Download a closer look at fibromyalgia and its management

PROCEEDINGS
A CLOSER LOOK AT FIBROMYALGIA
AND ITS MANAGEMENT*
—
Arthur G. Lipman, PharmD, FASHP†
ABSTRACT
Fibromyalgia, most commonly referred to as
fibromyalgia syndrome (FMS), is a functional
disorder with an unclear organic cause.
Although the etiology is not defined, it appears
to be mutifactorial, with increasing evidence of
central sensitization. Pharmacotherapy for FMS,
which should be integrated with rehabilitative
physical activity, is often based on open-label
trials and anecdotal reports, and could be
improved if the pathophysiology of FMS were
more fully elucidated. This article reviews the
pharmacologic options and nonpharmacologic
modalities available to treat FMS and its comorbidities, and explains why both approaches are
necessary for successful outcomes. It also
addresses the important role of the pharmacist
in referring patients to healthcare professionals
with experience in treating FMS and in counseling and educating patients about appropriate medication use and side effects.
(Adv Stud Pharm. 2009;6(5):140-146)
*Based on a presentation by Dr Lipman at a roundtable
held in Boulder, Colorado, on June 5, 2009.
†University Professor, Department of Pharmacotherapy,
College of Pharmacy; Adjunct Professor, Department of
Anesthesiology, School of Medicine; Director of Clinical
Pharmacology, Pain Management Center, University Health
Care, University of Utah Health Sciences Center; Editor,
Journal of Pain and Palliative Care Pharmacotherapy, Salt
Lake City, Utah.
Address correspondence to: Arthur G. Lipman,
PharmD, FASHP, University of Utah Health Sciences Center,
30 South 2000 E, Room 258, Salt Lake City, UT 84112.
E-mail: [email protected].
140
F
ibromyalgia, or fibromyalgia syndrome
(FMS), is a functional disorder, which is
defined as a physiologic dysfunction with no
known organic basis.1 Functional disorders,
which affect up to 15% of the population worldwide,2
share several characteristics: they occur predominantly
in females; they are frequently associated with psychiatric disorders, sleep disturbances, and neuroendocrine
dysregulation; patients with one of these syndromes
often meet the diagnostic criteria for some of the others; and they often—but not always—respond, to
varying degrees, to the same therapies (eg, exercise,
cognitive-behavioral therapy [CBT], and antidepressant medication).
Functional disorders are generally classified as gastrointestinal (GI) or non-GI. FMS is the most common non-GI functional disorder, followed by chronic
fatigue syndrome (CFS), migraine and tension
headache, temporomandibular joint disorder, posttraumatic stress disorder, chronic pelvic pain, interstitial cystitis and dysuria, noncardiac chest pain, and
multiple chemical sensitivity (MCS).3 As reported in a
recent study, 98% of patients with FMS (vs 39% of
controls) had at least one functional GI disorder—
most commonly irritable bowel syndrome, functional
bloating, and functional fecal incontinence—as well as
higher levels of somatization, obsessiveness, anxiety,
and depression.4
Although pharmacists often see patients with physical, psychiatric, and other conditions with poorly elucidated pathophysiology, it is important for them to
understand that the seemingly unrelated symptom
constellations that patients often complain about do,
in fact, fit the definition of functional disorders.
FIBROMYALGIA SYNDROME
As a diagnosis of exclusion, FMS presents several
Vol. 6, No. 5
n
October 2009
PROCEEDINGS
challenges. First, the lack of specific tests to “prove” (or
“disprove”) the presence of FMS is often frustrating for
patients, healthcare providers, managed care plans,
and third-party payers. Second is the tendency to focus
on pharmacotherapy at the expense of nonpharmacologic modalities such as patient education and rehabilitative physical activity, both of which are crucial to
successful treatment. Third is pharmacotherapy itself,
which is often based on open-label trials and anecdotal reports in a highly suggestible population.
Pharmacotherapy could be greatly improved if the
pathophysiology of FMS were more fully elucidated.
A recently published hypothesis for the pathophysiology of FMS attributes the syndrome to a genetic
predisposition for FMS that activates neuroendocrine,
neurotransmitter, and neurosensory dysfunction, all of
which produce clinical symptoms in response to triggering events.5
depression, and anxiety in patients with FMS and
CFS11 and data suggesting that FMS, CFS, and MCS
may qualify as a single syndrome, with a history of
childhood abuse and domestic violence serving as psychological predispositions to these syndromes.12
Similarly, the association of FMS with depressed natural killer cell counts and function, low circulating levels
of immune complexes, and altered immunoglobulin
levels suggest an immunologic etiology.13
As shown in numerous neuroendocrine studies,
stress plays a serious role in FMS. The hypothalamicpituitary-adrenocortical (HPA) axis is the primary
mechanism for generating a stress response, and the
HPA axis functions abnormally in at least some subsets
of patients with FMS.14,15 Stressors and medical conditions that may trigger FMS are listed in Table 2.
CLINICAL CHARACTERISTICS AND
ASSOCIATED SYMPTOMS
The clinical characteristics of FMS are listed in
Table 1. In 1990, when the American College of
Rheumatology published criteria for the classification
of FMS, muscle pain was present in all patients, followed by fatigue in 96% and insomnia in 86%, rates
that are consistent with those seen today.6 However,
the low incidence of major depression reported at that
time differs from the much higher rates reported more
recently, due in part to cumulative changes in the definitions of various affective and anxiety disorders since
1990. As noted in an ongoing study at the University
of Utah, 72% of patients with FMS had either a major
depressive disorder or situational depression, yet both
groups were categorized under depression (Okifuji A,
Personal communication, April 2009).
Table 1. Clinical Characteristics of Fibromyalgia
ETIOLOGY OF FIBROMYALGIA
The precise etiology of FMS is unknown, but there
is considerable evidence that physical, psychiatric,
immunologic, and other factors play contributory
roles. Studies implicating elevated levels of nitric oxide
and peroxynitrite in the pathology of FMS, CFS, and
MCS,7 enteroviral infection of skeletal muscle,8
Mycoplasma blood infection,9 and dietary intake of
excitotoxins such as aspartate and monosodium glutamate10 support a physical etiology.
Studies supporting a psychiatric etiology include
demonstration of a higher frequency of fatigue, pain,
University of Tennessee Advanced Studies in Pharmacy
n
•
•
•
•
•
•
•
Pain
Lightheadedness, dizziness, or syncope
Fatigue
Chronic insomnia
Cognitive deficits; short-term memory loss
Depression and/or anxiety
Numbness and/or dysesthesia in hands and feet
Table 2. Stressors and Medical Conditions that May
Trigger Fibromyalgia
Stressors
• Peripheral pain syndromes
• Infections (eg, parvovirus, Epstein-Barr virus, and Lyme disease)
• Physical trauma (automobile accidents)
• Psychological stress/distress
• Hormonal alterations (eg, hypothyroidism)
• Drugs and vaccines
• Certain catastrophic events (war or not natural disasters)
Medical Conditions
• Hypothyroidism
• Polymyalgia rheumatica
• Early course of autoimmune diseases (eg, rheumatoid arthritis
and lupus)
• Sjogren’s syndrome
• Hepatitis C
• Sleep apnea
• Chiari malformation
141
PROCEEDINGS
Other suggested etiologies associated with FMS
include hypersensitivity to inorganic mercury and
nickel,16 thyroid hormone resistance,17 and post-viral
infection, particularly hepatitis C.18
TREATMENT OF FIBROMYALGIA
Treatment of FMS typically is multimodal, combining pharmacotherapy with nonpharmacologic
modalities; interdisciplinary care often is needed.
Focusing on pharmacotherapy alone to manage pain,
particularly in the primary care setting, is inadequate
because no single drug—including the 3 that are
approved for FMS—is consistently effective in most
patients. Nevertheless, many patients do well under a
primary care physician’s guidance, provided there is
adequate patient education, initially gentle physical
activity and conditioning, appropriate pharmacotherapy, good psychological support, and attention to the
comorbidities that often confound FMS.
PHARMACOTHERAPY
Several agents from different drug classes—including tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors, and opioids—have
been used in the treatment of FMS, with varying
degrees of clinical efficacy and effectiveness. Of the
drugs used in present-day practice, only 3 (pregabalin,
duloxetine, and milnacipran) are approved in this
country for FMS; they are discussed elsewhere in this
publication (see the article by Jacquelyn Bainbridge,
PharmD, FCCP). Other drugs that are not specifically approved for FMS are indicated for the pain or
depression associated with FMS.
Tricyclic antidepressants
Tricyclic antidepressants are often used as initial
treatment for FMS. Observations in clinical practice
suggest that 25% to 50% of patients show clinical
improvement initially, but continued improvement is
elusive. The mechanism of action of the TCAs is
believed to be blockade of norepinephrine and serotonin reuptake at the neuronal membrane, with the
norepinephrine effect appearing to be more important
than the serotonin effect.
Amitriptyline, the most well-studied TCA in FMS,
has potent anticholinergic and sedative effects (Table
3).19 The number needed to treat (NNT) to see a 50%
reduction in symptoms is between 3 and 5. By comparison, desipramine has less potent anticholinergic
142
and sedative effects than amitriptyline (Table 3), but is
comparable to amitriptyline in relieving neuropathic
pain. Additionally, desipramine is more noradrenergic
and has a shorter half-life (still permitting once-daily
dosing at bedtime) than amitriptyline. Although
amitriptyline and desipramine have not been compared
in a head-to-head trial in FMS, desipramine should be
considered in place of amitriptyline because of its lower
risk for anticholinergic and sedative side effects.
Cyclobenzaprine, an amitriptyline analog with central muscle relaxant properties, has been considered for
FMS despite limited evidence of its effectiveness. It has
no apparent advantage over other tricyclic compounds
for most patients, and its muscle relaxant activity generally ceases after 4 to 8 days of continued use.
Dependence (but not addiction) is common.
Although the drug’s NNT for self-reported improvement was found to be approximately 5 in a metaanalysis,20 it might be a reasonable alternative in
patients with FMS who also have intermittent muscle
spasticity.
Opioids
Although the use of opioids in FMS is not supported by data from controlled trials, anecdotal reports
claim efficacy. All healthcare professionals who work in
the clinical setting have seen a small percentage of
patients, perhaps 10% to 15%, who do very well on
Table 3. Selected Characteristics of Amitriptyline
and Desipramine
Amitriptyline
Relative anticholinergic effects
Relative sedative effects
Relative norepinephrine reuptake inhibition
Relative serotonin reuptake inhibition
Half-life (hours)
+++
++++
++
++++
30–45
Desipramine
Relative anticholinergic effects
Relative sedative effects
Relative norepinephrine reuptake inhibition
Relative serotonin reuptake inhibition
Half-life (hours)
+
+
++++
++
12–25
Data from Lipman.19
Vol. 6, No. 5
n
October 2009
PROCEEDINGS
opioids and very poorly when these drugs are discontinued. Restarting opioid therapy is reasonable in
patients who use these drugs as prescribed (ie, no unauthorized dose escalation) and are adherent to the drug
regimen and other components of the plan of care.
Two recently published evidence-based guidelines
on opioid use in chronic noncancer pain provide
guidance.21,22
increase in blood pressure, pharmacists should counsel
patients about periodic blood pressure monitoring and
safe dosing of these agents.
Other agents and combinations
Tramadol alone and in combination with acetaminophen may be helpful in treating some patients
with FMS. One randomized-controlled trial demonstrated modest clinical efficacy with no serious adverse
effects in 156 women who received tramadol/acetaminophen combination tablets (37.5 mg/325 mg) up
to 4 times a day and 157 women who received placebo for 91 days.23 Tramadol is a relatively safe drug, and
is not a federally controlled substance.
The results of a small pilot study of naloxone, a systemic opioid antagonist, suggest that it deserves further study to determine whether it has a role in
treating FMS.24 Although the single-blind crossover
study included only 10 patients, the entire cohort
reported a 30% reduction in pain and other symptoms
compared with those receiving placebo after treatment
with low-dose (4.5 mg) oral naloxone, which must be
compounded. Interestingly, patients with elevated erythrocyte sedimentation rates had the greatest reduction in symptoms in response to therapy. Other
reports do not support these findings. It is too early to
reach any conclusions about naloxone in FMS.
Tapentadol is a new chemical entity that was
recently approved for the management of acute pain;
studies evaluating the drug in chronic pain are under
way. Tapentadol is both a µ-opioid receptor agonist
and a norepinephrine reuptake inhibitor, and its
mechanism of action suggests potential in the treatment of FMS, particularly as an alternative to pure µagonists in patients who respond to opioids. It has not
yet been studied for this indication.
Although the combined use of acetaminophen and
nonsteroidal anti-inflammatory drugs (NSAIDs) often
is helpful in relieving concurrent nociceptive pain in
patients with FMS, there is no evidence of its efficacy
in FMS per se. Clinical reports advocate the use of
acetaminophen and NSAIDs in selected patients (ie,
those whose pain worsens when the drugs are discontinued). Because NSAIDs are associated with an
N ONDRUG THERAPY
Nondrug therapy is essential to the overall treatment of patients with FMS. An interdisciplinary rehabilitative approach based on the chronic pain model is
the core of nondrug therapy. It consists of gentle physical activity and exercise, patient education, and CBT.
The effectiveness of CBT has been documented to
improve coping skills, functioning, and mood.25-27
However, studies have been relatively limited, and the
results have been moderate.
In 2001, researchers at the University of Utah
examined studies evaluating the efficacy of NSAIDs,
low-dose amitriptyline, exercise, and interdisciplinary
rehabilitation on the tender point count, myalgic
score, pain, sleep, fatigue, and mood in patients with
FMS-related problems. They found that NSAIDs were
not effective at all; amitriptyline had significant positive effects on sleep, pain, and fatigue; and exercise was
associated with significant reductions in tender point
count and myalgic score (Okifuji A, Ashburn MA,
University of Tennessee Advanced Studies in Pharmacy
n
Treatment of comorbidities
Treatment of FMS includes managing comorbid
conditions. Options for the comorbidities that most
frequently accompany FMS are outlined in Table 4.
Table 4. Symptomatic Pharmacotherapy for
Comorbidities
Irritable bowel syndrome
• Fiber, guar gum, and pitted prunes
Chronic fatigue syndrome
• Possible use of stimulants
Depression
• Antidepressants and psychotherapy
Insomnia
• Very conservative use of hypnotic agents
• Improved sleep hygiene
Anxiety
• Anxiolytic agents
Dry/itchy eyes
• Artificial tears
143
PROCEEDINGS
2001; Unpublished observations). Only the interdisciplinary approach was consistently effective across all
domains.
Ongoing research comparing the effect of patient
education, CBT, and motivation-based emotional
therapy (MET) on pain, function, and symptom coping in patients with FMS has found greater improvement in all 3 areas with MET than with traditional
CBT (Okifuji A, Personal communication, April
2009). It appears that improving motivation, not just
cognition, should be included in psychotherapeutic
approaches for optimal outcomes.
CONCLUSIONS
The etiology of FMS is unclear, but it appears to be
multifactorial, with accumulating evidence of central
sensitization. Optimal pharmacotherapy should be
based on etiology.
Pharmacotherapy should not be the sole intervention in the treatment of FMS, but should be integrated with rehabilitative modalities. In addition,
pharmacotherapy should not be directed to pain relief
alone, but to other symptoms as well. Because no single drug is effective for the majority of patients, therapy needs to be multimodal and customized to address
the patient’s symptoms.
Pharmacists should identify the best FMS clinicians in their communities and refer accordingly. They
should also continue to educate and counsel patients
with FMS about optimal medication use.
DISCUSSION
PHARMACOTHERAPY ISSUES
Dr Strassels: Why is it that no single drug is consistently effective in most patients?
Dr Lipman: That finding is based on the NNT
analyses. In other words, how many patients do we
have to treat with a given drug to get a 50% reduction
in symptoms? We typically look for an NNT of 5 to 6,
meaning that only 1 out of 5 or 1 out of 6 patients is
likely to respond to any single pharmacotherapy with
a 50% reduction in symptoms. The US Food and
Drug Administration criterion for approving drugs for
FMS is not the majority of patients responding, but a
statistically significant separation from placebo.
Dr Natelson: The major problem I have with
TCAs is weight gain. If I prescribe a TCA for a woman
who is in pain and she gains 20 pounds, the extra
weight is likely to make it even more difficult and
144
painful for her to get around.
Dr Lipman: I prefer not to use amitriptyline
because it has 4 times as much anticholinergic effect
per milligram as desipramine, which has been shown
to have comparable efficacy at equal doses in doubleblind studies of (non-FMS) neuropathic pain.
Although these drugs have not been tested for analgesic equivalence in FMS, it is reasonable to assume
that they have similar efficacy in FMS as well.
Moreover, desipramine has a far better side-effect profile than amitriptyline. The anticholinergic effect
appears to be the primary cause of the side effects we
are familiar with, including increased appetite leading
to weight gain.
Dr Natelson: The reason I use amitriptyline is for
its sedative effects.
Dr Lipman: Even when sleep is an issue,
desipramine may be a better choice because it produces initial sedation with far less anticholinergic
activity. Patients with functional pain disorders are not
lying awake at night because of low blood levels of
amitriptyline; they are awake because of pain.
Dr Strassels: Because naloxone is taken by mouth,
it seems to suggest peripheral activity. Have you seen
any evidence for the peripheral antagonists themselves?
Dr Lipman: The original supposition was that oral
naloxone for opioid-induced constipation would act
locally on the µ receptors in the gut, but the evidence
does not support that. Some absorption is needed for
systemic effect. Patients with functional pain disorders
may have a more porous gut than healthy individuals,
and that might account for the small amount of systemic absorption of naloxone that produces the
peripheral effect.
INTERDISCIPLINARY APPROACHES AND ALGORITHMS
Dr Kirsh: Including good psychological support in
the overall treatment plan for FMS is extremely important. As a licensed clinical psychologist, I can say that
not all psychologists are created equal, just as not all
physical therapists are the same, a point that was made
in the previous discussion. In chronic pain globally,
and in FMS in particular, the pharmacist needs to
know the psychologist’s approach to pain management
before making any recommendations or referrals. I was
trained at 1 of only 2 institutions in the country that
focus on medically based psychology, and we feel that
psychologists who are opposed to medications are
doing patients a disservice. Just as you have to find the
Vol. 6, No. 5
n
October 2009
PROCEEDINGS
right doctor to treat patients with FMS, you have to
find the right mental health professional as well.
Otherwise, you might do more damage.
Dr Lipman: Pharmacists should develop referral
patterns. Once the pharmacist identifies the knowledgeable physicians in the community, those physicians can help the pharmacist identify the best mental
health professionals and physical therapists for FMS.
Dr Penna: Are there any widely accepted treatment algorithms?
Dr Lipman: No. Individual clinicians usually
devise their own. The one that Dr Natelson presented
is perfectly reasonable, with the explicit caveat that the
pharmacotherapy runs parallel with physical activation
and psychosocial support.
Dr Penna: We are dealing with a condition that is
ill defined in terms of etiology and pathophysiology.
The treatments are also ill defined. It reminds me of
the time when lovastatin was approved and there was
a lot of buzz about lipid disorders. I was at Group
Health at the time, and it took us 2 years to figure out
what to do about treating lipid disorders because there
was no good outcomes evidence available. I remember
the frustration of a family physician who said, “I don’t
know what to do when I see a patient with a lipid disorder, but I will do something.” I believe many practitioners have the same problem with FMS. It is up to
the scientists working in the field to develop improved
treatment approaches and algorithms that better
define the approach.
Dr Lipman: I think you are right. But unless we
have solid evidence on which to base an algorithm and
advocate its use, then by definition we may be making
an error. The first thing we do at our clinic when we
see a patient with FMS is a careful workup. It is very
time intensive, but it is an up front cost that is costeffective in the long run.
It is also important to use an interdisciplinary
approach, but in today’s economic climate, the first service that is being cut back by third-party payers is psychological services. Without psychologists for our
patients with chronic noncancer pain, we are likely to
make mistakes and use very expensive medical interventions that are not indicated or are even contraindicated.
Managed care pharmacists should recognize that
up front costs often can save money in the long run,
and that we need good pharmacoeconomic analyses,
ideally during phase IIIA clinical studies. Waiting until
phase IV postmarketing studies is a problem because
University of Tennessee Advanced Studies in Pharmacy
n
practice patterns often are established soon after a drug
comes on the market. When evidence contrary to what
physicians are used to doing emerges, pharmacists can
help educate physicians about multiple reasonable
approaches to effective therapy.
REFERENCES
1. Functional disorders. The Free Dictionary Web site. Available
at: http://www.thefreedictionary.com/functional+disorder.
Accessed September 15, 2009.
2. Mayer EA, Bushnell C. Functional Pain Syndromes:
Presentation and Pathophysiology. Seattle, WA: IASP Press;
2009.
3. Gastrointestinal and non-gastrointestinal functional disorders.
International Foundation for Functional Gastrointestinal
Disorders. Available at: http://www.aboutibs.org/site/
about-ibs/other-disorders/ibs-non-gi-disorders. Accessed
September 15, 2009.
4. Almansa C, Rey E, Sánchez RG, et al. Prevalence of functional gastrointestinal disorders in patients with fibromyalgia
and the role of psychologic distress. Clin Gastroenterol
Hepatol. 2009;7:438-445.
5. Giamberardino MA. Update on fibromyalgia. Pain Clin
Updates. 2008;16(4):1-6.
6. 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;32:160-172.
7. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite
mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and post-traumatic stress
disorder. Ann NY Acad Sci. 2001;933:323-329.
8. Douche-Aourik F, Berlier W, Féasson L, et al. Detection of
enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy
subjects. J Med Virol. 2003;71:540-547.
9. Endresen GK. Mycoplasma blood infection in chronic
fatigue and fibromyalgia syndromes. Rheumatol Int.
2003;23:211-215.
10. Smith JD, Terpening CM, Schmidt SO, Gums JG. Relief of
fibromyalgia symptoms following discontinuation of dietary
excitotoxins. Ann Pharmacother. 2001;35:702-706.
11. Van Houdenhove B, Neerinckx E, Onghena P, et al. Daily
hassles reported by chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled quantitative and qualitative study. Psychother Psychosom. 2002;71:207-213.
12. Ciccone DS, Natelson BH. Comorbid illness in women with
chronic fatigue syndrome: a test of the single syndrome
hypothesis. Psychosom Med. 2003;65:268-275.
13. Buchwald D, Komaroff AL. Review of laboratory findings for
patients with chronic fatigue syndrome. Rev Infect Dis.
1991;13(suppl 1):S12-S18.
14. Crofford LJ. The hypothalamic-pituitary-adrenal stress axis in
fibromyalgia and chronic fatigue syndrome. Z Rheumatol.
1998;57(suppl 2):67-71.
145
PROCEEDINGS
15. Crofford LJ. Neuroendocrine abnormalities in fibromyalgia
and related disorders. Am J Med Sci. 1998;315:359-366.
16. Heap LC, Peters TJ, Wesserly S. Vitamin B status in patients
with chronic fatigue syndrome. J R Soc Med.
1999;92:183-185.
17. Garrison RL, Breeding PC. A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance
to thyroid hormone. Med Hypotheses. 2003;61:182-189.
18. Thompson ME, Barkhuizen A. Fibromyalgia, hepatitis C
infection, and the cytokine connection. Curr Pain Headache
Rep. 2003;7:342-347.
19. Lipman A. Analgesic drugs for neuropathic and sympathetically maintained pain. Clin Geriatr Med. 1996;12:501515.
20. Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgia
with cyclobenzaprine: A meta-analysis. Arthritis Rheum.
2004;51:9-13.
21. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for
the use of chronic opioid therapy in chronic noncancer pain.
J Pain. 2009;10:113-130.
146
22. Sundwell DN, Rolfs RT, Johnson E. Utah Clinical Guidelines
on Prescribing Opioids for Treatment of Pain. Salt Lake City,
UT: Utah Department of Health; 2009.
23. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and
acetaminophen combination tablets in the treatment of
fibromyalgia pain: a double-blind, randomized, placebocontrolled study. Am J Med. 2003;114:537-545.
24. Younger J, Mackey S. Fibromyalgia symptoms are reduced
by low-dose naloxone: a pilot study. Pain Med.
2009;10:663-672.
25. Bennett RM, Burckhardt CS, Clark SR, et al. Group treatment
of fibromyalgia: a 6-month outpatient program. J Rheumatol.
1996;23:521-528.
26. Turk DC, Okifuji A, Sinclair JD, Starz TW. Interdisciplinary
treatment for fibromyalgia syndrome: clinical and statistical
significance. Arthritis Care Res. 1998;11:186-195.
27. Turk DC, Okifuji A, Sinclair JD, Starz TW. Differential responses by psychosocial subgroups of fibromyalgia syndrome
patients to an interdisciplinary treatment. Arthritis Care Res.
1998;11:397-404.
Vol. 6, No. 5
n
October 2009