Download Duloxetine and Other Antidepressants in the

Blackwell Publishing IncMalden, USAPMEPain Medicine1526-2375American Academy of Pain Medicine20068S2S63S74
Original ArticleDuloxetine and Antidepressants in Fibromyalgia TreatmentArnold
PA I N M E D I C I N E
Volume 8 • Number S2 • 2007
Duloxetine and Other Antidepressants in the Treatment of Patients
with Fibromyalgia
Lesley M. Arnold, MD
Women’s Health Research Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
ABSTRACT
ABSTRACT
Objective. To review the use of duloxetine, a new selective serotonin and norepinephrine reuptake
inhibitor (SNRI), and other antidepressants in the treatment of patients with fibromyalgia.
Results. Duloxetine has been shown to be an effective and safe treatment for many of the symptoms
associated with fibromyalgia, particularly for women. Other selective SNRIs also show promise in
the treatment of fibromyalgia. Until recently, tricyclic agents that have serotonin and norepinephrine reuptake inhibitory activity had been the most commonly studied group of antidepressants,
and they are effective in treating pain and other symptoms associated with fibromyalgia, although
their use may be limited by safety and tolerability concerns. There are few randomized, controlled
studies of selective serotonin reuptake inhibitors in fibromyalgia, and the results have been mixed.
Conclusions. Antidepressants play an important role in the treatment of patients with fibromyalgia.
Agents with dual effects on serotonin and norepinephrine appear to have more consistent benefits
than selective serotonin antidepressants for the treatment of persistent pain associated with
fibromyalgia.
Key Words. Fibromyalgia; Antidepressant; Duloxetine; Serotonin; Norepinephrine
Introduction
F
ibromyalgia is a disorder of unknown etiology
characterized by chronic, widespread pain and
a decreased pain threshold to pressure and other
stimuli. Although the 1990 American College of
Rheumatology (ACR) criteria for fibromyalgia
include only widespread pain of at least 3 months’
duration and pain on digital palpation at 11 or
more of 18 specific tender point sites of the body
[1], most patients with fibromyalgia also experience other symptoms, including fatigue, sleep
disturbance (nonrestorative sleep or insomnia),
stiffness, anxiety, depression, cognitive disturReprint requests to: Lesley M. Arnold, MD, 222 Piedmont
Avenue, Suite 8200, Cincinnati, OH 45219, USA. Tel:
513-475-8110; Fax: 513-475-8116; E-mail: lesley.arnold@
uc.edu.
bances, irritable bowel or bladder syndromes,
headache, paresthesias, or other conditions [1].
There is substantial lifetime psychiatric comorbidity in patients with fibromyalgia, most commonly
mood and anxiety disorders [2]. Fibromyalgia
aggregates in families and coaggregates with major
mood disorder in families, suggesting that genetic
factors are involved in the etiology of fibromyalgia
and that mood disorders may share some of these
inherited factors [3].
Fibromyalgia affects approximately 2% of the
general population in the United States and is
more common in women than in men, affecting
3.4% of women compared with 0.5% of men [4].
Fibromyalgia is associated with functional impairment and work disability [5] and, compared with
other musculoskeletal diseases, is the only disorder
that is associated with lower scores than the gen-
© American Academy of Pain Medicine 1526-2375/07/$15.00/S63 S63–S74
doi:10.1111/j.1526-4637.2006.00178.x
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
Design. Two randomized, placebo-controlled, double-blind, parallel-group, 12-week trials of duloxetine in the treatment of fibromyalgia were reviewed. Other published, randomized, placebocontrolled, double-blind trials, and meta-analyses of antidepressant treatment of fibromyalgia were
identified by a PubMed search that was augmented by reference cross-check.
S64
peripheral neuropathic pain in nondepressed
patients [16,17], and is indicated by the Food and
Drug Administration for the treatment of major
depressive disorder in adults, generalized anxiety
disorder in adults, and neuropathic pain associated
with diabetic peripheral neuropathy in adults [18].
Methods
The two randomized, double-blind, placebocontrolled trials of duloxetine in the treatment
of fibromyalgia were reviewed. Other published,
randomized, double-blind, placebo-controlled
antidepressant trials in fibromyalgia and metaanalyses of antidepressant trials were identified by
a PubMed search that was augmented by reference
cross-check.
Results
Duloxetine
The first study of duloxetine in fibromyalgia
included 207 patients with fibromyalgia with or
without current major depressive disorder in a
randomized, placebo-controlled, double-blind,
parallel-group, multisite, 12-week study to assess
the safety and efficacy of duloxetine, titrated to
60 mg twice a day (BID) [19]. Co-primary outcome measures were the Fibromyalgia Impact
Questionnaire (FIQ) total score and pain score
[20]. The FIQ is a 20-item self-report instrument
that asks patients to rate their overall symptoms
and function over the previous week. The first 11
items make up a physical functioning scale, and
each item is rated on a 4-point Likert-type scale.
Items 12 and 13 ask patients to mark the number
of days they felt well and number of days they
missed work (including housework) because of
fibromyalgia symptoms. Items 14 through 20 are
measured on a 0–10 scale and rate difficulty doing
work, pain, tiredness, morning tiredness, stiffness,
anxiety, and depression. The total score of fibromyalgia impact ranges from 0 to 80, with 0 indicating no impact and 80 indicating maximum
impact. Duloxetine-treated patients compared
with placebo-treated patients improved significantly more on the FIQ total score, but not significantly more on the FIQ pain score. Compared
with placebo-treated patients, duloxetine-treated
patients also had significantly greater improvement in several secondary measures that included
the Brief Pain Inventory (short form) [21] average
pain severity score that measured pain over the
past 24 hours from 0 (no pain) to 10 (pain as bad
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
eral population in all of the health-related
quality of life dimensions involving mental health
problems [6].
Antidepressants are widely used to treat symptoms associated with fibromyalgia, and the rationale for their use is supported by several lines of
evidence. First, antidepressants are effective treatments for mood and anxiety disorders that are
common in patients with fibromyalgia and negatively impact function and quality of life. Second,
evidence of coaggregation of major mood disorder
and fibromyalgia in families suggests that fibromyalgia and mood disorders share common physiologic abnormalities that might respond to similar
treatments [3]. For example, dysfunction of central
monoaminergic neurotransmission might be one
of the shared etiologic factors involved in mood
disorders and fibromyalgia [3]. Serotonin and
norepinephrine are thought to mediate endogenous analgesic mechanisms through the descending pain inhibitory pathways in the brain and
spinal cord [7]. Antidepressant medications that
enhance serotonin and norepinephrine neurotransmission may therefore reduce pain in
patients with fibromyalgia. Third, there is substantial evidence that antidepressants that increase
serotonin and norepinephrine neurotransmission
are effective in the treatment of other chronic pain
conditions [8]. Fourth, some antidepressants have
other properties, including N-methyl-D-aspartate
(NMDA) antagonism and ion-channel blocking
activity that may also mediate antinociceptive
effects [9,10]. Finally, there is growing evidence
in large, well-designed clinical trials that some
antidepressants are effective in the treatment of
fibromyalgia.
The purpose of this review is to highlight the
recent clinical trials of one such antidepressant,
duloxetine, and to put this new evidence in the
context of other clinical trials of antidepressant
treatment of fibromyalgia. Duloxetine is a new,
potent selective serotonin and norepinephrine
reuptake inhibitor (SNRI) that has virtually no
affinity for cholinergic, histaminergic, and adrenergic receptors [11]. The dual reuptake inhibition
of serotonin and norepinephrine is active over
duloxetine’s entire clinically relevant dose range
[11]. Duloxetine has been shown to be a safe, tolerable, and effective antidepressant [12–14], and
duloxetine also significantly reduces painful physical symptoms, such as headache, back pain, stomach aches, and poorly localized musculoskeletal
pain, associated with major depressive disorder
[15]. Duloxetine is effective in reducing diabetic
Arnold
Duloxetine and Antidepressants in Fibromyalgia Treatment
as you can imagine) (Figure 1) and the average
pain interference score that assessed interference,
from 0 (does not interfere) to 10 (completely
interferes), with general activity, mood, walking
ability, normal work, relations with other people,
sleep, and enjoyment of life. Duloxetine-treated
patients compared with those on placebo also
experienced significant improvement in tender
point number and mean tender point pain threshold. For the tender point assessment, a Fisher
dolorimeter with a rubber disk of 1 cm2 [22] was
applied to the 18 tender point sites defined by the
ACR criteria [1], and the pressure was increased
at a rate of 1 kg/s until the patients verbally indicated that they first felt discomfort or pain. The
pressure was then stopped, and the threshold measurement was recorded in kg/cm2. The mean tender point threshold was calculated from 18 points,
and the tender point count was determined by the
number of tender points that had a threshold of
≤4 kg/cm2. Other secondary measures that significantly improved in the duloxetine-treated group
compared with the placebo group included the
FIQ stiffness score, Clinical Global Impression of
Severity scale that ranged from 1 (normal, not at
all ill) to 7 (among the most extremely ill patients)
[23], and the Patient Global Assessment of
Improvement scale that ranged from 1 (very much
better) to 7 (very much worse). Quality of life
measures that significantly improved in the duloxetine group compared with the placebo group
included the Quality of Life in Depression Scale
total score, the Sheehan Disability Scale total
score, and the Medical Outcomes Study Short
Form 36 (SF-36) physical subscore and scores for
bodily pain, general health perception, mental
health, physical functioning, and vitality [24–26].
In this first trial, duloxetine-treated female
patients demonstrated significantly greater improvement on most efficacy measures compared
with placebo-treated female patients, while the
duloxetine-treated male patients failed to significantly improve on any efficacy measure. The
interaction of treatment with sex approached the
significance level of 0.1 for the FIQ total score
(P = 0.101) and the FIQ pain score (P = 0.121)
(Figure 2). Significantly more duloxetine-treated
female patients (30.3%) had a clinically meaningful (≥50%) decrease in the FIQ pain score compared with placebo-treated female patients
(16.5%). Furthermore, the Brief Pain Inventory
average pain severity score decreased by ≥50%
in significantly more duloxetine-treated women
(30%) than women on placebo (16%). The reasons for the gender differences in response are
unclear, but may be related to the small male subgroup (23 [11%] of 207 patients), or to possible
sex differences in fibromyalgia than affect treatment response [19].
The duloxetine trial was the first fibromyalgia
clinical trial to assess baseline psychiatric comorbidity using a structured clinical interview and to
include patients with and without current major
depressive disorder in order to evaluate the impact
of major depressive disorder on the response to
treatment with duloxetine. Notably, duloxetine
treatment improved pain severity regardless of
baseline major depressive disorder status. In addition, the treatment effect of duloxetine on significant pain reduction in female patients was
Figure 2 Least-squares (LS) mean change from baseline
in the Fibromyalgia Impact Questionnaire (FIQ) total score
and FIQ pain score by sex. FIQ total score: duloxetine
(female N = 89, male N = 12), placebo (female N = 91, male
N = 11); FIQ pain score: duloxetine (female N = 89, male
N = 12), placebo (female N = 92, male N = 11).
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
Figure 1 Least-squares (LS) mean change from baseline
in the Brief Pain Inventory (BPI) average pain severity score
for all randomized patients. Duloxetine 60 mg BID =
duloxetine 60 mg twice a day.
S65
S66
Figure 3 Least-squares (LS) mean change from baseline
in the Brief Pain Inventory (BPI) average pain severity score
for all randomized patients. Duloxetine 60 mg BID =
duloxetine 60 mg twice a day; duloxetine 60 mg QD =
duloxetine 60 mg once a day.
60 mg BID (41%) compared with placebo (23%)
had a ≥50% reduction in the Brief Pain Inventory
average pain severity score. Compared with placebo, duloxetine 60 mg QD or duloxetine 60 mg
BID resulted in significantly greater improvement
in the remaining Brief Pain Inventory pain severity and interference scores, and other secondary
outcomes including the FIQ [20] Clinical Global
Impression of Severity [23], and the Patient Global Impression of Improvement. Consistent with
the first duloxetine study, several quality of life
measures significantly improved in both duloxetine groups compared with the placebo group
including the Quality of Life in Depression Scale
total score, the Sheehan Disability Scale total
score, and the SF-36 mental subscore, bodily pain,
mental health, role limit emotional, role limit
physical, and vitality [24–26]. There were no significant differences between duloxetine 60 mg QD
and duloxetine 60 mg BID treatment groups in
efficacy outcomes. However, only the duloxetine
60 mg BID dose, compared with placebo, significantly improved the tender point assessments.
This suggests that the higher dose may be necessary to improve pressure pain thresholds, which
have been found to be less responsive to treatment
in previous fibromyalgia trials using tricyclics
[28,29]. As in the first study of duloxetine, the
treatment effect of duloxetine on pain reduction
was independent of the effect on mood and the
presence of major depressive disorder.
The most frequent side effect in patients in the
duloxetine 60 mg QD and 60 mg BID groups was
nausea, and side effects were generally mild to
moderate in severity for most patients. Significantly more patients in the duloxetine 60 mg BID
group than the placebo group discontinued treatment due to adverse events. This finding differs
from the previous duloxetine trial of 60 mg BID
in which there were no differences between treatment groups in discontinuation due to treatmentemergent adverse events. The difference between
the studies might be explained by the slower titration of duloxetine in the first study, in which
duloxetine was titrated from a starting dose of
20 mg QD to 60 mg BID over 2 weeks. In the
second study, patients were started on 60 mg QD
and titrated to 60 mg BID over just 3 days. This
suggests that some patients would benefit from
a lower duloxetine starting dose and slower
titration.
The results of both duloxetine studies in fibromyalgia provide evidence that duloxetine 60 mg
QD and 60 mg BID for up to 12 weeks are safe
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
independent of the effect on mood or anxiety.
Therefore, the effect of duloxetine on the reduction of pain associated with fibromyalgia appears
to be independent of its effect on mood.
Duloxetine was well tolerated, and there was no
significant difference in the number of patients
who discontinued due to adverse events. Duloxetine-treated patients reported insomnia, dry
mouth, and constipation significantly more frequently than placebo-treated patients. Most treatment-emergent adverse events were of mild or
moderate severity.
The second, randomized, placebo-controlled,
double-blind, parallel-group, multisite, 12-week
study of duloxetine in fibromyalgia tested the
safety and efficacy of both 60 mg BID and a lower
dose of 60 mg once a day (QD) in 354 women
with fibromyalgia with or without current major
depressive disorder [27]. This study included only
women to confirm the results of the first duloxetine trial in which women, but not men, responded
significantly to duloxetine compared with the
same sex placebo-treated patients on efficacy measures. The primary outcome measure was pain
severity as measured by the Brief Pain Inventory
(short form) average pain severity score (score
range 0–10) [21]. Compared with the placebo
group, the duloxetine 60 mg QD group and the
duloxetine 60 mg BID group experienced significantly greater improvement in the Brief Pain
Inventory average pain severity score, beginning
at week 1 and continuing through week 12
(Figure 3). Significantly more patients treated
with duloxetine 60 mg QD (41%) and duloxetine
Arnold
Duloxetine and Antidepressants in Fibromyalgia Treatment
and effective in the treatment of fibromyalgia in
women with or without major depressive disorder.
Randomized, Double-Blind, Placebo-Controlled
Trials of Other Antidepressants in Fibromyalgia
fibromyalgia. The primary outcome measure was
based on change in pain recorded on an electronic
diary, comparing baseline to endpoint (last 2
weeks on treatment). The majority of milnacipran-treated patients titrated to the highest daily
dose (200 mg), suggesting that milnacipran was
well tolerated. The most frequently reported
adverse event was nausea, and most adverse events
were mild and transient. Patients treated with milnacipran on a twice daily schedule experienced
significant improvement in pain compared with
those on placebo. Significantly more patients
receiving milnacipran twice daily (37%) reported
a reduction in the weekly average pain scores by
50% or more, compared with 14% of patients in
the placebo group. Milnacipran-treated patients
on the once daily schedule did not exhibit the same
degree of improvement in pain, suggesting that
dosing frequency is important in the use of milnacipran for pain associated with fibromyalgia.
Both milnacipran groups (once daily and twice
daily dosing) had significantly greater improvement on secondary measures, including the
Patient Global Impression of Change score, and
the physical function and “days felt good” subscales of the FIQ [20]. As in the duloxetine trials,
patients were evaluated for psychiatric comorbidity and those with and without current major
depressive disorder were included. Unlike the
results of the duloxetine trials in which both
depressed and nondepressed patients responded
similarly to duloxetine, statistically greater improvement in pain reduction was seen in nondepressed patients vs depressed patients treated with
milnacipran. Although this finding needs to be
replicated in a larger clinical trial, the positive
response in nondepressed patients suggests that,
like duloxetine, the pain-relieving effects of milnacipran do not occur only through improvement
in mood.
Tricyclics
Tricyclics agents, which inhibit the reuptake of
serotonin and norepinephrine, have been the most
commonly studied antidepressants in clinical trials
of fibromyalgia, and there are three meta-analyzes
of tricyclics in the treatment of fibromyalgia. The
first meta-analysis [28] assessed nine placebocontrolled trials of cyclic agents, including
amitriptyline [36–39], dothiepin, which is structurally similar to amitriptyline and doxepin [40],
cyclobenzaprine [37,41–43], which possesses
structural and pharmacological properties of other
tricyclics that have antidepressant effects [44]; clo-
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
Selective SNRIs
Venlafaxine was the first newer-generation antidepressant to be classified as a dual, selective SNRI.
However, unlike duloxetine, venlafaxine sequentially engages serotonin uptake inhibition at low
doses and norepinephrine uptake inhibition at
higher doses (typically at doses above 100 mg),
which is consistent with venlafaxine’s ascending
dose–antidepressant response curve [30]. Like
duloxetine, venlafaxine lacks the side-effect profile
of tricyclics associated with adrenergic, cholinergic, and histaminergic antagonism. Two openlabel studies of venlafaxine showed promise in the
treatment of fibromyalgia [31,32]. However, in the
only known randomized, placebo-controlled, double-blind trial of venlafaxine in 90 patients with
fibromyalgia, published just as an abstract [33],
venlafaxine at a fixed dose of 75 mg/day for
6 weeks did not improve the primary measures of
pain (visual analog scale [VAS] pain today and
McGill Pain Questionnaire [34]) significantly better than placebo. Notably, secondary measures,
including the total FIQ [20] and FIQ pain and
fatigue subscales improved significantly more in
the venlafaxine-treated group than the placebotreated patients. The short duration of this trial
and low dose of venlafaxine may explain the mixed
results, and controlled studies of doses of venlafaxine at 150 mg/day or higher are needed.
Milnacipran is another selective SNRI that has
been approved for treatment of depression since
1997 in parts of Europe, Asia, and elsewhere, but
is currently unavailable in the United States. Milnacipran is a dual serotonin and norepinephrine
reuptake inhibition within its therapeutic dose
range and also exerts mild NMDA inhibition [9].
Like duloxetine and venlafaxine, milnacipran lacks
the side effects of tricyclics associated with
antagonism of adrenergic, cholinergic, and histaminergic receptors. In a double-blind, placebocontrolled, multicenter trial, 125 patients (98%
women) with fibromyalgia were randomized to
receive placebo or milnacipran for 4 weeks of dose
escalation to the maximally tolerated dose followed by 8 weeks of stable dose (25–200 mg/day)
[35]. The study evaluated the efficacy and safety
of two different dosing regimens of milnacipran
(once daily vs twice daily) for the treatment of
S67
S68
ment in fibromyalgia and change in depression
scores [37,39]. The effect of tricyclics on pain
relief appears to be independent of modulation of
mood, which is consistent with the findings of the
duloxetine studies.
No fibromyalgia trials have directly compared
duloxetine or other selective SNRIs with tricyclics, and it is unknown whether the selective
SNRIs are more effective than the tricyclics in the
treatment of fibromyalgia. To date, tricyclics have
been the most studied agents in the treatment of
fibromyalgia, and they are frequently recommended for the treatment of patients with fibromyalgia [55]. However, the new selective SNRIs
provide an alternative for patients who have tolerability or safety concerns related to the anticholinergic, antiadrenergic, antihistaminergic, and
quinidine-like effects of tricyclics [56].
SSRIs
Selective serotonin reuptake inhibitors, which
have a high affinity for the serotonin transporter,
have been examined in six double-blind, placebocontrolled trials in fibromyalgia: two with citalopram [52,57], three with fluoxetine [39,51,58], and
one with paroxetine controlled release (CR) [59].
The first study of 42 patients with fibromyalgia
randomized to citalopram (20–40 mg/day) or placebo for 8 weeks found no significant differences
in efficacy between the citalopram and placebo
groups [52]. In the second randomized, doubleblind, placebo-controlled, 4-month study of 40
women with fibromyalgia, citalopram (20–40 mg/
day) treatment resulted in a significant decrease in
depressive symptoms compared with placebo, but
there were no significant differences between
groups in other symptoms of fibromyalgia [57].
The first fluoxetine trial of 20 mg/day did not
find a significant therapeutic effect over placebo
[51]. In two other controlled trials, fluoxetine was
superior to placebo in reducing pain and other
symptoms associated with fibromyalgia [39,58]. In
a double-blind, crossover study in which 19 subjects with fibromyalgia received four, 6-week trials
of fluoxetine 20 mg/day, amitriptyline 25 mg/day,
the combination, or placebo, both fluoxetine and
amitriptyline produced significant improvement
in pain, global well-being, and function compared
with placebo. Combination treatment produced
significantly greater improvement than did either
drug alone [39]. In a randomized, placebo-controlled, parallel-group, flexible-dose, 12-week trial
of fluoxetine in fibromyalgia, 60 female subjects
who did not have any current comorbid psychiat-
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
mipramine [45], and maprotiline [45], a tetracyclic
drug that primarily blocks the reuptake of norepinephrine. Seven outcome measures were assessed,
including the patients’ self-ratings of pain, stiffness, fatigue, and sleep; the patient and the physician global assessment of improvement; and
tender points. The largest effect was found in
measures of sleep quality, with more modest
changes in tender point measures and stiffness.
Thus, the most consistent improvement may be
attributed to the sedative properties of these medications. Overall, significant clinical response to
tricyclic agents was observed in 25% to 37% of
patients with fibromyalgia, and the degree of efficacy was modest in most studies [28].
The results of a meta-analysis of randomized,
placebo-controlled studies of cyclobenzaprine
were consistent with the Arnold et al. (2000)
[28] meta-analysis. Cyclobenzaprine treatment
resulted in moderate improvement in sleep, modest improvement in pain, and no improvement in
fatigue or tender points. Patients were about three
times as likely to report improvement in their
symptoms compared with those on placebo [46].
Another meta-analysis of antidepressants in the
treatment of fibromyalgia included 13 trials of
antidepressants, including amitriptyline in eight
studies [36–39,47–50], and clomipramine and
maprotiline in one study [45]. The meta-analysis
also included the selective serotonin reuptake
inhibitors (SSRIs), fluoxetine [39,51] and citalopram [52]; a reversible inhibitor of the MAO-A
enzyme, moclobemide [47]; and S-adenosylmethionine [53,54]. Outcome measures included the
number of tender points, and patients’ self-ratings
of pain, sleep, fatigue, and overall well-being. The
pooled results showed a significant symptomatic
benefit of antidepressants that was moderate for
sleep, overall well-being, and pain severity, and
mild for fatigue and number of tender points.
Patients treated with antidepressants were more
than four times as likely to improve as those on
placebo [29]. The magnitude of benefit was similar
to that found in the Arnold et al. (2000) [28] metaanalysis.
None of the controlled tricyclic studies systematically evaluated patients for psychiatric disorders, so the impact of comorbid major depressive
disorder on the response to tricyclic antidepressants is unknown. Few of the studies measured
depressive symptoms using standardized psychometric instruments, two of which evaluated the
impact of these symptoms on response to treatment and found no relationship between improve-
Arnold
Duloxetine and Antidepressants in Fibromyalgia Treatment
ies. On the other hand, positive studies of fluoxetine and paroxetine CR suggest that these
SSRIs have unique pharmacologic properties that
may underlie their efficacy in fibromyalgia.
Indeed, fluoxetine has been shown to increase
extracellular concentrations of norepinephrine as
well as serotonin in the prefrontal cortex in preclinical models [65], and paroxetine, at higher
doses, may exhibit norepinephrine transporter
inhibition [66]. Consistent with the results of
antidepressants like duloxetine that have dual
effects on serotonin and norepinephrine, SSRIs
that have additional effects on norepinephrine,
at adequate doses, may also be effective for
fibromyalgia.
Monoamine Oxidase Inhibitors (MAOIs)
Antidepressant medications that reversibly
inhibit the monoamine oxidase (MAO)-A
enzyme increase levels of norepinephrine, serotonin, and dopamine, and have improved side
effect profiles compared with MAOIs, like
phenelzine and tranylcypromine, that have irreversible and nonspecific effects on the MAO-A
and MAO-B enzymes [67]. Two MAO-A inhibitors, moclobemide and pirlindole, available in
Europe, have been studied in fibromyalgia. In a
12-week, double-blind, placebo-controlled study,
130 female patients with fibromyalgia, but without current psychiatric comorbidity, were randomized to moclobemide (450–600 mg/day),
amitriptyline (25–37.5 mg/day), or placebo for
12 weeks [47]. Response to treatment was
defined as a rating of minimally improved, much
improved, or very much improved on a clinical
impression of change scale. Fifty-four percent of
patients on moclobemide were judged to be
responders, but this did not significantly separate
from placebo. Moclobemide treatment also did
not improve secondary measures of pain significantly better than placebo. Amitriptyline treatment, on the other hand, led to significant
improvement compared with placebo on several
outcomes. The treatments were well tolerated,
with no differences between the groups in discontinuation rates due to side effects. More
promising results were reported in a pilot, 4week, randomized, double-blind, placebo controlled study of 100 patients with fibromyalgia,
in which pirlindole 75 mg twice daily was well
tolerated and produced significantly superior
improvement in pain, the manual tender point
score, and patient and physician global evaluation compared with placebo [68].
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
ric disorders or depressive symptoms based on a
score of 10 or greater on the 17-item Hamilton
Depression Scale [60] were randomized to receive
fluoxetine 10–80 mg/day or placebo and evaluated
with the FIQ [20] total score and FIQ pain score
as the primary outcome measures. Subjects receiving fluoxetine (mean dose 45 ± 25 mg/day) had
significantly greater reductions in FIQ total score,
and FIQ subscales of pain, fatigue, and depression
compared with subjects receiving placebo. A
≥25% improvement in the total FIQ score was
observed in 32% of the fluoxetine-treated subjects
compared with 15% of the subjects who received
placebo, although the difference was not significant. A ≥25% improvement in the FIQ pain
score was observed in significantly more of the
fluoxetine-treated subjects (56%) compared with
the placebo-treated subjects (15%). There was no
significant interaction between treatment and
either a history of major depressive disorder or by
baseline level of depression, and the effect of fluoxetine on pain was significant after adjustment
for change in the depression score. Therefore, as
was seen in the duloxetine trials, the effect of fluoxetine on reduction of pain associated with fibromyalgia appears to be independent of an effect on
mood. Fluoxetine was generally well tolerated;
there were no significant differences between the
two groups in dropouts due to side effects. Because
of the beneficial effects of higher doses of fluoxetine in this study, some patients who fail to respond
to a 20 mg/day dose of fluoxetine may improve
with higher doses, if tolerated.
In a randomized, double-blind, placebo-controlled, flexible-dose, 12-week trial of paroxetine
CR (dose 12.5–62.5 mg/day) in 116 patients with
fibromyalgia, response to treatment was defined
as 25% or greater reduction in the FIQ total
score [59]. Significantly more patients in the paroxetine CR group (57%) responded compared
with placebo (33%). However, there were no significant differences between treatment groups in
reduction of pain. The study of other SSRIs in
fibromyalgia is limited, due to either lack of a
placebo arm [61,62] or inadequate blinding
[63,64].
The mixed results for SSRIs in fibromyalgia
suggest that antidepressants with selective serotonin effects are less consistent in relieving pain
and other symptoms associated with fibromyalgia. Citalopram, which has the highest selectivity
for the serotonin reuptake transporters among
the SSRIs, was not effective for the treatment of
fibromyalgia in two controlled, albeit small stud-
S69
S70
Issues Related to the Design of the Antidepressant
Trials in Fibromyalgia
The review of duloxetine and other antidepressant
studies in fibromyalgia reveals several important
trial design issues to be considered in future clinical trials of antidepressants in the treatment of
fibromyalgia.
Trial Duration
Most of the antidepressant trials were of short
duration, and there is a need for more data on the
long-term efficacy of antidepressants in the treatment of fibromyalgia, a disorder that typically has
a chronic course. In the longest study of tricyclics
in fibromyalgia that extended to 6 months [37],
neither amitriptyline nor cyclobenzaprine demonstrated significantly greater efficacy than placebo
after 6 months of treatment. The two duloxetine
studies showed efficacy in 12-week trials, but longterm studies with duloxetine and other antidepressants would also be useful to establish maintenance
therapies for fibromyalgia.
Symptom Domains
The clinical presentation of fibromyalgia is heterogeneous. Although most fibromyalgia clinical trials have assessed change in the intensity of pain as
the primary outcome, they have inconsistently
evaluated other associated symptoms, such as sleep
disturbance, fatigue, depression, anxiety, and cog-
nitive function, which reduces the comparability
and clinical applicability of the trials. For example,
among the nine studies included in the Arnold
et al. (2000) [28] meta-analysis, seven outcomes
that were most commonly used included the
patients’ self-ratings of pain, stiffness, fatigue, and
sleep; the patient and the physician global assessment of improvement; and tenderness as measured
by tender points. However, none of the studies
included all of these outcomes. The more recent
studies of duloxetine and other SNRIs and SSRIs
included an assessment of pain, sleep, fatigue,
and depressive symptoms, which are symptom
domains thought to be of importance in the treatment of fibromyalgia. But other symptoms of
interest, such as anxiety, stiffness, and tenderness,
were not evaluated in all of the studies. Advances
in the treatment of fibromyalgia have been
impeded by the lack of consensus about symptom
domains that should be assessed in clinical trials.
Outcome Measures
Fibromyalgia antidepressant clinical trials have
used dissimilar measures to assess symptom
domains. For example, there were different methods for collecting information about pain (e.g.,
electronic daily diaries, or scales completed during
a visit), variable time frames for the evaluation of
pain (e.g., over the past week or past 24 hours),
and different scales (e.g., 0–10 numerical scales, 0–
100 VASs, or 0–20 anchored logarithmic box
scale). The method for determining tenderness as
a secondary outcome also varied between manual
exams, dolorimetry of the 18 tender point sites,
and a random sequence of pressure stimuli applied
to the nail bed of the thumb. Other important
outcomes such as impact on functioning and quality of life were not explored by many of the earlier
studies. The duloxetine and milnacipran trials
used the SF-36, a generic measure of function and
health-related quality of life, and also included the
FIQ. Neither the SF-36 domains nor the FIQ
scores were consistently responsive to change
across the studies, which suggest that either function may not be as responsive as other clinical
manifestations of fibromyalgia over 8–12 weeks of
treatment or that the measures are not sensitive
enough to detect treatment effects.
The primary outcome measure of most recent
fibromyalgia trials has been the mean reduction of
pain in the patients receiving a treatment compared with those receiving placebo. Although this
approach provides information about the overall
efficacy of a particular treatment in reducing pain,
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
Antidepressant Dosing
Most studies of tricyclic antidepressants used low
doses that were subtherapeutic for the treatment
of depression. This approach may have been influenced by concern about the undesirable side
effects of the tricyclics from their anticholinergic,
antihistaminergic, and α-adrenergic receptor
blockade activities. Considering the possible association between depression and fibromyalgia [69],
standard antidepressant doses may be needed to
obtain more than moderate improvement in
symptoms of fibromyalgia. More recent studies of
antidepressants have assessed a wider range of
antidepressant doses. The studies of standard therapeutic antidepressant doses of the SNRIs, duloxetine and milnacipran, and the SSRIs fluoxetine
and paroxetine CR indicate that these doses were
well tolerated by most patients and were effective
in reducing many of the symptoms of fibromyalgia. Based on these findings, doses of antidepressants at the therapeutic level for the treatment of
depression should be tested in future trials.
Arnold
Duloxetine and Antidepressants in Fibromyalgia Treatment
Comorbidity
Patients with fibromyalgia frequently have
comorbid disorders that may affect their response
to treatment. Despite evidence of elevated prevalence rates of mood and anxiety disorders in
patients with fibromyalgia and their possible
prognostic significance [31], few clinical trials
systemically evaluated patients for comorbid psychiatric disorders. The recent trials of duloxetine
were the first to diagnose psychiatric disorders
using structured clinical psychiatric interviews
and to include patients with and without current
major depressive disorder. Because about a third
of patients with fibromyalgia report major current problems with depression in the general
population [71], the finding that the improvement with duloxetine was independent of the
presence or absence of major depressive disorder
suggests that duloxetine could be a treatment
option for a diverse group of patients with fibromyalgia. Furthermore, the effect of duloxetine on
pain reduction was found to be independent of
its effect on depressive and anxiety symptoms,
consistent with the results of previous trials that
included assessment of psychiatric symptoms
[37,39,58]. The weight of the evidence from antidepressant trials of fibromyalgia suggests that,
although functional deficits of serotonin and
norepinephrine neurotransmission may be shared
between major depression and fibromyalgia, the
pain-modulating effects in spinal and supraspinal
pathways are not dependent on modulation of
mood.
Structured clinical psychiatric interviews are
also useful in identifying patients with psychiatric
disorders that may not be responsive to antidepressant monotherapy. For example, the duloxetine trials excluded patients with certain forms of
comorbid psychopathology, such as bipolar disorder. The co-occurrence of bipolar disorder in
fibromyalgia patients has received little attention
in previous studies. A recent study found that individuals with fibromyalgia were significantly more
likely to have comorbid bipolar disorder than
those without fibromyalgia [2]. The presence of
comorbid bipolar disorder has important implications for an antidepressant clinical trial, because
antidepressants may precipitate hypomanic,
manic, or mixed episodes in predisposed individuals who have existing or latent bipolar disorder
[72].
The duloxetine trials also excluded patients
with primary anxiety disorders. Antidepressants
are effective treatments for anxiety disorders,
which are also commonly comorbid in patients
with fibromyalgia, and more study is needed on
the potential impact of anxiety disorders on
response to treatment of fibromyalgia with antidepressants. In addition, assessments of personality
traits and disorders have rarely been included in
fibromyalgia clinical trials and may also be helpful
in identifying possible clinical predictors of
response to antidepressants.
Patients with fibromyalgia also have high rates
of other chronic pain disorders, including chronic
headache, irritable bowel syndrome, and temporomandibular disorder [73] as well as chronic fatigue
syndrome [74]. However, most fibromyalgia trials
have not assessed for these conditions or determined the effect of comorbidity on response to
treatment. Future trials should include an assessment of comorbid medical conditions.
Most trials excluded patients with pain from
some other disorders, such as rheumatoid arthritis,
inflammatory arthritis or autoimmune disease. As
many as 25% of patients with these rheumatic
conditions have secondary fibromyalgia [75], and
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
it does not determine the proportion of patients
who experience clinically important improvement.
The duloxetine trials included secondary outcome
measures for response to treatment of 30% and
50% reduction in a pain intensity scale. However,
more study is needed to establish consensus about
the definition of clinically meaningful reduction in
pain for fibromyalgia clinical trials. In addition, it
is unclear whether improvement in pain intensity
alone should define response to treatment in fibromyalgia, which is a syndrome characterized by
multiple symptoms in addition to pain. For example, other characteristics of pain might be of particular importance in fibromyalgia patients such as
the degree to which the pain is widespread and the
level of tenderness. It might also be important to
include other domains of interest in a measure of
response such as quality of life, physical and emotional function, sleep, fatigue, and cognition. Standardized, operationally defined outcome measures
of fibromyalgia activity and improvement would
greatly enhance the comparability, validity, and
clinical applicability of fibromyalgia trials. Defining efficacy in terms of an individual response to
treatment would allow clinicians to compare the
efficacy of different therapies and define factors
that predict response [70]. With this information,
clinicians could determine whether individual
patients would improve with a particular
treatment.
S71
S72
future trials should examine the efficacy of antidepressants in these patients.
Summary of Antidepressant Trials in Fibromyalgia
Although more trials are needed to explore the
efficacy of antidepressants in fibromyalgia, especially in long-term treatment studies, the evidence
supports the use of antidepressants in treating pain
and other symptoms associated with fibromyalgia.
Newer selective SNRIs, like duloxetine, milnacipran, and venlafaxine, that have the dual serotonin
and norepinephrine reuptake inhibition activity of
tricyclic antidepressants, but lack many of the
adverse side effects associated with tricyclics, show
promise in the treatment of fibromyalgia, and may
become the first-line choice for antidepressant
treatment.
Disclosures
Dr. Lesley Arnold—Grant/Research: Eli Lilly,
Pfizer, Cypress Biosciences, Wyeth, SanofiAventis, Boehringer Ingelheim, Allergan, Forest
Consultant: Eli Lilly, Pfizer, Cypress Biosciences,
Sanofi-Aventis, Wyeth, Forest, Sepracor, Forest, Allergan, Boehringer Ingelheim
Speaker: Eli Lilly, Pfizer
References
1 Wolfe F, Smythe HA, Yunus MB, 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.
2 Arnold LM, Hudson JI, Keck PE Jr, et al. Comorbidity of fibromyalgia and psychiatric disorders. J
Clin Psychiatry 2006;67:1219–25.
3 Arnold LM, Hudson JI, Hess EV, et al. Family
Study of Fibromyalgia. Arthritis Rheum 2004;
50:944–52.
4 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.
5 Walker EA, Keegan D, Gardner G, et al. Psychosocial factors in fibromyalgia compared with rheumatoid arthritis: I. Psychiatric diagnoses and functional
disability. Psychosom Med 1997;59:565–71.
6 Picavet HSJ, Hoeymans N. Health related quality
of life in multiple musculoskeletal diseases: SF-36
and EQ-5D in the DMC3 study. Ann Rheum Dis
2004;63:723–9.
7 Millan MJ. Descending control of pain. Prog Neurobiol 2002;66:355–474.
8 Fishbain D. Evidence-based data on pain relief with
antidepressants. Ann Med 2000;32:305–16.
9 Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: A drug development
perspective. Psychopharmacol Bull 2002;36:165–
213.
10 Lawson K. Tricyclic antidepressants and fibromyalgia: What is the mechanism of action? Expert Opin
Investig Drugs 2002;11:1437–45.
11 Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG,
et al. Comparative affinity of duloxetine for serotonin and norepinephrine transporters in vitro and in
vivo, human serotonin receptor subtypes, and other
neuronal receptors. Neuropsychopharmacology
2001;25:871–80.
12 Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack
MA. Duloxetine in the treatment of major depressive disorder: A double-blind clinical trial. J Clin
Psychiatry 2002;63:225–31.
13 Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine 60 mg once daily for major
depressive disorder: A randomized double-blind
placebo-controlled trial. J Clin Psychiatry
2002;63:308–15.
14 Detke MJ, Lu Y, Goldstein DJ, McNamara RK,
Demitrack MA. Duloxetine 60 mg once daily dosing
versus placebo in the acute treatment of major
depression. J Psychiatr Res 2002;36:383–90.
15 Goldstein DJ, Lu Y, Detke MJ, et al. Effects of
duloxetine on painful physical symptoms associated
with depression. Psychosomatics 2004;45:17–28.
16 Raskin J, Pritchett YL, Wang F, et al. A doubleblind, randomized multicenter trial comparing
duloxetine with placebo in the management of
diabetic peripheral neuropathic pain. Pain Med
2005;6:346–56.
17 Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S.
Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005;116:109–18.
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
Sex Differences
The majority of patients studied in the trials were
women, which reflects the much higher prevalence of fibromyalgia in women [1]. The results
of the studies may therefore not be generalizable
to men with fibromyalgia. Indeed, sex differences
in response to treatment were found in one of
the studies of duloxetine in fibromyalgia [19].
Although the reasons for the sex differences in
response to duloxetine are unclear, as discussed
above, there may be sex differences in the pathophysiology of fibromyalgia that could affect
response to treatment. For example, studies of
fibromyalgia clinical features have found that
women had significantly more tender points than
men, as well as more fatigue, sleep disturbance,
irritable bowel syndrome, and “pain all over”
[76].
Arnold
Duloxetine and Antidepressants in Fibromyalgia Treatment
35 Gendreau RM, Thorn MD, Gendreau JF, et al.
Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol 2005;32:1975–85.
36 Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis: A doubleblind, placebo-controlled study. Arthritis Rheum
1986;29:655–9.
37 Carette S, Bell MJ, Reynolds WJ, et al. Comparison
of amitriptyline, cyclobenzaprine, and placebo in
the treatment of fibromyalgia: A randomized,
double-blind clinical trial. Arthritis Rheum
1994;37:32–40.
38 Carette S, Oakson G, Guimont C, Steriade M.
Sleep electroencephalography and the clinical
response to amitriptyline in patients with fibromyalgia. Arthritis Rheum 1995;38:1211–7.
39 Goldenberg DL, Mayskiy M, Mossey C, Ruthazer
R, Schmid C. A randomized double-blind crossover trial of fluoxetine and amitriptyline in the
treatment of fibromyalgia. Arthritis Rheum
1996;39:1852–9.
40 Caruso I, Puttini PCS, Boccassini L, et al. Doubleblind study of dothiepin versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med
Res 1987;15:154–9.
41 Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The
effects of cyclobenzaprine on sleep physiology and
symptoms in patients with fibromyalgia. J Rheumatol 1991;18:452–4.
42 Bennett RM, Gatter RA, Campbell SM, et al. A
comparison of cyclobenzaprine and placebo in
the management of fibrositis. Arthritis Rheum
1988;31:1535–42.
43 Quimby LG, Gratwick GM, Whitney CD, Block
SR. A randomized trial of cyclobenzaprine for
the treatment of fibromyalgia. J Rheumatol
1989;16(suppl 19):140–3.
44 Kobayashi H, Hasegawa Y, One H. Cyclobenzaprine, a centrally acting muscle relaxant, acts on
descending serotonergic systems. Eur J Pharmacol
1996;311:29–35.
45 Bibolotti E, Borghi C, Pasculli E, et al. The management of fibrositis: A double-blind comparison of
maprotiline (Ludiomil), chlorimipramine, and placebo. J Clin Trials 1986;23:269–80.
46 Tofferi JK, Jackson JL, O’Malley PG. Treatment of
fibromyalgia with cyclobenzaprine: A meta-analysis.
Arthritis Rheum 2004;51:9–13.
47 Hannonen P, Malminiemi K, Yli-Kerttula U,
Isomeri R, Roponen P. A randomized, doubleblind, placebo-controlled study of moclobemide
and amitriptyline in the treatment of fibromyalgia
in females without psychiatric disorder. Br J Rheumatol 1998;37:1279–86.
48 Scudds RA, McCain GA, Rollman GB, Harth M.
Improvements in pain responsiveness in patients
with fibrositis after successful treatment with
amitriptyline. J Rheumatol 1989;16(suppl 19):98–
103.
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
18 Eli Lilly and Company, Cymbalta, USPI, May
2007.
19 Arnold LM, Lu Y, Crofford LJ, et al. A doubleblind, multicenter trial comparing duloxetine to placebo in the treatment of fibromyalgia patients with
or without major depressive disorder. Arthritis
Rheum 2004;50:2974–84.
20 Burckhardt CS, Clark SR, Bennett RM. The Fibromyalgia Impact Questionnaire: Development and
validation. J Rheumatol 1991;18:728–34.
21 Cleeland CS, Ryan KM. Pain assessment: Global
use of the brief pain inventory. Ann Acad Med
1994;23(2):129–38.
22 Fischer AA. Pressure threshold meter: Its use for
quantification of tender spots. Arch Phys Med
Rehabil 1986;67:836–8.
23 Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. US Department of Health,
Education, and Welfare publication (ADM). Rockville, MD: National Institute of Mental Health;
1976:76–338.
24 Sheehan DV, Harnett-Sheehan K, Raj BA. The
measurement of disability. Int Clin Psychopharmacol 1996;11(suppl 3):89–95.
25 Ware JE, Sherbourne CD. The SF-36 health status
survey: I. Conceptual framework and item selection.
Med care 1992;30:473–83.
26 Hunt SM, McKenna SP. The QLDS: A scale for
the measurement of quality of life in depression.
Health Policy 1992;22:307–19.
27 Arnold LM, Rosen A, Pritchett YL, 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.
28 Arnold LM, Keck PE Jr, Welge JA. Antidepressant
treatment of fibromyalgia. A meta-analysis and
review. Psychosomatics 2000;41:104–13.
29 O’Malley PG, Balden E, Tomkins G, et al.
Treatment of fibromyalgia with antidepressants.
A meta-analysis. J Gen Intern Med 2000;15:659–
66.
30 Harvey AT, Rudolph RL, Preskorn SH. Evidence
of the dual mechanisms of action of venlafaxine.
Arch Gen Psychiatry 2000;57:503–9.
31 Dwight MM, Arnold LM, O’Brien H, et al. An open
clinical trial of venlafaxine in fibromyalgia. Psychosomatics 1998;39:14–7.
32 Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother 2003;
37:1561–5.
33 Zijlstra TR, Barendregt PJ, van de Laar MAF. Venlafaxine in fibromyalgia: Results of a randomized,
placebo-controlled, double-blind trial. Presented at
the 66th Annual Meeting of the American College
of Rheumatology, 2002.
34 Melzack R. The McGill Pain Questionnaire: Major
properties and scoring methods. Pain 1975;1:277–
99.
S73
S74
63 Syuertsen JO, Smedsrud T, Lane RM. An open
study of sertraline in fibromyalgia syndrome. Eur
Neuropsychopharmacol 1995;5:315.
64 Giordano N, Geraci S, Santacroce C, et al. Efficacy
and tolerability of paroxetine in patients with fibromyalgia syndrome: A single-blind study. Curr Ther
Res 1999;60:696–702.
65 Bymaster FP, Zhang W, Carter PA, et al. Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine
extracellular levels in prefrontal cortex. Psychopharmacology 2002;160:353–61.
66 Nemeroff CB, Owens MJ. Neuropharmacology of
paroxetine. Psychopharmacol Bull 2003;37(suppl
1):8–18.
67 Priest RG, Baldwin DS, Bullock T, et al. Recent
advances in antidepressant drugs. S Afr Med J
1992;Jun 6(suppl):1–4.
68 Ginsberg F, Joos E, Géczy J, et al. A pilot randomized placebo-controlled study of pirlindole in the
treatment of primary fibromyalgia. J Musculoskeletal Pain 1998;6:5–17.
69 Hudson JI, Pope HG Jr. The relationship between
fibromyalgia and major depressive disorder. Rheum
Dis Clin North Am 1996;22:285–303.
70 Simms RW, Felson DT, Goldenberg DL. Development of preliminary criteria for response to treatment in fibromyalgia syndrome. J Rheumatol
1991;18:1558–63.
71 White KP, Nielson WR, Harth M, Østbye T,
Speechley M. Chronic widespread musculoskeletal
pain with or without fibromyalgia: Psychological
distress in a representative community adult sample.
J Rheumatol 2002;29:588–94.
72 Wehr T, Goodwin F. Rapid cycling in manic
depression induced by tricyclic antidepressants.
Arch Gen Psychiatry 1979;36:555–9.
73 Hudson JI, Goldenberg DL, Pope HG Jr, Keck PE
Jr, Schlesinger L. Comorbidity of fibromyalgia with
medical and psychiatric disorders. Am J Med
1992;92:363–7.
74 White KP, Speechley M, Harth M, Østbye T. Coexistence of chronic fatigue syndrome with fibromyalgia syndrome in the general population. Scand J
Rheumatol 2000;29:44–51.
75 Clauw DJ. Fibromyalgia syndrome: An update on
current understanding and medical management.
Rheumatology Grand Rounds 2000;3:1–9.
76 Yunus MB, Inanici F, Aldag JC, Mangold RF.
Fibromyalgia in men: Comparison of clinical features with women. J Rheumatol 2000;27:485–90.
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on November 18, 2016
49 Ginsberg F, Mancaux A, Joos E, Vanhove P, Famaey
JP. A randomized placebo-controlled trial of sustained-release amitriptyline in primary fibromyalgia. J Musculoskeletal Pain 1996;4:37–47.
50 Kempenears CH, Simenon G, Vander Elst M, et al.
Effect of an antidiencephalon immune serum on
pain and sleep in primary fibromyalgia. Neuropsychobiology 1994;30:66–72.
51 Wolfe F, Cathey MA, Hawley DJ. A double-blind
placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol 1994;23:255–9.
52 Nørregaard J, Volkmann H, Danneskiold-Samsoe
B. A randomized controlled trial of citalopram in
the treatment of fibromyalgia. Pain 1995;61:445–
9.
53 Tavoni A, Vitali C, Bombardieri S, Pasero G.
Evaluation of S-adenosylmethionine in primary
fibromyalgia. Am J Med 1987;83(suppl 5A):107–
10.
54 Jacobsen S. Danneskiold-Samsoe B, Andersen RB.
Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scan J Rheumatol 1991;20:294–302.
55 Goldenberg DL, Burckhardt C, Crofford L.
Management of fibromyalgia syndrome. JAMA
2004;292:2388–95.
56 Beliles K, Stoudemire A. Psychopharmacologic
treatment of depression in the medically ill. Psychosomatics 1998;39:S2–S19.
57 Anderberg UM, Marteinsdottir I, von Knorring L.
Citalopram in patients with fibromyalgia—A randomized, double-blind, placebo-controlled study.
Eur J Pain 2000;4:27–35.
58 Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of
women with fibromyalgia. Am J Med 2002;112:
191–7.
59 Patkar AA, Masand PS, Krulewicz S, et al. A
randomized, controlled trial of controlled release
paroxetine in fibromyalgia. Am J Med 2007;120:
448–54.
60 Hamilton M. A rating scale for depression. J Neurol
Neurosurg Psychiatry 1960;23:56–62.
61 Sarzi-Puttini P, Cazzola M, Pettorossi R, et al.
Comparative efficacy and tolerability of sertraline vs
amitriptyline in patients with fibromyalgia syndrome. J Functional Syndromes 2001;1(2/3):164–
70.
62 Nishikai M, Akiya K. Fluvoxamine therapy for
fibromyalgia. J Rheumatol 2003;30:1124–5.
Arnold