Chronic widespread pain (CWP) is defined as a pain on four quadrants of the body as well as the axial skeleton persisting over 3 months. The prevalence of CWP occurs in 10-14% of the general population and is more common in women than men.^1,2) CWP is a long-lasting condition and worsens patients' quality of life.^3-5) Numerous studies have been performed on patients with fibromyalgia syndrome (FMS) and CWP since Wolfe et al.⁶⁾ suggested a criteria for FMS (American College of Rheumatology, ACR) in 1990. CWP has distinct symptoms for specific organic and psychological disorders although some are medically unexplained in clinical practice.⁷⁾ FMS is not a specific disease but a syndrome of several medically unexplained symptoms such as chronic pain, chronic fatigue, sleep disturbances and mood disorders.^8,9) CWP patients are difficult for the physician to treat and there are few studies for distinct clinical characteristics of medically unexplained CWP. This study was designed to investigate the differential clinical characteristics between medically unexplained and explained (organic or psychological) CWP patients.

According to the physicians' diagnosis, 109 CWP patients were classified into 3 groups, 39 for MUE, 25 for ORG and 45 for PSY. Table 1 shows the socio-demographic characteristics of each group. In the MUE group, ex-smokers were significantly more frequent than in the other groups.

Major problems associated with CWP patients were shown in Table 2. Thirty-nine patients of MUE were diagnosed as FMS (n = 24, 61.5%), CFS (n = 15, 25.5%), and ICF (n = 5, 12.8%). In ORG, rheumatoid arthritis (RA ; n = 10, 40%) was the most common medical problem followed by osteoarthritis (OA; n = 6, 24%), other musculoskeletal or metabolic diseases and malignancies. In PSY, depression (n = 23, 53%) was the most common problem as well as stress and being overworked. Panic, anxiety and somatization disorders were also diagnoses for PSY.

Table 3 showed Clinical Distress Scales among three groups. Physical impairment scores were 15.3 ± 7.9 for MUE, 11.3 ± 8.7 for ORG, and 14.8 ± 8.1 for PSY but there was no difference among them (P = 0.145). The numbers of days feeling good in the past seven days were significantly lower for MUE and PSY than ORG (P = 0.001). Work missed was not different among groups. Tiredness was significantly higher in MUE than ORG and anxiety scores were higher in PSY than ORG. But, the ability to do work, pain, rest, stiffness and depression levels were not significantly different among groups. Comparing the FIQ-K scores of each group, MUE had a higher score than ORG group (P = 0.003). MUE had a higher level of fatigue severity as assessed by FSS than PSY and ORG (P = 0.007). BDI score was highest in PSY. MUE showed a higher stress score than ORG and more numbers of tender points than the other two groups (P < 0.0001). As a result of multivariated analysis, MUE group showed significantly higher score in FIQ, FSS, and SRI than ORG group. PSY group showed higher score in VAS anxiety scale, FIQ, BDI, and SRI than ORG group significantly. MUE had a higher number of tender points than the other two groups after mutlivariated analysis. Otherwise the number of days felt good last week was slightly higher in MUE group than other 2 groups. The results were presented in Figure 1.

It is known that patients with CWP suffer more psychological illness and often experience more disorders such as CFS, FMS, depression, and irritable bowel disease than those without CWP.^15,16) FMS and CFS are also well known disorders with CWP.¹⁷⁾ These syndromes have common complaints including severe fatigability, disability, chronic pain and depressive mood as well as a tendency to progress to a chronic state.¹⁸⁾ But neither biologic indicators nor specific diagnostic criteria exist to explain these syndromes.⁴⁾ We therefore conducted this study to search for differential clinical characteristics of MUE for which diagnoses and definitions are unclear between psychological illness and organic disorders.

Our research showed that patients with MUE had a higher level of fatigue, physical impairment and number of tender points on the body than ME, especially ORG but clinical distress symptoms such as severity of depression and level of stress were no different between MUE and PSY. MUE had differential clinical distress symptoms from ORG such as rheumatoid arthritis and osteoarthritis but similar with PSY. We suggest a few explanations for these similarities between MUE and PSY. First, MUE (FMS and CFS in our study) is not a single disorder but a spectrum of several disorders. Bradley¹⁹⁾ and Hudson et al.²⁰⁾ had suggested that ten types of mental illnesses including major depression, generalized anxiety disorder and four kinds of medical conditions including FMS, IBS, migraine and cataplexy as referred as affective spectrum disorders. Additionally, another study showed that lifetime prevalence of major depression in FMS patients was significantly higher than in the general population and as with depression, FMS is accompanied by similar symptoms including various functional disabilities, depressive moods, memory impairment, vulnerability to stress and autonomic nervous system dysfunction. Therefore, both disorders have been claimed to have the same underlying mechanism.²¹⁾ Second, in patients with CFS or FMS, antidepressants can relieve their pain regardless of the mood of patients.^22,23) Thus, medically unexplained syndromes like FMS and CFS are likely to have a similar disease mechanism including depression and somatization disorders. Third, the prevalence of depression in patients with FMS or CFS is higher than in the general population. In a Finnish study, the prevalence of depression was much higher in FMS patients than those without FMS (56% vs. 17%).²⁴⁾ Raphael et el.²⁵⁾ also reported that women with FMS had a 69.8% chance of life-time prevalence of depression compared to 34.3% of women with no FMS in a community-based study. Lars et al. reported that 20% and 10% of CWP complaints were due to rheumatoid arthritis and degenerative arthritis, respectively.²⁶⁾

In our study, ORG of CWP patients was 22.9% (25/109), 9.2% (10/109) for RA and 5.5% for OA (6/109). These low percentages of RA and OA for CWP in our study were thought to be due to the difference of study subjects visiting our center and further research is needed in Korea for clarification.

Our study showed that MUE tended to have poorer physical functioning, higher levels of stress response and fatigue severity than PSY. FMS had a number of associated symptoms such as chronic fatigue, irritable bowel and chronic pelvic pain while patients with multiple conditions had a poor quality of life, more severe functional disabilities and depressive moods.^27,28) Although co-morbidity conditions of MUE were not evaluated in this study, they were more likely to have associated psychological diseases which give rise to the functional disability and psychological symptoms.

MUE showed more severe depressed moods, higher levels of stress response and severe fatigue than the ORG. And functional impairment due to pain was more severe in MUE. These results were consistent with previous studies.^10,29)

The number of tender points over the entire body was significantly higher in MUE than in ME. Because MUE included FMS, the result was not surprising. These results were also consistent with previous studies showing that FMS had more tender points and also higher distress such as fatigue as well as impairment of physical functioning.^18,30) Additionally, Yunus³¹⁾ suggested a concept of central sensitization (CS) that pain in FMS is related to CS and the pathophysiological mechanism of CS is associated with activation of peripheral nociceptive C fibers in chronic pain by several neurochemicals (substances P, serotonin and bradykinin). In practice, CS can be checked by tender points on the body indirectly. Thus, our results that MUE had increased numbers of tender points on the body may be consistent with the aforementioned hypothesis of CS.

There are some limitations of our study. First, the major problem associated with CWP of subjects was determined by only a single disorder. Most of the patients with CWP had several diseases and it is difficult to confirm whether one or two specific diseases or a syndrome were the major cause of CWP.³²⁾ Thus, we had a difficulty in differentiating between MUE and PSY because most MUE patients had psychological co-morbidities such as depression, sleep disturbances etc. However, in our study, physicians interviewed the patients more than three times and performed CWP-related laboratory tests, if necessary and then decided only a major cause explaining CWP. Thus we think that this limitation is not big enough to affect our results but further studies will be necessary in the future. Second, the study results can't represent the characteristics of all CWP patients because the subjects were patients visiting the department of a university hospital. Third, the number of study subjects was relatively small so that some clinical characteristics of MUE were unlikely to be significantly different from ME.

Despite these limitations, we found MUE had some differential clinical distress symptoms from ME, especially ORG and our study was the first investigation for clinical characteristics of medically unexplained CWP patients in Korea. In the future, further studies are needed to determine whether the various symptoms presented in patients with medically unexplained chronic widespread pain might explain the pathophysiology of the pain mechanisms.