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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 1, 2006
Contents
New Strategies in Follow-Up and Treatment of Fibromyalgia
Executive Editor: Ali Gur
Editorial Pp. 1-2
Fibromyalgia Syndrome: Which Antidepressant Drug Should
We Choose Pp. 3-9
G.O. Littlejohn and E.K. Guymer
[Abstract]
Combination Therapy in Fibromyalgia Pp. 11-16
A.H. Clayton and S.G. West
[Abstract]
Is There a Role for Cytokine Based Therapies in Fibromyalgia
Pp. 17-22
D.J. Wallace
[Abstract]
Are Tender Point Injections Beneficial: The Role of
Tonic Nociception in Fibromyalgia Pp. 23-27
R. Staud
[Abstract]
Physical Therapy Modalities in Management of Fibromyalgia
Pp. 29-35
A. Gur
[Abstract]
Exercise and Cognitive-Behavioural Treatment in Fibromyalgia
Syndrome Pp. 37-45
Y. Kurtais, S. Kutlay and S. Ergin
[Abstract]
Complementary and Alternative Medical Therapies in
Fibromyalgia Pp. 47-57
A.J. Sarac and A. Gur
[Abstract]
Multidisciplinary Approaches for Management of Fibromyalgia
Pp. 59-66
C.S. Burckhardt
[Abstract]
New Strategies in Evaluation of Therapeutic Efficacy
in Fibromyalgia Syndrome Pp. 67-73
S. Ozgocmen
[Abstract]
General Articles
Metabolism-Directed Optimisation of Antithrombotics:
The Prodrug Principle Pp. 73-91
L. Peterlin-Mašic, J. Cesar and A. Zega
[Abstract]
PPAR-γ
Agonists as Regulators of Microglial Activation and Brain
Inflammation Pp. 93-109
A. Bernardo and L. Minghetti
[Abstract]
Novel Agents Aiming at Specific Molecular Targets Increase
Chemosensitivity and Overcome Chemoresistance in Hematopoietic
Malignancies Pp. 111-120
S. Boehrer, D. Nowak, D. Hoelzer, P.S. Mitrou and
K.U. Chow
[Abstract]
Abstracts
[Back to top]
Editorial
Fibromyalgia syndrome (FM) is a musculoskeletal disease characterized
by chronic widespread pain, tender points, fatigue, and poor
quality sleep. Although several mechanisms have been proposed
for the etiopathogenesis, they are still obscure and the prognosis
for symptomatic recovery is generally poor. A wide variety
of interventions are used in the management of FM. There is,
however, no clear consensus on the choice of treatment, and
FM relatively refractory to treatment. It is estimated that
there are six million individuals in the United States having
clinical fibromyalgia, and an additional six million having
“community fibromyalgia” where the symptoms and
tender points are present but the individual has not complained
to a health practitioner about it in the United States. In
spite of current interventions approximately $14 billion a
year is spent on the diagnosis and treatment of FM.
FM is an extraordinarily complex disorder with a wide variety
of clinical components that must be accounted for in both
the theories describing its origin and the combination of
treatments used to ameliorate its symptoms. There are a number
of treatments available to patients suffering from FM, both
pharmacological and non-pharmacological. The diverse symptoms,
poorly understood etiology and pathophysiology, make FM a
frustrating condition for the patients and the physicians.
With further understanding of the pathophysiologic abnormalities
involved in FM, we might expect to find more effective and
possibly longer-lasting medical treatments.
From the standpoint of this issue of the Current Pharmaceutical
Design, I have been honored by Prof. Banks to be a chooser.
I am very pleased with what the authors share in this issue.
I have been very fortunate to be able to choose and select
an outstanding panel of contributors, each of whom focuses
on different segments of the issues that permit us to diagnose
with reasonable confidence and to rationally treat the various
manifestations of fibromyalgia. It is the purpose of this
issue to provide to reader with an understanding of the state-of-the-art
and the state-of-the-science so that a rational basis for
the selection of therapeutic interventions may be chosen and
excessive proceeduring or redundant, costly, or potentially
hazardous therapeutic interventions may be avoided.
This issue of the Current Pharmaceutical Design covers a
very important topic entitled “new strategies in follow-up
and treatment of Fibromyalgia”. Its practical articles
will help physicians provide the best help to patients. I
hope you enjoy this issue as much as I have.
This issue consists of nine invited review articles prepared
by some of the experts in their field. They represent some
of the important current trends in the management of FM.
In their review Drs. Littlejohn and Guymer [1] from Monash
University discuss the main effect and pharmacological aspects
of different groups of antidepressants drugs able to control
FM symptoms and answer the question which antidepressant drug
should we choose.
The next article by Drs. Clayton and West [2] from University
of Virginia reviews the combination therapy in FM, followed
by that of Dr. Wallace [3] entitled “is there a role
for cytokine based therapies in fibromyalgia” mainly
emphasing on the possible therapeutic application of the anti-cytokine
agents.
There is compelling evidence that peripheral tonic nociceptive
input represents a necessary component for the clinical pain
of FM patients. In addition to altered peripheral pain mechanisms
like secondary hyperalgesia and central sensitization. These
relevant pain mechanisms almost always require tonic nociceptive
input to maintain heightened pain sensitivity. Therefore the
reduction of peripheral nociceptive input by muscle injections
can alleviate FM pain and thus may represent an important
strategy for the treatment of chronic pain as well as the
improvement of central sensitization. The article by Dr. Staud
[4] entitled “Are tender point injectionsbeneficial?
The role of tonic nociception in fibromyalgia” makes
very important contribution in this issue.
In his article Dr. Gur [5] from Dicle University reviews
some of the existing studies of physical therapy relevant
in the treatment of FM and give some practical advice for
their use, followed by the article by Drs. Kurtais, Kutlay
and Ergin [6] from Ankara University, review exercise and
cognitive-behavioral methods, which exist in the multimodal
approach, in FM. Dr. Sarac [7] with her article entitled “Complementary
and Alternative Medical Therapies in Fibromyalgia” mainly
presents complementary and alternative medical therapies for
efficacy and some adverse events in fibromyalgia.
The article by Burckhardt [8] from Oregon Health and Science
University focuses on the multidisciplinary approaches. It
describes conceptual and methodological frameworks for the
multidisciplinary approach, summarizes the evidence base for
multidisciplinary approaches in the treatment of FM, and also
recommends an approach to multidisciplinary research and treatment.
The last article of this issue by Dr. Ozgocmen [9] from the
Firat University mentions the new strategies in evaluation
of therapeutic efficacy in fibromyalgia are introduced and
briefly explained.
I would like to thank all the authors for taking the time
and trouble to write informative and authoritative reviews.
All are experts in their fields. I believe that these reviews
offer the reader up-to-the-minute information on some of the
latest findings about treatment of FM. They all will provide
an update for researchers on current progress in this area
and will be of use to medical agents planning to enter the
field.
I would be gratified if the articles within this issue kindle
innovative ideas among the readers who are involved with the
design and discovery of agents for the therapy of FM.
References
[1] Littlejohn GO, Guymer EK. Fibromyalgia Syndrome: Which
Antidepressant Drug Should We Choose. Curr Pharm Design 2006;
12(1): 3-9.
[2] Clayton AH, West SG. Combination Therapy in Fibromyalgia.
Curr Pharm Design 2006; 12(1): 11-16.
[3] Wallace DJ. Is There a Role for Cytokine Based Therapies
in Fibromyalgia. Curr Pharm Design 2006; 12(1): 17-22.
[4] Staud R. Are Tender Point Injections Beneficial: The
Role of Tonic Nociception in Fibromyalgia. Curr Pharm Design
2006; 12(1): 23-27.
[5] Gur A. Physical Therapy Modalities in Management of Fibromyalgia.
Curr Pharm Design 2006; 12(1): 29-35.
[6] Kurtais Y, Kutlay S, Ergin S. Exercise and Cognitive-Behavioural
Treatment in Fibromyalgia Syndrome. Curr Pharm Design 2006;
12(1): 37-45.
[7] Sarac AJ, Gur A. Complementary and Alternative Medical
Therapies in Fibromyalgia. Curr Pharm Design 2006; 12(1):
47-57.
[8] Burckhardt CS. Multidisciplinary Approaches for Management
of Fibromyalgia. Curr Pharm Design 2006; 12(1): 59-66.
[9] Ozgocmen S. New Strategies in Evaluation of Therapeutic
Efficacy in Fibromyalgia Syndrome. Curr Pharm Design 2006;
12(1): 67-71.
Ali GUR, MD.
Department of Physical Medicine
and Rehabilitation
Medical Faculty of Dicle University
Diyarbakir
TURKEY
E- mail: alig@dicle.edu.tr
[Back to top]
Fibromyalgia Syndrome: Which Antidepressant
Drug Should We Choose
G.O. Littlejohn and E.K. Guymer
Fibromyalgia syndrome [FM] has core clinical features of
widespread pain and widespread abnormal tenderness. The specific
cause of the altered neurophysiology that underpins these
clinical manifestations remains unclear. However, increased
sensitisation of neural networks that relates to pain, as
well as interacting mechanoreceptors, appear important targets
for modulation by pharmacological agents. Further, many FM
patients have emotional distress and some are depressed. Antidepressant
agents have therapeutic benefits in FM. If depression is present
antidepressant drugs will provide typical benefits to mood
but not always to other key outcome measures, such as pain
or tenderness. Selective serotonin receptor reuptake blockers
are not as effective for overall FM improvement as drugs that
block both serotonin and norepinephrine in a relatively balanced
way. Thus tricyclic antidepressants will improve many important
FM outcomes but are effective in only about 40 percent of
individuals. Newer agents of this class, such as duloxetine
and milnacipran, show improvement in key FM outcomes in about
60 percent of patients. Longer term studies will indicate
the durability of these responses and the overall tolerance
of the drugs. Any drug therapy will need to be integrated
with appropriate education, exercise and attention to psychological
modulatory factors to achieve best results.
[Back to top]
Combination Therapy in Fibromyalgia
A.H. Clayton and S.G. West
Fibromyalgia is an enigmatic medical condition whose specific
etiology remains undiscovered but currently plagues five million
Americans [1]. Research indicates that the origin of the disease
is most likely multifactorial. Treatment should therefore
be tailored accordingly. Thus, it is often necessary to combine
different options in order to achieve the maximum benefit
in patients suffering from fibromyalgia.
[Back to top]
Is There a Role for Cytokine Based Therapies
in Fibromyalgia
D.J. Wallace
Cytokines are glycoproteins that serve as chemical messengers
between cells. They assist in the regulation of cell growth
and repair and also have immune modulating properties. Cytokines
play a role in diverse clinical processes and phenomena such
as fatigue, fever, sleep, pain, stress and aching. A review
of the fibromyalgia literature and related studies suggest
that IL-1, IL-6 and IL-8 are dysregulated in the syndrome.
Therapies directed against these cytokines may be of potential
importance in the management of fibromyalgia.
[Back to top]
Are Tender Point Injections Beneficial: The Role of
Tonic Nociception in Fibromyalgia
R. Staud
Characteristic symptoms of fibromyalgia syndrome (FM) include
widespread pain, fatigue, sleep abnormalities, and distress.
FM patients show psychophysical evidence for mechanical, thermal,
and electrical hyperalgesia. To fulfill FM criteria, the mechanical
hyperalgesia needs to be widespread and present in at least
11 out of 18 well-defined body areas (tender points). Peripheral
and central abnormalities of nociception have been described
in FM and these changes may be relevant for the increased
pain experienced by these patients. Important nociceptor systems
in the skin and muscle seem to undergo profound changes in
FM patients by yet unknown mechanisms. These changes may result
from the release of algesic substances after muscle or other
soft tissue injury. These pain mediators can sensitize important
nociceptor systems, including the transient receptor potential
channel, vanilloid subfamily member 1 (TRPV1), acid sensing
ion channel (ASIC) receptors, and purino-receptors (P2X3).
Subsequently, tissue mediators of inflammation and nerve growth
factors can excite these receptors and cause substantial changes
in pain sensitivity. FM pain is widespread and does not seem
to be restricted to tender points (TP). It frequently comprises
multiple areas of deep tissue pain (trigger points) with adjacent
much larger areas of referred pain. Analgesia of areas of
extensive nociceptive input has been found to provide often
long lasting local as well as general pain relief. Thus interventions
aimed at reducing local FM pain seem to be effective but need
to focus less on tender points but more on trigger points
(TrP) and other body areas of heightened pain and inflammation.
[Back to top]
Physical Therapy Modalities in Management of Fibromyalgia
A. Gur
The etiology of fibromyalgia syndrome (FM) is uncertain
and the prognosis for symptomatic recovery is generally poor.
A wide variety of interventions are used in the management
of FM. There is, however, no clear consensus on the treatment
of choice and FM remains relatively refractory to treatment.
Therefore, prevention, causal therapy and rehabilitation are
not possible. FM patients frequently use alternative therapies,
indicating dissatisfaction or ineffectiveness of traditional
medical therapy. Alternative therapies are generally perceived
to be more “natural” and as a result, to have
fewer adverse effects. Despite the positive results found,
the number of publications related to the application of physical
therapy modalities such as acupuncture, transcutaneous electrical
stimulation, laser, biofeedback, electrotherapy and magnetic
field is still scant, especially concerning FM treatment.
The demonstration of a long-term effective intervention for
managing the symptoms associated with FM is needed. Multidisciplinary
approaches to management include physical and medical therapeutic
strategies. Treatment modalities should be individualised
for patients based on target symptoms and impairment in functioning.
Patience and positive attitude on part of the physician and
active involvement of patients and their families in treatment
are likely to enhance improvement. It can be concluded that
there is a need for larger, more systematic and methodologically
sound randomised controlled clinical trials to evaluate the
effectiveness of physical therapy modalities of managing FM.
We will review some of the existing studies of physical therapy
relevant in the treatment of FM and give some practical advice
for their use.
[Back to top]
Exercise and Cognitive-Behavioural Treatment in Fibromyalgia
Syndrome
Y. Kurtais, S. Kutlay and S. Ergin
Fibromyalgia syndrome is a nonarticular rheumatic disorder
characterised by diffuse musculoskeletal pain, stiffness,
fatigue, disturbed sleep and tender points. The pathophysiology
is not well understood and treatment remains a challenge.
Although pharmacological therapy is still the primary treatment
choice, a long-term effective intervention has not been demonstrated
yet. Thus, besides pharmacotherapy, other multimodal interventions
are often used. Exercise and cognitive-behavioural treatments
which exist in the multimodal approach and encompass largely
self-managed strategy, are reviewed in this article. Although,
there is a great number of exercise studies, the large diversity
of outcome measures and measurement instruments that have
been used in studies, varying intensity and types of exercises,
small sample sizes, high attrition rates, large variability
in baseline function, symptom severity and psychosocial status
limit to come to a conclusion about the efficacy of exercise
in the treatment of fibromyalgia syndrome. There are also
inconclusive results about the efficacy of cognitive-behavioural
treatment because of limited number of studies with small
sample sizes of patients with fibromyalgia syndrome. However,
the results of the trials overall demonstrate the beneficial
effects of both different types of exercise and cognitive-behavioural
treatment, on the other hand, there is still a need for larger,
more systematic and randomised controlled trials to evaluate
the effectiveness.
[Back to top]
Complementary and Alternative Medical Therapies in
Fibromyalgia
A.J. Sarac and A. Gur
This article describes the studies that have been performed
evaluating complementary or alternative medical (CAM) therapies
for efficacy and some adverse events fibromyalgia (FM). There
is no permanent cure for FM; therefore, adequate symptom control
should be goal of treatment. Clinicians can choose from a
variety of pharmacologic and nonpharmacologic modalities.
Unfortunately, controlled studies of most current treatments
have failed to demonstrate sustained, clinically significant
responses. CAM has gained increasing popularity, particularly
among individuals with FM for which traditional medicine has
generally been ineffective. Some herbal and nutritional supplements
(magnesium, S- adenosylmethionine) and massage therapy have
the best evidence for effectiveness with FM. Other CAM therapies
such as chlorella, biofeedback, relaxation have either been
evaluated in only one randomised controlled trials (RCT) with
positive results, in multiple RCTs with mixed results (magnet
therapies) or have positive results from studies with methodological
flaws (homeopathy, botanical oils, balneotherapy, anthocyanidins
and dietary modifications). Another CAM therapy such as chiropractic
care has neither well-designed studies nor positive results
and is not currently recommended for FM treatment. Once CAM
therapies have been better evaluated for safety and long-term
efficacy in randomised, placebo-controlled trials, they may
prove to be beneficial in treatments for FM. It would then
be important to assess studies assessing cost-benefit analyses
comparing conventional therapies and CAM.
[Back to top]
Multidisciplinary Approaches for Management of Fibromyalgia
C.S. Burckhardt
Multidisciplinary approaches to fibromyalgia syndrome (FMS)
treatment are advocated for treating the complex symptoms
and problems confronting many patients. Exercise and cognitive-behavioral
strategies together with patient education commonly comprise
the multidisciplinary approach to treatment in clinical trials.
A review of the research literature suggests that they are
effective for decreasing pain and FMS impact and increasing
self-efficacy and physical functioning. Limitations of the
current evidence base include a lack of studies that include
medication treatment as part of the multidisciplinary approach
as well as lack of attention to the diversity of patient psychosocial
issues that may interfere with treatment effectiveness. The
review recommends that further randomized clinical trials
be carried out with subgroups of patients using standardized
outcome measurements, adequate treatment length and sufficient
length of follow-up to be able to observe and document changes
in patient symptoms and behaviors over time.
[Back to top]
New Strategies in Evaluation of Therapeutic Efficacy
in Fibromyalgia Syndrome
S. Ozgocmen
Fibromyalgia (FM) is continuing to be a challenging and
confusing disorder for researchers and clinicians with its
diverse symptoms, poorly understood etiology and pathophysiology.
The use of multiple outcome variables reflecting the complexity
of FM and co-morbid syndromes, makes it difficult to evaluate
the efficacy or effectiveness of the treatment in clinical
trials. Additionally researchers inevitably rely on patients'
self reported outcome data, which is prone to error and bias.
In this paper, new researches in the field of FM and practical
issues on methodology of pain assessment (visual analogueue
scales, paper or electronic diaries and compliance), core
outcome domains in chronic pain assessment (IMMPACT recommendations),
and advances in neuroimaging techniques like functional magnetic
resonance imaging have been reviewed. Consequently, clinicians
and researchers have various highly validated and adequate
outcome domains to assess FM symptoms and new researches continue
to add new valuable domains. Nevertheless the current problem
is to conclude, which treatment works best for whom and which
are the outcome domains suitable for FM patients or patients'
subgroups with different prominent features. Standardised
and appropriate core outcome domains for FM clinical trails
will encourage more complete investigations, relevant outcome
reporting and well-designed multicenter trials.
General Articles
[Back to top]
Metabolism-Directed Optimisation of Antithrombotics:
The Prodrug Principle
L. Peterlin-Mašic, J. Cesar and A. Zega
Thromboembolic disorders are the major cause of mortality
and morbidity in Western societies. Coagulation enzymes, such
as thrombin, factor Xa and a tissue factor/factor VIIa complex,
together with platelet GPIIb/IIIa receptors, are the focal
point of attention in pharmaceutical research aimed at finding
new antithrombotic agents. However, finding orally active
drugs for these particular molecular targets has proved to
be anything but straightforward. Thrombin, factor Xa, tissue
factor/factor VIIa and platelet GPIIb/IIIa receptors display
a preference for molecules containing highly basic arginine
and/or acidic aspartate moieties, which are, however, associated
with poor bioavailability after oral application. Different
approaches have been taken to achieve favourable absorption,
metabolism, distribution and clearance, without compromising
the antithrombotic activity of the compounds. This review
highlights the use of the prodrug principle in optimising
antithrombotic agents.
[Back to top]
PPAR-γ
Agonists as Regulators of Microglial Activation and Brain
Inflammation
A. Bernardo and L. Minghetti
The peroxisome proliferator-activated receptor-γ
(PPAR-γ)
belongs to a large group of nuclear receptors controlling
reproduction, metabolism, development and immune response.
Upon activation by specific agonists, these receptors form
dimers and translocate to the nucleus, where they act as agonist-dependent
transcription factors and regulate gene expression by binding
to specific promoter regions of target genes. The observation
that PPAR-γ
is involved in the regulation of macrophage differentiation
and activation in the peripheral organs has prompted the investigation
of the functional role of PPAR-γ
in microglial cells, the main macrophage population of the
CNS. The present review summarizes the several lines of evidence
supporting that PPAR-γ
natural and synthetic agonists may control brain inflammation
by inhibiting several functions associated to microglial activation,
such as the expression of surface antigens and the synthesis
of nitric oxide, prostaglandins, inflammatory cytokines and
chemokines. Moreover, one of the major natural PPAR-γ
agonist, 15d-prostaglandin J2 may contribute to
the safe elimination of activated microglia by inducing apoptosis.
Synthetic PPAR-γ
agonists do not entirely reproduce the range of 15d-prostaglandin
J2 effects, suggesting that PPAR-γ
independent mechanisms are also involved in the action of
this prostaglandin. In addition to microglia, PPAR-γ
agonists affect functions and survival of other neural cells,
including astrocytes, oligodendrocytes and neurons. Although
most of the evidence comes from in vitro observations,
an increasing number of studies in animal models further supports
the potential therapeutic use of PPAR-γ
agonists in human brain diseases including multiple sclerosis,
Parkinson’s disease and Alzheimer’s disease.
[Back to top]
Novel Agents Aiming at Specific Molecular Targets Increase
Chemosensitivity and Overcome Chemoresistance in Hematopoietic
Malignancies
S. Boehrer, D. Nowak, D. Hoelzer, P.S. Mitrou and
K.U. Chow
In hematologic neoplasias primary or secondary resistance
of malignant cells towards the applied treatment presents
the major clinical obstacle in the induction of remission
and definite cure. Evaluation of the underlying molecular
mechanisms determining response or resistance not only enables
the clinician to define prognostic markers, but moreover facilitates
the design of molecularly targeted agents potentially reversing
the causative lesion. Deregulation of apoptosis is considered
to contribute to the emergence and propagation of the malignant
clone, and several molecular alterations hindering programmed
cell death and thus leading to chemoresistance have been defined.
While reviewing these molecular alterations this article moreover
focuses on the impact of new therapeutic agents, which specifically
exploit the knowledge of the molecular characteristics of
malignant hematopoetic cells.
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