вход по аккаунту


Anxiety and depressive symptoms in fibromyalgia are related to poor perception of health but not to pain sensitivity or cerebral processing of pain.

код для вставкиСкачать
Vol. 62, No. 11, November 2010, pp 3488–3495
DOI 10.1002/art.27649
© 2010, American College of Rheumatology
Anxiety and Depressive Symptoms in Fibromyalgia Are
Related to Poor Perception of Health but Not to
Pain Sensitivity or Cerebral Processing of Pain
Karin B. Jensen,1 Frank Petzke,2 Serena Carville,3 Peter Fransson,1 Hanke Marcus,2
Steven C. R. Williams,4 Ernest Choy,3 Yves Mainguy,5 Richard Gracely,6
Martin Ingvar,1 and Eva Kosek1
Objective. Mood disturbance is common among
patients with fibromyalgia (FM), but the influence of
psychological symptoms on pain processing in this
disorder is unknown. We undertook the present study to
investigate the differential effect of depressive symptoms, anxiety, and catastrophizing on 1) pain symptoms
and subjective ratings of general health status and 2)
sensitivity to pain and cerebral processing of pressure
Methods. Eighty-three women (mean ⴞ SD age
43.8 ⴞ 8.1 years) who fulfilled the American College of
Rheumatology 1990 criteria for the classification of FM
participated in the study. Patients rated pain intensity
(100-mm visual analog scale [VAS]), severity of FM
(Fibromyalgia Impact Questionnaire), general health
status (Short Form 36), depressive symptoms (Beck
Depression Inventory), anxiety (State-Trait Anxiety Inventory), and catastrophizing (Coping Strategies Questionnaire). Experimental pain in the thumb was induced using a computer-controlled pressure stimulator.
Event-related functional magnetic resonance imaging
was performed during administration of painful stimuli
representing 50 mm on a pain VAS, as well as nonpainful pressures.
Results. A correlation analysis including all selfratings showed that depressive symptoms, anxiety, and
catastrophizing scores were correlated with one another
(P < 0.001), but did not correlate with ratings of clinical
pain or with sensitivity to pressure pain. However, the
subjective rating of general health was correlated with
depressive symptoms and anxiety (P < 0.001). Analyses
of imaging results using self-rated psychological measures as covariates showed that brain activity during
experimental pain was not modulated by depressive
symptoms, anxiety, or catastrophizing.
Conclusion. Negative mood in FM patients can
lead to a poor perception of one’s physical health (and
vice versa) but does not influence performance on
assessments of clinical and experimental pain. Our data
provide evidence that 2 partially segregated mechanisms are involved in the neural processing of experimental pain and negative affect.
This study was performed in collaboration with Pierre Fabre
Médicament, Labège, France. The results in this study are derived in
part from a placebo-controlled drug intervention study (EudraCT
#2004-004249-16) financed by Pierre Fabre Médicament.
Karin B. Jensen, PhD (current address: Massachusetts General Hospital and Harvard Medical School, Boston), Peter Fransson,
PhD, Martin Ingvar, MD, PhD, Eva Kosek, MD, PhD: Stockholm
Brain Institute, Osher Center for Integrative Medicine, Karolinska
Institutet, Stockholm, Sweden; 2Frank Petzke, MD, Hanke Marcus,
MD: Department of Anesthesiology and Postoperative Intensive Care
Medicine, University Hospital of Cologne, Cologne, Germany; 3Serena Carville, PhD, Ernest Choy, MD, FRCP: King’s Musculoskeletal
Clinical Trials Unit, Academic Department of Rheumatology, King’s
College London, London, UK; 4Steven C. R. Williams, PhD: Centre
for Neuroimaging Science, Institute of Psychiatry, King’s College
London, London, UK; 5Yves Mainguy, MD, PhD: Pierre Fabre
Médicament, Labège, France; 6Richard Gracely, PhD: Center for
Neurosensory Disorders, University of North Carolina, Chapel Hill.
Dr. Petzke has received speaking fees from Pierre Fabre
Médicament (less than $10,000) and has provided expert testimony on
behalf of Pierre Fabre Médicament. Dr. Choy has received consulting
fees, speaking fees, and/or honoraria from Pierre Fabre Médicament
(more than $10,000). Dr. Gracely has received consulting fees, speaking fees, and/or honoraria from Pierre Fabre Médicament (more than
Address correspondence and reprint requests to Karin B.
Jensen, PhD, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129. E-mail:
Submitted for publication November 17, 2009; accepted in
revised form July 1, 2010.
Pain represents an emotional construct (1,2), and
the neural processing of pain can be altered with
changes in emotional status (3–6). Mood disorders are
common among individuals with chronic pain (7), but
the causality is unknown. One study using functional
magnetic resonance imaging (MRI) has shown that the
experience of sustained low back pain was associated
with a selective activation of a prefrontal brain circuitry,
an area that has been implicated in the cognitive and
motivational-affective aspects of pain (8). In another
functional MRI study, Schweinhardt et al (9) observed
depression-related activity in the medial prefrontal cortex of patients with rheumatoid arthritis (RA) during
provocation of clinical pain, but not during experimental
pain. These results provide evidence of a complex interaction between brain processes underlying the specific
circuitry of chronic pain and that of negative mood. In
the present study, we addressed this clinically important
interaction by investigating the effect of depressive
symptoms, anxiety, and catastrophizing on pain processing in patients with fibromyalgia (FM).
FM is a chronic pain syndrome characterized by
widespread pain, disturbed sleep, fatigue, and tenderness (10). Early reports of a generalized increase in pain
sensitivity (11) and lack of endogenous pain inhibition in
FM patients (12,13) have now gained support from
studies using functional MRI. Results include findings of
augmented neural signaling in response to pain stimulation (14), reduced ability to activate brain areas involved in endogenous pain modulation (15), and other
central nervous system abnormalities (16).
The effect of psychological symptoms in FM is
still an area of debate. There is a high frequency of
comorbidity with major depressive disorder (17), and
FM is still regarded by some as “occupying the grey area
between medicine and psychiatry” (18). Two studies
investigated the effect of mood on pain processing in
FM, one focusing on depressive symptoms (19) and the
other on catastrophizing thoughts (20). Depressive
symptoms had no influence on the intensity of clinical
pain or the sensory-discriminative processing of induced
pressure pain. However, with increasing depressive
symptoms, activity in 2 brain regions pertaining to
emotional processing, i.e., the insula and the amygdala,
increased during sustained pain provocation (19). Pain
catastrophizing (20), independent of depressive symptoms, was associated with increased activity in many
different brain areas, including the anterior cingulate
cortex, cerebellum, secondary sensory cortex, and frontal gyrus (none of these regions overlapping with the
brain regions found by Giesecke et al [19]).
It is possible that negative affect has a selective
impact on cognitive functions such as attention (21) and
anticipation (22) but not on the processing of pain per
se. In 2 previous functional MRI studies (21,22) the
pressure pain stimulations were administered in blocks,
making the pain predictable and introducing confounding due to the possible impact of negative affect on
attention and anticipation of pain. The use of an unpredictable stimulation paradigm is thus preferable when
investigating the influence of negative affect on pain
In a previous study, we were able to demonstrate
a specific dysfunction in pain regulation among patients
with FM, using functional MRI during randomly presented pain stimuli (15). In that study, FM patients were
compared with healthy controls, and a possible difference in pain processing related to the presence of
negative affect was not investigated. Using the same
experimental paradigm, the present study addressed the
differential effect of depressive symptoms, anxiety, and
catastrophizing on cerebral processing of pain in a large
number of FM patients (n ⫽ 83). Secondary aims were
to assess the influence of depressive symptoms, anxiety,
and catastrophizing on clinical pain, sensitivity to pressure pain, ratings of general health, and impact of FM
Patients were recruited as part of a pharmacologic
multicenter study conducted at 3 sites in Europe: London,
Stockholm, and Cologne (EudraCT #2004-004249-16). The
present study was performed using data from the baseline
measurements in that study, before patients were randomized
and treatment initiated. All patients were female and were
right-handed, and all had been recruited from primary care
settings and had been diagnosed as having FM according to the
1990 American College of Rheumatology criteria (23). The
patients ranged in age from 18 to 55 years. Criteria for
enrollment included a self-reported average pain intensity of at
least 40 mm on a 100-mm visual analog scale (VAS) over the
last week, as well as discontinuation of all treatments that
could influence the patient’s pain perception (i.e., antidepressants and mood stabilizers, analgesics, strong opioids, anticonvulsants, centrally acting relaxants, joint injections, trigger/
tender point injections, biofeedback, and transcutaneous
electrical nerve stimulation).
Patients with severe psychiatric illness or with significant risk of suicide were excluded from the study, as were
patients with a history of substance, drug, or alcohol abuse.
Qualified investigators (mainly rheumatologists) used the Beck
Depression Inventory (BDI) (24) in combination with a clinical
interview to ensure that patients were not severely depressed.
This was done to ensure the safety of the patients during the
clinical trial. Additional exclusion criteria included risk of
significant cardiovascular/pulmonary disease (including electrocardiographic abnormalities and hypertension), liver disease, renal impairment, autoimmune disease, current systemic
infection, malignancy, sleep apnea, active peptic ulcer, unsta-
Figure 1. Cross-sectional representation of the pneumatic pain stimulator. The thumb is inserted from the left side and rests on the wedge.
The thumbnail is positioned straight under the piston.
ble endocrine disease, pregnancy or breastfeeding, participation in a pharmacologic trial during the prior 3 months, and
unwillingness to discontinue prohibited medications. The reasons men were not included in the study were the possibility of
different pathogenetic presentations in men and women and
the male:female prevalence ratio of 1:9 in FM (25). Similar
prevalence ratios have also been observed in related syndromes, such as chronic fatigue syndrome and headaches (26),
but the mechanisms underlying these sex differences are still
poorly understood.
A total of 157 FM patients were screened, of whom 92
(mean ⫾ SD age 44 ⫾ 8.2 years [range 24–55 years]) fulfilled
the inclusion criteria and were enrolled in the study. Nine of
the 92 patients were excluded from functional MRI analyses
due to image artifacts or incidental findings of intracranial
anomalies, leaving 83 patients for the functional MRI analysis.
Image artifacts included extensive head movement during
scans or metal in the mouth causing image distortions. All
reported analyses are based on the 83 patients (mean ⫾ SD
age 43.8 ⫾ 8.1 years) with intact data from both the behavioral
and the neuroimaging experiments.
Pressure pain thresholds were assessed using a pressure algometer (Somedic). An algometer is a handheld apparatus with a 1-cm2 hard rubber probe that is held at a 90° angle
against the body and then pressed with a steady rate of
pressure increase (30 kPa/second) in order to induce pain.
Pressure pain thresholds were assessed bilaterally at 4 different
sites, i.e., trapezius muscle, elbows (lateral epicondyle), quadriceps femoris muscle, and knees (medial fat pad proximal to
the joint line), with one assessment per anatomic site. The total
average pressure pain threshold was calculated for each patient and used for further analysis.
For the purpose of calibration and induction of pain
during functional MRI, a custom-made tool was used to inflict
pain to the thumbnail (27). The stimulations were performed
using an automated, pneumatic, computer-controlled stimulator with a plastic piston that applies pressure via a 1-cm2 hard
rubber probe. The thumb is inserted into a cylindrical opening
and positioned such that the probe applies pressure to the
nailbed (Figure 1). Pressure pain was chosen as the stimulation
modality, because it elicits a deep pain sensation that is
clinically valid and represents a diagnostic criterion for FM.
The thumb is not a commonly reported tender point, which
makes it a suitable neutral target for stimulation.
Images were collected using 3 different 1.5T scanners,
programmed with identical scanning parameters. Multiple
T2*-weighted single-shot gradient-echo echo planar imaging
(EPI) sequences were used to acquire blood oxygen level–
dependent contrast images. The following parameters were
used: repetition time 3,000 msec (35 slices acquired), echo time
40 msec, flip angle 90°, field of view 24 ⫻ 24 cm, matrix 64 ⫻
64, slice thickness 4 mm, slice gap 0.4 mm, sequential image
acquisition order, and voxel size 2 ⫻ 2 ⫻ 4 mm. In the scanner,
cushions and headphones were used to reduce head movement
and dampen scanner noise. Visual distraction during scans was
minimized by placing a blank screen in front of the patient’s
field of view.
High-resolution T1-weighted structural images were
acquired in coronal orientation for anatomic reference purposes and screening for cerebral anomalies. Parameters were
as follows: spoiled gradient-recalled 3-dimensional sequence,
repetition time 24 msec, echo time 6 msec, flip angle 35°, 124
contiguous 1.5-mm coronal slices (image resolution 256 ⫻
256 ⫻ 186 mm, voxel size 0.9 ⫻ 0.9 ⫻ 1.5 mm).
The scanning procedure was standardized between
sites by using written manuscripts for all oral instructions and
providing practical training for all investigators involved in the
study. A central coordinator made several visits to the 3 sites
to ensure calibration of experimental procedures. Functional
data were collected in pilot patients in order to assure similar
results between sites. Full-factorial analysis of variance
(ANOVA) including the 3 sites as well as the experimental
conditions, probing for any possible difference in brain activation for any of the conditions at any of the sites, was performed
using SPM5 software. Data on the median, SD, and 95%
confidence interval for the signal intensity at each site are
available from the corresponding author upon request.
The BDI was used to quantitatively assess depressive
symptoms. The BDI is a 21-item measure of the severity of
depressive symptoms, and it has been extensively validated
for use with both medical and mental health populations (24).
Scoring allows for the identification of mild, moderate, and
severe levels of depressive symptoms. The BDI does not
provide information about possible specific major depressive
disorders according to the Diagnostic and Statistical Manual of
Psychiatric Disorders (28); rather, it gives a quantified measure
of the degree of depressive symptoms. A high score on the BDI
corresponds to a high level of depressive symptoms.
The State-Trait Anxiety Inventory (STAI) was used to
assess the participants’ levels of state anxiety. STAI is a
self-report questionnaire with 2 independent 20-item scales for
measuring state-related or trait-related anxiety (29). A high
score on the STAI corresponds to a high level of anxiety
The Coping Strategies Questionnaire (CSQ) was used
to assess levels of catastrophizing thoughts about pain, a
parameter commonly described in studies of chronic pain. The
CSQ is a self-reported measure of cognitive and behavioral
responses utilized to cope with chronic pain, and patients are
asked to rate the frequency with which they use each strategy
on a 7-point scale (30). A high score on the CSQ corresponds
to a high level of catastrophizing.
The Short Form 36 (SF-36) is a well-established questionnaire measuring 8 domains of health status: physical
functioning, role limitations because of physical problems,
bodily pain, general health perceptions, energy/vitality, social
functioning, role limitations due to emotional problems, and
mental health (31). A low general health score on the SF-36
corresponds to a poor rating of one’s health.
The Fibromyalgia Impact Questionnaire (FIQ) is a
20-item questionnaire that assesses the overall symptom severity in patients with FM (32). A high score on the FIQ
corresponds to a perceived high severity of FM.
The day before scanning, patients rated their pain
using a VAS ranging from 0 mm to 100 mm. Patients were
asked to score their current pain and their average pain during
the last week.
For each patient, subjective pain ratings were calibrated by application of one ascending series of pressure
stimuli to the thumbnail and one randomized series, using the
automated thumb pressure device. Pressures with a duration of
2.5 seconds were delivered at 30-second intervals. Patients
were instructed to rate the intensity of the pain evoked by each
stimulus, by placing a mark on a 100-mm horizontal VAS
ranging from “no pain” to “worst imaginable pain.” During the
ascending series, the pressure stimuli were presented in steps
of 50 kPa of increased pressure. Data from the ascending series
were used to determine each patients’ pain threshold (first
VAS score of ⬎0 mm) and stimulation maximum (first rating
of ⬎60 mm). These values were then used to compute the
magnitude of 5 different pressure intensities within the range
of each patients’ threshold and maximum. A total of 15 stimuli,
3 of each intensity, were delivered in a randomized order at
30-second intervals, preventing the patients from being able to
anticipate the intensity of the next stimulus. A polynomial
regressed function was used to determine each individual’s
calibrated pain rating of 50 mm on the VAS, derived from the
15 ratings from the randomized series.
Patients returned for scanning the day after the procedure for calibrating pain rating. Two types of stimulation
were used during scans: pain that would be rated 50 mm on a
VAS based on the previously obtained calibration and a
nonpainful pressure perceived only as light touch. All stimulations were randomly applied over the scanning time, preventing patients from anticipating the onset time and event type.
The time interval between consecutive events was randomized,
with a mean stimulus onset asynchronicity of 15 seconds (range
10–20). Four different random sequences were created. Each
patient received all 4 sequences, but the order of the sequences
was randomized for each. The total duration of the scans was
⬃35 minutes. Before scanning, patients were instructed to
focus on the pressures on the thumb and to use no distraction
or coping techniques.
Behavioral data and self-ratings were analyzed using
Spearman’s rank correlation coefficient with SPSS version
16.0. P values less than 0.001, with Bonferroni correction for
multiple comparisons, were considered significant.
Imaging data were analyzed using Matlab 7.1 (MathWorks) and SPM5. All functional brain volumes were re-
aligned to the first volume, spatially normalized to a standard
EPI template, and finally smoothed using an 8-mm full-width
at half-maximum isotropic Gaussian kernel (33). Data were
also subjected to high-pass filtering (cutoff period 128 seconds)
and correction for temporal autocorrelations. Data analysis
was performed using a generalized linear model and modeling
of the 2 different conditions (calibrated pain of 50 mm on a
VAS and nonpainful pressure) as delta functions convolved
with a canonical hemodynamic response function (HRF).
A file containing the movement parameters for each
individual (6 directions) was obtained from the realignment
step and saved for inclusion in the model. A design matrix
prepared for each patient included regressors for the 2 conditions (calibrated pain and no pain). Regression coefficients for
both regressors were estimated using least squares within
SPM5. Specific effects were tested with appropriate linear
contrasts of the parameter estimates for the HRF regressor of
both conditions, resulting in a t-statistic for each voxel. Data
were analyzed for each patient individually (first-level analysis)
and for the group (second-level analysis). To assess painspecific cerebral activity and to control for individual differences in cerebral responsiveness, brain activation during nonpainful pressures was individually subtracted from activity
during calibrated pain. ANOVA was performed in order to
determine whether there was any difference in pain-evoked
brain activity that could be explained by a study site–related
factor. The effect of depressive symptoms, anxiety, or catastrophizing on brain activity during pain processing was measured by performing 3 individual regression analyses using
each patient’s depression, anxiety, or catastrophizing scores as
a covariate. In addition to the regression analysis, which is a
sensitive measure for the full range of depressive scores,
2-sample t-tests were performed to compare brain activity
between the 20 highest-scoring and the 20 lowest-scoring
subjects for depression, anxiety, and catastrophizing scores.
The mean ⫾ SD score on the BDI was 18 ⫾ 10
(range 0–47). Twelve patients had BDI scores of ⬎29
(indicating severe depressive symptoms), 23 patients
scored between 19 and 29 (indicating moderate to severe
depressive symptoms), 30 patients scored between 10
and 18 (indicating mild to moderate depressive symptoms), and 18 patients scored between 0 and 9 (normal
range). Mean ⫾ SD scores for the various psychological
measures and pain assessments are shown in Table 1.
Correlation analysis (Spearman’s rho) including
all self-ratings (n ⫽ 83) demonstrated that depressive
symptoms, anxiety, and catastrophizing scores were significantly correlated with one another (␳ ⫽ 0.8 for
depression and anxiety, 0.5 for depression and catastrophizing, and 0.5 for anxiety and catastrophizing; P ⬍
0.001), but did not correlate with any measure of pain
sensitivity (weekly pain, sensitivity to pressure pain
thresholds, and calibrated pain). However, the subjec-
Table 1. Mean ⫾ SD values for all variables investigated in the 83
patients with FM*
Duration of FM, months†
BDI score
STAI-T score
CSQ score
Average pain in a week, 100-mm VAS
Thumb pressure, kPa‡
Algometer pressure, kPa§
FIQ score
SF-36 general health score
136 ⫾ 94
18 ⫾ 10
48 ⫾ 11
15 ⫾ 8
65 ⫾ 15
401 ⫾ 165
160 ⫾ 107
65 ⫾ 15
38 ⫾ 19
* BDI ⫽ Beck Depression Inventory; STAI-T ⫽ trait anxiety on the
State-Trait Anxiety Inventory; CSQ ⫽ Coping Strategies Questionnaire; FIQ ⫽ Fibromyalgia Impact Questionnaire; SF-36 ⫽ Short
Form 36.
† From the time the patient first subjectively reported fibromyalgia (FM) symptoms.
‡ Pressure needed to evoke calibrated pain scored at 50 mm on a
100-mm visual analog scale (VAS).
§ Average pain threshold from locations all over the body.
tive measure of general health (SF-36) was inversely
correlated with ratings of depressive symptoms (␳ ⫽
⫺0.36, P ⬍ 0.001) (Figure 2) as well as anxiety (␳ ⫽
⫺0.40, P ⬍ 0.001), but not with any measure of pain
sensitivity. The subjective rating of FM symptom severity (FIQ) correlated both with psychological measures
and with ratings of pain (for depressive symptoms, ␳ ⫽
0.49, P ⬍ 0.001; for anxiety, ␳ ⫽ 0.51, P ⬍ 0.001; for
weekly pain, ␳ ⫽ 0.43, P ⬍ 0.001; for pressure pain
thresholds, ␳ ⫽ 0.34, P ⬍ 0.01; for self-rated general
health, ␳ ⫽ ⫺0.54, P ⬍ 0.001). The variables time since
onset of FM symptoms and calibrated pain did not
Figure 2. Scatterplot of the fibromyalgia patients’ scores for depressive symptoms (measured using the Beck Depression Inventory [BDI])
and subjective ratings of physical health (measured using the Short
Form 36 [SF-36]). A significant inverse correlation was found (␳ ⫽
⫺0.36, P ⬍ 0.001).
Figure 3. Main effect of brain activity evoked by painful stimulation
minus that evoked by nonpainful sensory stimulation in the 83 patients
with fibromyalgia. The sections shown represent the anterior cingulate
cortex, thalamus, cerebellum, insula, and S1. Coordinates correspond
to the anatomic space as defined in the Montreal Neurological
Institute Standard Brain Atlas (36).
correlate with any other variables in the correlation
To validate the pain provocation paradigm, we
calculated the main effect of brain activity occurring
during calibrated pain minus that occurring during nonpainful pressure in the 83 FM patients, using a 1-sample
t-test. The results showed significant increases in painrelated structures such as S1, S2, the anterior cingulate
cortex, bilateral insulae, periaqueductal gray matter,
amygdalae, thalamus, and cerebellum (Figure 3 and
Table 2), thus reproducing the pain matrix previously
described in the literature (34,35).
ANOVA, performed with SPM5, revealed no
site-specific variation in pain-evoked brain activity
among the 3 study sites (Stockholm, London, Cologne).
In order to further investigate for possible variance
among study sites, the signal intensity in S2 (⫺42, ⫺20,
20 in the Montreal Neurological Institute Standard
Brain Atlas [36]) was ascertained for each patient.
Values for pain-evoked brain intensity in S2 were compared statistically, by ANOVA using SPSS, among the 3
study sites, and no significant difference between sites
was revealed (F[2,81] ⫽ 0.69, P ⫽ 0.51).
The 3 regression analyses in which depressive
symptoms, anxiety, or catastrophizing scores were used
as covariates showed no significant results, i.e., brain
activity during pain was not modulated by different
Table 2. Representation of brain activity during painful stimulation
minus brain activity during nonpainful sensory stimulation, in the 83
patients with FM*
Brain region
T score
Left posterior
Right posterior
* Coordinates (X, Y, and Z) correspond to the anatomic space as
defined in the Montreal Neurological Institute Standard Brain Atlas (36). Laterality in relation to the painful stimuli on the right thumb
is shown where applicable. FM ⫽ fibromyalgia; PAG ⫽ periaqueductal
gray matter; ACC ⫽ anterior cingulate cortex.
levels of depressive symptoms, anxiety, or catastrophizing. In analyses using SPM5, there was no significant
finding for any brain region, and there were no significant clusters, Z values, or P values to report (threshold
was set at P ⬍ 0.001, uncorrected for multiple comparisons). Further post hoc analyses of the data included
t-tests, which revealed no significant differences in brain
activity during pain provocation among the 20 patients
with the highest depression scores versus the 20 with the
lowest depression scores (threshold set at P ⬍ 0.001,
uncorrected for multiple comparisons). When the 20
patients with the highest scores on the BDI, STAI, and
CSQ combined (range 100–143) were compared with
the 20 patients with the lowest scores on these 3 tests
combined (range 31–59), there was also no significant
difference in brain activity.
We found no relationship between negative
mood and cerebral processing of pain among patients
with FM. We also found that patients’ reports of clinical
and experimentally induced pain were not affected by
levels of depressive symptoms, anxiety, or catastrophizing. These findings add to evidence from earlier studies
that 2 different, partially segregated neural mechanisms
are involved with pain processing and negative affect in
FM patients.
The pressure pain stimulation paradigm used in
this study produced an adequate response of the pain
matrix (37), i.e., all expected brain regions involved in
pain processing were activated. Several regions of the
brain have been associated with depression and anxiety,
including altered function of the prefrontal cortex and
limbic structures (38). In order to create a situation that
closely corresponded to the emotional stress associated
with uncontrollable clinical pain, the paradigm used in
this study was a randomized design that precluded
prediction of the pain stimuli. Despite the large variations in depressive symptoms and anxiety, we found no
brain regions with significant covariation with depressive
symptoms, anxiety, or catastrophizing during pain.
Giesecke et al (19) found increased neuronal
activity in the bilateral amygdalae and contralateral
anterior insula in association with depressive symptoms,
indicating more involvement of emotional processing in
response to the pain stimulation in depressed patients.
The paradigm they used was a block design with inherent predictability of the pain stimuli. It is possible that
with this paradigm, nondepressed patients were not
challenged enough, since they could have coped better
with the situation by steeling themselves prior to pain
block, therefore not activating the emotional structures
as much as occurred in the depressed patients. Thus,
previously reported results could be due to a difference
in pain anticipation and do not necessarily provide any
information about pain processing per se. This possible
effect was controlled for in the present design. Moreover, Gracely et al (20) found an association between
high levels of catastrophizing and increased brain activity in regions involved in attention to pain and anticipation of pain. That finding was not reproduced in the
present study. However, the high and low catastrophizing patients in Gracely and colleagues’ study differed in
levels of clinical pain as well as sensory and affective
Therefore, we conclude that mood does not
affect the perception or processing of experimentally
induced nociceptive stimuli in FM patients when anticipation and differences in behavioral measures are controlled for. An alternative explanation for the differences between previous and current findings is that the
duration of the painful stimuli in the present study was
only 2.5 seconds, compared with blocks of 25 seconds.
Even if the blocks were highly predictable in earlier
studies, they could have been more distressing and
thereby more sensitive to emotional activation.
In a study of patients with RA (9), no relationship
was found between depressive symptoms and cerebral
pain processing in RA patients during experimental pain
(heat). However, there was a positive correlation be-
tween ratings of depressive symptoms and activation of
the medial prefrontal cortex during provoked joint pain
in RA patients. We might have observed a similar effect
in the present study had we used pressure to a tender
point instead of the thumbnail. Furthermore, RA patients do not differ from healthy controls in heat pain
sensitivity (39), whereas FM patients have been shown
to be more sensitive to pressure also at the thumbnail
(27). Increased cerebral processing of pain (14), disinhibition (15), and normalization after successful treatment (40) have repeatedly been demonstrated using
thumb pressure in patients with FM, demonstrating
aberrations in central pain processing in this disorder.
The current results show that these aberrations exist
independent of psychological factors such as depressive
symptoms, anxiety, and catastrophizing.
The generalized, multimodal increase in pain
sensitivity and widespread pain that are characteristic of
FM make it difficult to clearly distinguish between
experimental and “clinical” pain stimulation. This is a
limitation to our study design that hinders clear interpretation of our data. Another major difference between
the present study and the RA study is the pronounced
difference in depressive symptoms. In our study, depressive symptoms were severe in 12 patients, moderate to
severe in 23, mild to moderate in 30, and low (normal) in
18. In the RA study, there was no representation of
severe depressive symptoms at all, and only 3 patients
had scores that indicated moderate to severe depression.
It has been speculated that emotional response is
generally exaggerated in FM patients, suggesting that
the disorder is caused by psychological vulnerability
(41). However, the effects of antidepressants on pain
seem to be independent of mood, since the antidepressant and analgesic effects are independent of each other
in clinical trials (42,43). Also, recent studies have provided evidence that affective modulation is not increased
in FM patients (44,45). We have previously demonstrated that FM patients do exhibit augmented pain
sensitivity in response to pain provocation compared
with controls, but there was no difference in the brain
regions relating to the affective aspect of pain (15). The
only difference in pain processing between FM patients
and controls was seen in a specific region of the frontal
lobe that is highly involved in descending inhibition of
pain (the rostral anterior cingulate cortex) (15).
In the present study, scores for depressive symptoms, anxiety, and catastrophizing did not correlate with
any measure of pain sensitivity. Therefore, our results do
not support the notion that there is pronounced affective
pain modulation in FM. Rather, the significant correla-
tion between depression, anxiety, and the subjective
rating of one’s health (general health score on the SF-36
and FIQ) suggests that negative mood affects the perception of one’s health status. Negative mood in FM
patients could thus lead to a poor perception of physical
health but not to poor performance on clinical and
experimental pain assessments. Furthermore, the duration of disease did not correlate with any other measurement, indicating that symptoms in FM are relatively
stable over time, and that there is no linear relationship
between FM duration and development of depression
and anxiety.
In conclusion, among patients with FM, depression, anxiety, and catastrophizing did not correlate with
ratings of clinical experimental pain and did not modulate brain activity during experimental pain. Our data
therefore provide evidence that there are 2 different,
partially segregated neural mechanisms involved in pain
processing and negative affect in FM.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Jensen had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Jensen, Petzke, Fransson, Marcus,
Williams, Choy, Mainguy, Gracely, Ingvar, Kosek.
Acquisition of data. Jensen, Petzke, Carville, Marcus, Williams, Choy,
Mainguy, Ingvar, Kosek.
Analysis and interpretation of data. Jensen, Petzke, Fransson, Marcus,
Williams, Choy, Mainguy, Gracely, Ingvar, Kosek.
1. Craig AD. A new view of pain as a homeostatic emotion. Trends
Neurosci 2003;26:303–7.
2. Merskey H, Bogduk N. Classification of chronic pain. 2nd ed.
Seattle: IASP Press; 1994. p. 209–14.
3. Godinho F, Magnin M, Frot M, Perchet C, Garcia-Larrea L.
Emotional modulation of pain: is it the sensation or what we
recall? J Neurosci 2006;26:11454–61.
4. Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R,
et al. Exacerbation of pain by anxiety is associated with activity in
a hippocampal network. J Neurosci 2001;21:9896–903.
5. Edwards RR, Bingham CO III, Bathon J, Haythornthwaite JA.
Catastrophizing and pain in arthritis, fibromyalgia, and other
rheumatic diseases. Arthritis Rheum 2006;55:325–32.
6. De Souza JB, Potvin S, Goffaux P, Charest J, Marchand S. The
deficit of pain inhibition in fibromyalgia is more pronounced in
patients with comorbid depressive symptoms. Clin J Pain 2009;25:
7. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and
pain comorbidity: a literature review. Arch Intern Med 2003;163:
8. Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, Parrish
TB, et al. Chronic pain and the emotional brain: specific brain
activity associated with spontaneous fluctuations of intensity of
chronic back pain. J Neurosci 2006;26:12165–73.
9. Schweinhardt P, Kalk N, Wartolowska K, Chessell I, Wordsworth
P, Tracey I. Investigation into the neural correlates of emotional
augmentation of clinical pain. Neuroimage 2008;40:759–66.
10. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population.
Arthritis Rheum 1995;38:19–28.
11. Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain
12. Kosek E, Hansson P. Modulatory influence on somatosensory
perception from vibration and heterotopic noxious conditioning
stimulation (HNCS) in fibromyalgia patients and healthy subjects.
Pain 1997;70:41–51.
13. Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 1997;13:189–96.
14. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic
resonance imaging evidence of augmented pain processing in
fibromyalgia. Arthritis Rheum 2002;46:1333–43.
15. Jensen KB, Kosek E, Petzke F, Carville S, Fransson P, Choy E, et
al. Evidence of dysfunctional pain inhibition in fibromyalgia
reflected in rACC during provoked pain. Pain 2009;144:95–100.
16. Staud R. Fibromyalgia pain: do we know the source? Curr Opin
Rheumatol 2004;16:157–63.
17. Goldenberg DL. The interface of pain and mood disturbances in
the rheumatic diseases. Semin Arthritis Rheum 2010;40:15–31.
18. Wessely S, Hotopf M. Is fibromyalgia a distinct clinical entity?
Historical and epidemiological evidence. Baillieres Best Pract Res
Clin Rheumatol 1999;13:427–36.
19. Giesecke T, Gracely RH, Williams DA, Geisser ME, Petzke FW,
Clauw DJ. The relationship between depression, clinical pain, and
experimental pain in a chronic pain cohort. Arthritis Rheum
20. Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F,
Williams DA, et al. Pain catastrophizing and neural responses to
pain among persons with fibromyalgia. Brain 2004;127:835–43.
21. Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith S, Tracey I.
Imaging how attention modulates pain in humans using functional
MRI. Brain 2002;125:310–9.
22. Song GH, Venkatraman V, Ho KY, Chee MW, Yeoh KG,
Wilder-Smith CH. Cortical effects of anticipation and endogenous
modulation of visceral pain assessed by functional brain MRI in
irritable bowel syndrome patients and healthy controls. Pain
23. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C,
Goldenberg DL, et al. The American College of Rheumatology
1990 criteria for the classification of fibromyalgia: report of the
Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–72.
24. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An
inventory for measuring depression. Arch Gen Psychiatry 1961;4:
25. Bartels E, Dreyer L, Jacobsen S, Jespersen A, Bliddal H, Danneskiold-Samsoe B. Fibromyalgia, diagnosis and prevalence: are
gender differences explainable? Ugeskr Laeger 2009;171:3588–92.
In Danish.
26. Yunus MB. The role of gender in fibromyalgia syndrome. Curr
Rheumatol Rep 2001;3:128–34.
27. Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH. Increased
pain sensitivity in fibromyalgia: effects of stimulus type and mode
of presentation. Pain 2003;105:403–13.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.
Spielberger CD. Manual for the State-Trait Anxiety Inventory
(Form Y). Palo Alto: Consulting Psychologists Press; 1983.
Rosenstiel AK, Keefe F. The use of coping strategies in chronic
low back pain patients: relationship to patient characteristics and
current adjustment. Pain 1983;17:33–44.
Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form
health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–83.
Burckhardt CS, Clark SR, Bennett RM. The Fibromyalgia Impact
Questionnaire: development and validation. J Rheumatol 1991;18:
Frackowiak RS, Friston KJ, Frith C, Dolan R, Price C, Zeki S, et
al. Human brain function. San Diego: Academic Press; 2004.
Ingvar M. Pain and functional imaging. Philos Trans R Soc Lond
B Biol Sci 1999;354:1347–58.
Tracey I. Nociceptive processing in the human brain. Curr Opin
Neurobiol 2005;15:478–87.
Evans AC, Marrett S, Neelin P, Collins L, Worsley K, Dai W, et al.
Anatomical mapping of functional activation in stereotactic coordinate space. Neuroimage 1992;1:43–53.
Tracey I, Mantyh PW. The cerebral signature for pain perception
and its modulation. Neuron 2007;55:377–91.
Drevets WC. Functional neuroimaging studies of depression: the
anatomy of melancholia. Annu Rev Med 1998;49:341–61.
Leffler AS, Kosek E, Lerndal T, Nordmark B, Hansson P.
Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid
arthritis. Eur J Pain 2002;6:161–76.
Kosek E, Jensen K, Carville S, Choy E, Gracely RH, Ingvar M, et
al. All responders are not the same: distinguishing Milnacipranfrom placebo-responders using pressure pain sensitivity in a
fibromyalgia clinical trial [abstract]. Pain in Europe V: Fifth
Congress of the European Federation of IASP Chapters (EFIC);
2009 Sept 9–12; Istanbul, Turkey.
Ehrlich G. Fibromyalgia, a virtual disease. Clin Rheumatol 2003;
Arnold LM, Rosen A, Pritchett YL, D’Souza DN, Goldstein DJ,
Iyengar S, et al. A randomized, double-blind, placebo-controlled
trial of duloxetine in the treatment of women with fibromyalgia
with or without major depressive disorder. Pain 2005;119:5–15.
Russell IJ, Mease PJ, Smith TR, Kajdasz DK, Wohlreich MM,
Detke MJ, et al. Efficacy and safety of duloxetine for treatment of
fibromyalgia in patients with or without major depressive disorder:
results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain 2008;136:432–44.
Arnold BS, Alpers GW, Suss H, Friedel E, Kosmutzky G, Geier A,
et al. Affective pain modulation in fibromyalgia, somatoform pain
disorder, back pain, and healthy controls. Eur J Pain 2008;12:
Petzke F, Harris RE, Williams DA, Clauw DJ, Gracely RH.
Differences in unpleasantness induced by experimental pressure
pain between patients with fibromyalgia and healthy controls. Eur
J Pain 2005;9:325–35.
Без категории
Размер файла
150 Кб
perception, pain, anxiety, fibromyalgia, health, poor, sensitivity, symptom, related, depression, cerebral, processing
Пожаловаться на содержимое документа