Current Pharmaceutical Design - Volume 12, Issue 1, 2006

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.

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.

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.

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.

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.

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.

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, Sadenosylmethionine) 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.

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.

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.

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.

The peroxisome proliferator-activated receptor-g (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- g 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.

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.