 | 0.14 | 5.12 | 0.38 | <0.001 |
| HADS depression | 0.28 | 0.28 | 8.09 | 0.53 | <0.001 | 0.31 | 0.22 | 7.26 | 0.45 | <0.001 |
| HADS anxiety-depression | 0.24 | 0.24 | 7.14 | 0.49 | <0.001 | 0.24 | 0.22 | 6.90 | 0.49 | <0.001 |
-
Pain total includes pain frequency and pain intensity.
3.3 Pain, quality of life, anxiety and depression in the CFS/ME patient group.
Regression analyses within the pain group with the three pain dimensions; pain total, pain intensity and pain frequency as predictor variables respectively, showed statistically significant associations between pain total and all the QoL variables except from role physical functioning (see Table 3 for details). There were no significant associations between the pain variables and anxiety, depression or anxiety-depression combined. The pain intensity variables were significantly related with physical functioning (p<0.006), bodily pain (p<0.001), general health (p<0.05), and social functioning (p<0.05). For Pain frequency there was significant associations with physical functioning (p<0.01), bodily pain (p<0.001), vitality (p<0.01), and social functioning (p<0.01). Controlling for age did not change the results significantly except for Pain frequency and General Health functioning, where controlling for age resulted in a slight change and non-significancy (p=0.054)
Hierarchical regression analyses in ME/CFS patients (n=87): pain total, pain intensity, pain frequency, quality of life, anxiety and depression.
| R2 | ΔR2 | t | β | p-Value | R2 | ΔR2 | t | β | p-Value | |
|---|---|---|---|---|---|---|---|---|---|---|
|
Pain total
|
Pain total controlling for age
|
|||||||||
| Qol | ||||||||||
| Physical functioning | 0.12 | 0.11 | −3.10 | −0.33 | 0.003 | 0.12 | 0.11 | −3.04 | −0.33 | 0.003 |
| Role physical | 0.03 | 0.03 | −1.50 | −0.17 | 0.15 | 0.07 | 0.03 | −1.54 | −0.17 | 0.130 |
| Bodily pain | 0.48 | 0.48 | −8.49 | −0.69 | <0.001 | 0.49 | 0.47 | −8.44 | −0.69 | <0.001 |
| General health functioning | 0.06 | 0.06 | −2.30 | −0.25 | 0.024 | 0.09 | 0.06 | −2.23 | −0.24 | 0.029 |
| Vitality | 0.06 | 0.06 | −2.14 | −0.24 | 0.035 | 0.06 | 0.05 | −2.1 | −0.23 | 0.039 |
| Social functioning | 0.07 | 0.07 | −2.44 | −0.27 | 0.017 | 0.07 | 0.07 | −2.4 | −0.26 | 0.019 |
| Role emotional | 0.01 | 0.01 | −0.97 | −0.11 | 0.33 | 0.02 | 0.01 | −0.95 | −0.11 | 0.350 |
| Mental health functioning | 0.01 | 0.01 | −1.06 | −0.12 | 0.29 | 0.02 | 0.01 | −1.01 | −0.11 | 0.316 |
| HADS | ||||||||||
| Anxiety | 0.02 | 0.02 | 1.17 | 0.13 | 0.25 | 0.04 | 0.01 | 1.10 | 0.12 | 0.278 |
| Depression | 0.01 | 0.01 | 0.81 | 0.09 | 0.42 | 0.05 | 0.01 | 0.92 | 0.10 | 0.358 |
| Anxiety-Depression | 0.02 | 0.02 | 1.17 | 0.13 | 0.25 | 0.02 | 0.02 | 1.17 | 0.13 | 0.250 |
|
Pain intensity
|
Pain intensity controlling for age
|
|||||||||
| Qol | ||||||||||
| Physical functioning | 0.01 | 0.09 | −2.87 | −0.31 | <0.01 | 0.10 | 0.10 | −2.86 | −0.31 | 0.006 |
| Role physical | 0.02 | 0.02 | −1.26 | −0.14 | 0.21 | 0.06 | 0.02 | −1.34 | −0.15 | 0.19 |
| Bodily pain | 0.46 | 0.45 | −8.07 | −0.67 | <0.001 | 0.47 | 0.45 | −8.02 | −0.67 | <0.001 |
| General health functioning | 0.07 | 0.07 | −2.49 | −0.27 | 0.02 | 0.10 | 0.07 | −2.42 | −0.26 | 0.02 |
| Vitality | 0.04 | 0.04 | −1.69 | −0.19 | 0.10 | 0.04 | 0.03 | −1.65 | −0.19 | 0.10 |
| Social functioning | 0.06 | 0.06 | −2.16 | −0.24 | <0.05 | 0.06 | 0.06 | −2.12 | −0.24 | 0.037 |
| Role emotional | 0.01 | 0.01 | −0.63 | −0.07 | 0.53 | 0.01 | 0.01 | −0.61 | −0.07 | 0.547 |
| Mental health functioning | 0.01 | 0.01 | −0.75 | −0.09 | 0.46 | 0.01 | 0.01 | −0.71 | −0.08 | 0.483 |
| HADS | ||||||||||
| Anxiety | 0.01 | 0.01 | 1.05 | 0.12 | 0.30 | 0.04 | 0.01 | 0.98 | 0.12 | 0.33 |
| Depression | 0.00 | 0.00 | 0.59 | 0.07 | 0.56 | 0.05 | 0.01 | 0.70 | 0.08 | 0.485 |
| Anxiety-Depression | 0.01 | 0.02 | 0.97 | 0.11 | 0.33 | 0.01 | 0.01 | 0.97 | 0.11 | 0.333 |
|
Pain frequency
|
Pain frequency controlling for age
|
|||||||||
| Qol | ||||||||||
| Physical functioning | 0.08 | 0.08 | −2.67 | −0.29 | <0.01 | 0.09 | 0.08 | −2.69 | −0.29 | 0.009 |
| Role physical | 0.03 | 0.03 | −1.60 | −0.18 | 0.11 | 0.07 | 0.03 | −1.70 | −0.18 | 0.093 |
| Bodily pain | 0.40 | 0.40 | −7.42 | −0.63 | <0.001 | 0.41 | 0.40 | −7.32 | −0.63 | <0.001 |
| General health functioning | 0.05 | 0.05 | −2.06 | −0.22 | <0.04 | 0.08 | 0.04 | −1.96 | −0.21 | 0.054 |
| Vitality | 0.09 | 0.09 | −2.76 | −2.9 | <0.01 | 0.09 | 0.08 | −2.7 | −0.29 | 0.009 |
| Social functioning | 0.07 | 0.07 | −2.49 | −2.7 | <0.05 | 0.07 | 0.07 | −2.46 | −0.27 | 0.016 |
| Role emotional | 0.02 | 0.02 | −1.23 | −0.14 | 0.22 | 0.02 | 0.02 | −1.21 | −0.13 | 0.23 |
| Mental health functioning | 0.02 | 0.02 | −1.23 | −0.13 | 0.22 | 0.02 | 0.02 | −1.17 | −0.13 | 0.24 |
| HADS | ||||||||||
| Anxiety | 0.22 | 0.22 | 1.37 | 0.15 | 0.17 | 0.05 | 0.02 | 1.27 | 0.14 | 0.21 |
| Depression | 0.01 | 0.01 | 1.00 | 0.11 | 0.32 | 0.05 | 0.02 | 1.14 | 0.12 | 0.26 |
| Anxiety-Depression | 0.23 | 0.23 | 1.40 | 0.15 | 0.17 | 0.02 | 0.02 | 1.40 | 1.15 | 0.166 |
-
Pain total includes pain frequency and pain intensity. Pain intensity includes the intensity scores for all the six pain sites. Pain frequency includes the frequency scores for all the six pain sites.
3.4 Pain sites, quality of life, depression and anxiety
All pain sites, intensity as well as frequency parts, were entered into the analyses one by one. As could be expected, all variables were strongly related with bodily pain. Pain intensity and frequency of Muscle pain were both significantly related with physical functioning (p<0.01 and p<0.05), role physical (p<0.01 and p<0.05), and vitality (p<0.05 and p<0.01). See Table 4 for details. For joint pain intensity and frequency the results showed a significant association with role physical (p<0.05 and p<0.05), while frequency of joint pain was significant related with vitality (p<0.01), depression (p<0.05), and anxiety-depression combined (p<0.05). Chest pain intensity related with general health (p<0.05) and head frequency related with social functioning (p=0.01).
Hierarchical regression analyses in ME/CFS patients (n=87): the six different pain sites on both Pain intensity and Pain frequency, quality of life, anxiety and depression.
| R2 | ΔR2 | t | β | p-Value | R2 | ΔR2 | t | β | p-Value | R2 | ΔR2 | t | β | p-Value | R2 | ΔR2 | t | β | p-Value | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Muscle intensity controlling for age
|
Muscle frequency controlling for age
|
Joint intensity controlling for age
|
Joint frequency controlling for age
|
|||||||||||||||||
| Qol | ||||||||||||||||||||
| Physical functioning | 0.10 | 0.10 | −2.8 | −0.30 | 0.006 | 0.08 | 0.08 | −2.57 | −0.28 | 0.012 | 0.03 | 0.02 | −0.43 | −0.05 | 0.668 | 0.02 | 0.01 | −0.11 | −0.12 | 0.286 |
| Role physical | 0.09 | 0.09 | −2.84 | −0.30 | 0.006 | 0.08 | 0.08 | −2.57 | −0.28 | 0.012 | 0.09 | 0.06 | −2.23 | −24 | 0.028 | 0.08 | 0.05 | −0.21 | −2.02 | 0.047 |
| Bodily pain | 0.47 | 0.46 | −8.34 | −0.68 | 0.000 | 0.37 | 0.35 | −5.73 | −0.60 | 0.000 | 0.25 | 0.24 | −5.10 | −0.49 | <0.001 | 0.13 | 0.11 | −3.24 | −0.33 | 0.002 |
| General health functioning | 0.08 | 0.04 | −1.92 | −0.21 | 0.058 | 0.06 | 0.03 | −1.58 | −0.17 | 0.118 | 0.06 | 0.03 | −1.48 | −1.60 | 0.143 | 0.05 | 0.02 | −1.26 | −0.14 | 0.211 |
| Vitality | 0.07 | 0.06 | −2.26 | −0.25 | 0.027 | 0.11 | 0.11 | −3.13 | −0.33 | 0.002 | 0.05 | 0.05 | −2.01 | −0.23 | 0.047 | 0.10 | 0.01 | −3.03 | −0.31 | 0.003 |
| Social functioning | 0.04 | 0.03 | −1.69 | −0.19 | 0.094 | 0.04 | 0.04 | −1.91 | −0.21 | 0.60 | 0.02 | 0.02 | −1.34 | −0.15 | 0.19 | 0.04 | 0.04 | −1.82 | −0.19 | 0.073 |
| Role emotional | 0.04 | 0.03 | −1.67 | −0.89 | 0.100 | 0.03 | 0.03 | −1.40 | −0.16 | 0.164 | 0.03 | 0.03 | −1.47 | −0.16 | 0.145 | 0.02 | 0.02 | −1.28 | −0.14 | 0.204 |
| Mental health functioning | 0.02 | 0.01 | −1.05 | −0.12 | 0.298 | 0.02 | 0.01 | −0.93 | −0.10 | 0.35 | 0.02 | 0.02 | −1.18 | −0.13 | 0.241 | 0.03 | 0.02 | −1.38 | −0.15 | 0.171 |
| HADS | ||||||||||||||||||||
| Anxiety | 0.06 | 0.03 | −1.68 | 0.18 | 0.097 | 0.06 | 0.03 | 0.68 | 0.18 | 0.096 | 0.06 | 0.04 | 1.78 | 0.19 | 0.079 | 0.07 | 0.04 | 1.84 | 0.19 | 0.070 |
| Depression | 0.06 | 0.02 | 1.43 | 0.16 | 0.158 | 0.05 | 0.01 | 1.12 | 0.12 | 0.271 | 0.05 | 0.02 | 1.26 | 0.14 | 0.21 | 0.08 | 0.05 | 2.05 | 0.22 | 0.043 |
| Anxiety -Depression | 0.04 | 0.04 | 1.81 | 0.19 | 0.074 | 0.03 | 0.03 | 1.63 | 0.18 | 0.107 | 0.04 | 0.04 | 1.84 | 0.19 | 0.069 | 0.06 | 0.06 | 2.21 | 0.24 | 0.030 |
|
Eye intensity controlling for age
|
Eye frequency controlling for age
|
Chest intensity controlling for age
|
Chest frequency controlling for age
|
|||||||||||||||||
| Qol | ||||||||||||||||||||
| Physical functioning | 0.02 | 0.02 | −1.12 | −0.13 | 0.267 | 0.01 | 0.01 | −0.87 | −0.09 | 0.388 | 0.05 | 0.05 | −2.11 | −0.23 | 0.038 | 0.05 | 0.05 | −1.99 | −0.22 | 0.49 |
| Role physical sjekk denne | 0.05 | 0.01 | −0.94 | −0.10 | 0.351 | 0.03 | 0.002 | −0.36 | −0.04 | 0.719 | 0.03 | 0.00 | −0.21 | −0.02 | 0.836 | 0.03 | 0.00 | 0.11 | 0.01 | 0.91 |
| Bodily pain | 0.13 | 0.11 | −3.19 | −0.33 | 0.002 | 0.08 | 0.03 | −1.7 | −0.18 | 0.92 | 0.13 | 0.11 | −3.28 | −0.34 | 0.002 | 0.13 | 0.11 | −3.24 | −0.34 | 0.002 |
| General health functioning | 0.05 | 0.02 | −1.36 | −0.15 | 0.176 | 0.06 | 0.03 | −1.63 | −0.17 | 0.108 | 0.09 | 0.06 | −2.41 | −0.25 | 0.018 | 0.07 | 0.04 | −1.76 | −0.19 | 0.082 |
| Vitality | 0.01 | 0.00 | −0.17 | −0.02 | 0.89 | 0.01 | 0.01 | −0.55 | −0.06 | 0.59 | 0.03 | 0.03 | −1.47 | −0.16 | 0.145 | 0.03 | 0.02 | −1.27 | −0.14 | 0.207 |
| Social functioning | 0.05 | 0.05 | −1.99 | −0.22 | 0.049 | 0.03 | 0.03 | −1.62 | −18 | 0.11 | 0.02 | 0.02 | −1.33 | −0.15 | 0.187 | 0.02 | 0.02 | −1.12 | −0.12 | 0.268 |
| Role emotional | 0.01 | 0.00 | −0.42 | −0.05 | 0.68 | 0.00 | 0.00 | 0.04 | 0.01 | 0.965 | 0.00 | 0.00 | 0.02 | 0.00 | 0.98 | 0.01 | 0.00 | −0.59 | −0.07 | 0.56 |
| Mental health functioning | 0.01 | 0.00 | −0.45 | −0.05 | 0.65 | 0.01 | 0.01 | −0.07 | 0.52 | 0.01 | 0.00 | −0.18 | −0.02 | 0.868 | 0.01 | 0.01 | −0.76 | −0.08 | 0.452 | |
| HADS | ||||||||||||||||||||
| Anxiety | 0.01 | 0.00 | 0.18 | 0.02 | 0.86 | 0.03 | 0.00 | 0.07 | 0.01 | 0.94 | 0.03 | 0.00 | 0.61 | 0.07 | 0.55 | 0.03 | 0.00 | 0.21 | 0.02 | 0.838 |
| Depression | 0.04 | 0.00 | −0.46 | −0.05 | 0.65 | 0.04 | 0.00 | −0.39 | −0.04 | 0.701a | 0.04 | 0.00 | 0.49 | 0.05 | 0.624 | 0.04 | 0.01 | 0.78 | 0.09 | 0.436 |
| Anxiety-Depression | 0.00 | 0.00 | −0.17 | −0.02 | 0.87 | 0.00 | 0.00 | −0.21 | −0.02 | 0.838 | 0.01 | 0.01 | 0.64 | 0.07 | 0.53 | 0.00 | 0.00 | 0.56 | 0.06 | 0.58 |
|
Stomach intensity controlling for age
|
Stomach frequency controlling for age
|
Head intensity controlling for age
|
Head frequency controlling for age
|
|||||||||||||||||
| Qol | ||||||||||||||||||||
| Physical functioning | 0.03 | 0.03 | −1.51 | −0.17 | 0.136 | 0.03 | 0.03 | −1.55 | −0.17 | 0.125 | 0.05 | 0.04 | −1.91 | −0.21 | 0.059 | 0.04 | 0.04 | −1.78 | −0.19 | 0.081 |
| Role physical | 0.04 | 0.01 | −0.76 | −0.08 | 0.448 | 0.05 | 0.02 | −1.22 | −0.13 | 0.225 | 0.03 | 0.01 | −0.64 | −0.07 | 0.521 | 0.06 | 0.04 | −1.81 | −0.20 | 0.08 |
| Bodily pain | 0.16 | 0.15 | −3.73 | −0.38 | <0.001 | 0.17 | 0.15 | −3.86 | −0.39 | <0.001 | 0.21 | 0.20 | −4.53 | −0.46 | <0.001 | 0.25 | 0.24 | −5.16 | −51 | <0.001 |
| General health functioning | 0.06 | 0.02 | −1.44 | −0.16 | 0.154 | 0.05 | 0.02 | −1.25 | −0.13 | 0.215 | 0.05 | 0.01 | −1.06 | −0.12 | 0.293 | 0.04 | 0.00 | −0.06 | −0.01 | 0.953 |
| Vitality | 0.01 | 0.00 | 0.17 | 0.02 | 0.869 | 0.01 | 0.00 | 0.04 | 0.00 | 0.971 | 0.01 | 0.01 | −0.93 | −0.11 | 0.358 | 0.05 | 0.04 | −1.95 | −0.22 | 0.06 |
| Social functioning | 0.02 | 0.02 | −1.18 | −0.13 | 0.243 | 0.01 | 0.01 | −0.69 | −0.08 | 0.492 | 0.03 | 0.03 | −1.48 | −0.17 | 0.14 | 0.08 | 0.07 | −2.58 | −0.28 | 0.01 |
| Role emotional | 0.01 | 0.01 | −0.64 | −0.07 | 0.527 | 0.02 | 0.02 | −1.34 | −0.15 | 0.183 | 0.00 | 0.00 | 0.32 | 0.04 | 0.754 | 0.00 | 0.00 | −0.36 | −0.04 | 0.718 |
| Mental health functioning | 0.01 | 0.00 | 0.15 | 0.02 | 0.879 | 0.01 | 0.00 | 0.04 | 0.00 | 0.969 | 0.01 | 0.00 | −0.45 | −0.06 | 0.619 | 0.01 | 0.01 | −0.71 | −0.08 | 0.481 |
| HADS | ||||||||||||||||||||
| Anxiety | 0.03 | 0.00 | 0.49 | 0.05 | 0.63 | 0.03 | 0.01 | 0.74 | 0.08 | 0.463 | 0.03 | 0.00 | −0.17 | −0.02 | 0.864 | 0.03 | 0.00 | 0.43 | 0.05 | 0.666 |
| Depression | 0.04 | 0.00 | 0.21 | 0.02 | 0.833 | 0.04 | 0.00 | 0.24 | 0.34 | 0.813 | 0.04 | 0.00 | 0.39 | 0.04 | 0.701 | 0.05 | 0.01 | 1.01 | 0.12 | 0.29 |
| Anxiety-Depression | 0.00 | 0.00 | 0.41 | 0.05 | 0.68 | 0.00 | 0.00 | 0.57 | 0.06 | 0.569 | 0.00 | 0.00 | 0.11 | 0.01 | 0.912 | 0.01 | 0.01 | 0.86 | 0.09 | 0.395 |
4 Discussion
The main finding in the current study was a relationship between higher levels of pain and reduced QoL among patients classified as CFS/ME. Significant differences were revealed between patients and healthy controls related to pain, QoL and psychological variables including anxiety and depression. Regression analyses also showed that various dimensions of pain related with QoL, anxiety and depression for the total sample (patients as well as healthy controls). For the patient group pain intensity and pain frequency were both associated with QoL scales except from the role emotion and mental health scales. When examining the intensity and frequency of the separate pain sites only the frequency part of joint pain related with the psychological variables. More frequent joint pain predicted more depression and higher anxiety-depression combined score.
4.1 Comparing patients with ME/CFS to healthy controls
The healthy control group reported QoL levels equivalent to the Norwegian norm for the same age group [55], and QoL levels in the patient group were similar to other studies examining patients with ME/CFS [56]. The only QoL scale not differing between patients and healthy controls related to emotional roles. All the other scales (SF-36) were significantly lower for patients than controls. Also, mental health was worse in the patient group than the controls group, in consistence with the results showing more anxiety and depression for some of the patients. The fact that both anxiety and depression were significantly higher in the patients than in the controls is in accordance with former studies on FM and patients with rheumatoid arthritis [22], [23], [24]. Patients reporting extensive bodily symptoms and reduced functional level also experienced more psychologically challenging symptoms, which is not surprising. Experiencing extensive symptoms with no clear explanation could likely initiate negative psychological reactions. As the current study is cross-sectional and not prospective, it is difficult to know whether higher anxiety and depression was primary or secondary to pain. Patients in the current study did however report more fear and depression than healthy controls, and some patients had more anxiety and depression than others. The most consistent finding in this study was the relationship between more pain and reduced QoL or level of functioning, particularly reduced physical functioning but also lower levels of social and general health functioning. The association between pain and functioning level is important and also in consistence with findings from a recent study on ME/CFS patients with a comorbidity of FM [12]. Pain in muscles and joints can be induced by physical activity, as for example shown in patients with FM [57], and this may also be the case in patients with CFS/ME. Activity-induced pain may restrict patient`s everyday activity and limit their activity level in many ways. Lower levels of physical activity may also indicate fear of motion and lack of distractions from the unpleasant experience of pain and thus increase both pain focus and pain reports. Also it is important to know that there is so strong connection between pain and limited functioning as significantly reduced function is a main criteria for fulfilling the ME/CFS diagnosis [1]. If pain could be reduced then patients` level of function might increase.
4.2 Pain sites and psychological variables in ME/CFS
The final analyses focus on pain sites, pain dimensions, QoL and psychological variables. More unexplained bodily discomfort was expected to associate with more negative psychological reactions. An association between pain frequency, HADS scores and pain location was clear, with only the frequency part of joint pain significantly related to more depression and more anxiety-depression combined. None of the other pain sites, or the intensity part of joint pain, related to the psychological variables. The relationship between pain site and depression is actually in accordance with former studies on CFS patients showing a link between depression and pain [38], [39]. Anxiety alone did not make any significant difference in the pain experience and this is not in accordance with former studies on patients with FM [21] and CFS [40] showing a link between anxiety and pain intensity.
4.3 Anxiety and depression in ME/CFS
The proportion of patients with anxiety and depression in the current study is similar to findings from other pain and ME/CFS studies, and from other patient populations with chronic somatic illness [14], [15], [35], [36], [41]. Higher levels were reported on anxiety than on depression among the patients. This pattern is consistent with other studies with various chronic somatic and painful conditions [18], [19], [23]. For subgroups of the patients, the clinical cut-off was met for anxiety (35.6%) and depression (28.8%), and a larger proportion of the patient cohort met the cut-off for anxiety than depression. Previous research has found a similar pattern for anxiety and depression [41], with prevalence rates for anxiety and depression on 42.2% and 33.3%, respectively.
4.4 Limitations and strengths
The patients in the ME/CFS group are older than the healthy controls in the current study. This could have implication for interpretation of the results, although only when comparing patients and healthy controls. Age was however included as a control factor in the analyses. The differences found between patients and controls related to QoL and functioning (SF-36), and psychological factors (HADS) are of great importance, although not surprising. Also, when looking at demographics and characteristics of the current patient cohort, these are similar to previous indicators about the ME/CFS population in terms of age, gender distribution and functional level [4], [56]. This suggests that results from the current study may be generalized to other patients diagnosed with ME/CFS based on the CCC.
The cross-sectional design of the current study is another limitation as the analyses cannot provide causal or longitudinal perspective on pain and psychological aspects. Among definite study strengths are the comparison of patients with ME/CFS vs. a healthy control group and a large scale dataset. Also, the patient sample was well-diagnosed by physicians with extensive experiences with diagnosis and counselling of patients with ME/CFS. Also, the patients went through an extended clinical interview by an experienced psychologist to make sure no primary psychological diseases could explain their symptoms. Thus, one may at least hypothesize that anxiety and depression could be a consequence of having ME/CFS, and not prior or predisposing. This should be further investigated in a study with a better suitable study design. Even though self-report questionnaires still suffer the weakness of self-report, the fact that an extended illness specific, validated and reliability tested symptom questionnaire was applied for pain assessment could be considered a major strength.
5 Conclusion
This study reveals that high levels of pain associate with reduced health related QoL and reduced functioning level. Also, findings show that frequency of joint pain to be associated with higher levels of depression and anxiety-depression combined. Clinically, this suggests that assessing pain and also psychological factors may be a necessity when seeing patients with ME/CFS for consultation. A variety of evidence based pain, self-management and psychological support strategies should also be offered and taken into account when examining and counseling patients with ME/CFS.
Acknowledgements
We want to thank research nurse Hilde Haukeland for her contribution in the data sampling of this project and the participants who provided us with valuable data.
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Authors’ statements
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Research funding: Funding for the CFS/ME biobank and thematic register data sampling was received from the Norwegian National Health directory.
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Conflict of interest: The authors report no conflicts of interest in this work.
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Informed consent: All participants in this study received information about the study and gave their consent to attend.
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Ethical approval: Regional Ethical Committee (ref REK 2011/473, and REK South-East, ref: 2017/375) has approved the current study.
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Author contributions: All authors were involved in planning and design of the study. EBS and SA were responsible for data collection. LS, EBS, AMM and LSN were responsible for data analysis. All authors were involved in drafting and revising of the manuscript.
References
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