Management of Fibromyalgia: What are the Best Treatment Choices?

Forseth, Karin Øien, Betanien Hospital, The Department of Rheumatology, Skien, Norway, Gran, Jan Tore, Department of Rheumatology, Institute of Clinical Medicine, University of TromsØ, Norway


Fibromyalgia (FM) still represents an enigma to modern medicine, and the aethiopathogenesis is far from explored. The management of FM thus is mostly based on empirical research, and rather few controlled studies have been performed. The basic drug therapy rests on the administration of amitriptylin (AMI) and convential analgesics. Such therapy should be initiated only after careful patient information and delineation of therapeutic goals. The drug therapy should be administered in combination with physical treatment and cognitive behavioural therapy. Due to the appearing contours of pathogenic mechanisms, hopefully a number of new drugs will be available to the patients with this complex pain syndrome in the near future.

1. Background

During the last few decades, an apparently new and increasing cause of disability has been much focused: a condition of generalised pain accompanied by excessive fatigue and exhaustion. The most common symptoms are poor sleep, not feeling refreshed in the morning, headache, anxiety, depression, irritable bowel symptoms, paresthesias and a feeling of swelling, most often located to hands and fingers [1,2]. Modulating factors such as pain aggravation after physical activity and in relation to stress and changes in weather are often reported. This condition has been coined fibromyalgia (FM).

The American College of Rheumatology (ACR) – 90 classification criteria [3] for FM are based on two cut-off values, for pain extent and for number of tenderpoints (TP). Thus, to fulfil the ACR-90 criteria an individual has to present chronic widespread pain and at least 11 out of 18 positive TP. The presence of associated symptoms is not required, and the distinction between primary (which excludes individuals with concomitant diseases) and secondary FM is no longer made. These criteria have established a basis for comparing patients from various studies.

The occurrence of FM is extremely common and ranges from 2.0 to 10.5% (only women) in the general population (4-8). It should be noted, however that though the prevalence is high, there exist both milder and more serious variants of the syndrome, showing great variations regarding outcome [9,10-15]. There is so far only one study addressing the incidence of FM. During a 5.5 years observation time an incidence of 0.58% yearly was reported among initially pain-free women [16].

Several studies have been undertaken to study outcome and prognosis [13,17-26]. So far, the majority of studies of adults have concluded that complete and sustained disease remission in FM is rather rare [9,13, 17, 19-21]. Other authors have, however, reported a considerable number of individuals who no longer fulfilled the ACR-criteria for FM at follow-up [18,23-26]. Thus, FM as defined by the criteria does not seem to reflect a discrete disease entity exhibiting stable and persistent clinical manifestations. It should also be noted that according to the studies of Buskila and Mikkelson [24,25], children seem to have a better outcome than adults.

The aetiology of FM is still unknown, while the pathogenesis is hopefully soon to be disclosed. A few clinical observations suggest a familial aggregation of FM [27,28], and sibship analysis have shown significant genetic linkage of FM to the HLA-region [29]. Genetic analyses have also disclosed some allelic abnormalities in serotonin precursor genes [30].

Different hypotheses have involved theories about major affective disorder mechanisms [31], various peripheral mechanisms involving muscle deconditioning, mictrotrauma [32,33], disturbed energy metabolism [34] and microcirculation in microfibers that may confer sensitisation of nociceptive neurones in the muscle [35,36] and disorder of pain modulations [37-39].

In 1992, Yunus suggested pain in FM to be due to an interaction of central and peripheral physiological mechanisms [40]. This view has later been supported among others by Henriksson and co-workers [41] and Russell [42]. Different studies showed significantly elevated substance P levels in the cerebrospinal fluid (CSF) of FM patients [43-45] and decreased blood and CSF levels of serotonin and tryptofan [46]. The possible role of excitatory amino acids in enhancing synthesis of nitric oxide in the pathogenesis of pain in FM patients is discussed in an article by Larson and co-workers [47].

The phenomenon of CNS plasticity [48] is further investigated and may perpetuate the aberrant central mechanisms in a vicious circle, resulting in self-sustained chronicity. Furthermore, the theory of dysfunction in the central pain-modulating system is supported by the findings of non-rapid eye-movement sleep (stage 4) abnormalities [49,50].

Finally, it is becoming increasingly clear that the deficiency of a single neurochemical substance is not the single cause of fibromyalgic symptomatology. Almost all of the hormonal feedback mechanisms controlled by the hypothalamus are altered. Elevated basal values of ACTH, follicle-stimulating hormone (FSH), and cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatodin C), free triiodothyronine (FT3), and oestrogen [51] appear rather characteristic of FM. The present findings of dysfunctions in such a variety of different fields do mirror the heterogeneity of FM, and probably indicate that FM have a complex aethiopathogenesis.

Thus, due to the lack of a known clear-cut aethiopathogenesis, most therapeutic options have so far rested on an empirical basis. In the last decade, numerous studies with different new, possibly pain-modulating substances, have been undertaken on the basis of neurophysiological research. Several of these studies show promising results, and hopefully this field of research will be expanded and lead to available efficacious new drugs for FM.

2. General therapeutic considerations

Before considering any therapeutic options, a definite diagnosis should be established. Moreover, as FM very often co-exists with other diseases [52-55], such conditions must be ruled out and if possible treated.

FM is a chronic condition, often with an insidious onset. As the condition becomes chronic and more severe, a number of secondary problems occur. The accumulation of pain and fatigue during years influences work capacity and exerts considerable impact on daily life [13]. Failure to continue working often leads to economical problems, and the diminished capacity to participate in daily life comprises social activities, possibly leading to familial problems, hopelessness and isolation. Clearly, any therapeutic program in FM should include a broad multi-disiplinary approach.

As there is no known cure for FM, therapy should be aimed at reducing pain and ease the management of the whole situation for the patient and her family. At present, the available tools for treatment have been of mainly non-pharmaceutical nature, as only a few drugs have been shown effective in some patients.

Before initiating therapy, however, the expectations of the patient should be clarified. Careful patient information ought to include information regarding the chronic disease course, and the lack of a causal cure. Information of the lack of an association between FM and other serious diseases, including rheumatoid arthritis, should also be stressed. Previous use of therapy should be delineated and any secondary problems enlightened. Finally, the goal of treatment should be clarified and agreed upon. The choices of further strategies depend on what has been tried earlier, the availability of local treatment possibilities, and the patient’s total situation.

3. Non-pharmaceutical treatment

Physical treatment, biofeedback and coping strategies including cognitive therapy are the most important approaches. Transcutaneous electrical nerve stimulation (TENS) and acupuncture are often applied, but due to the lack of controlled studies, the possible effects are not well documented.

3.1 Physical treatment

Physical treatment in FM is aimed at altering clinical features such as pain, fatigue, deconditioning, muscle weakness and sleep disturbances. During the last decade, about 10 – 15 studies have been undertaken to evaluate the efficacy of physical training aimed at minimising the symptoms. Bennett and co-workers [56] as well as Clark and co-workers [57] have reported that the majority of FM patients are physically unfit, and also suggested that deconditioning might result in concomitant symptoms such as tachycardia, dizziness, fatigue and anxiety. McCain and co-workers [58] showed that patients who performed a supervised cardiovascular fitness training not only improved in cardiovascular fitness, but also showed improvement in measures of pain compared to a similar group receiving flexibility exercises.

In support of these findings, Wigers and co-workers [59] found that subjects who took part in an aerobic exercise group experienced reduced pain distribution and improved perceived energy. Moreover, Martin, Nichols and Verstappen and co-workers[60-62] all found some benefits in the exercising groups with respect to pain reduction, TP score, and increased physical and social activities. In contrast, Mengshoel and co-workers were unable to demonstrate any differences between the exercise group and a control group [63]. The studies of Grange and co-workers [23] and Wigers [64] concluded that maintenance of adequate physical activity is associated with a positive long term outcome in FM.

There are, however, shortcomings in most of the above mentioned studies. Short duration of intervention, variation between the studies of components of the actual physical activity applied, small numbers of patients, control groups also receiving effective intervention, absence of long-term follow-up, high dropout rates and different outcome parameters all make it difficult to compare the value of the different factors tested. In spite of these limitations, however, it may be concluded that FM patients should be encouraged to perform regular physical activity, and that a significant number of such patients experience improvement.

3.2 Transcutaneous electric nerve stimulation (TENS) and acupuncture

TENS is based on electrically induced analgesia. The mechanisms involved are reviewed by Minor and Sanford [65]. The major biophysical effect is probably due to stimulation of afferent nerves that transmit or inhibit noxious inputs from the spinal cord to the brain related to the gate-control theory [66]. Justin reviewed the role of TENS as treatment for chronic pain, and concluded that the clinical response is variable and unpredictable [67]. Johnson showed in 1991, however, that some patients do gain significant benefit without serious adverse effects [68]. TENS is generally most useful in more localised cases of pain, which limit the usefulness of the method in generalised pain as FM. Nevertheless do some cases with FM profit in low frequency treatment with TENS.

Berman and co-workers [69] critically reviewed published reports on the effectiveness of acupuncture in the treatment of FM. All randomised or quasi-randomised controlled trials, or cohort studies of patients with FM who were treated with acupuncture, were selected for analyses. The methodological quality, sample characteristics, type of acupuncture treatment, and outcome were evaluated. Seven studies were reviewed, of which only one was of high methodological quality. In this study, Deluze and co-workers [70] reported a three weeks double blind randomised trial of electro-acupuncture in FM and concluded that the limited amount of high quality evidence suggests that real acupuncture is more effective than sham acupuncture for improving symptoms of patients with FM. However, further high quality randomised trials are needed to provide more firm data on the possible efficacy of acupuncture in FM.

3.3 Bio-feedback

Bio-feedback is a therapeutic approach in which feedback is given by different methods to facilitate control of physiological processes such as muscle tension and frequency of breathing. Only a few studies have been performed in FM patients. Ferraccioli and co-workers [71] studied 12 FM patients who received auditory feedback of muscle tension in the scalp. The authors reported 50% clinical improvement in nine patients at six month.

In a study by Buckelew and co-workers [72] improved self-efficacy, reduced disease severity and increased physical activity were found in FM patients treated by bio-feedback. However, these patients underwent a multi-disciplinary approach also including relaxation training and structured exercise programs. In spite of a limited number of studies undertaken, the methods seems to have a positive therapeutic effect and further studies should be encouraged.

3.4 Cognitive behavioural therapy

A biopsychological perspective is partly adopted in assessing FM. This perspective emphasises the psychological dimensions of chronic pain, and has led to the development of psychological management strategies. The purpose of cognitive-behaviour therapy is to teach individuals the skills necessary to control pain and disability [73] Morley and co-workers [74] provided a review and meta-analysis of 25 randomised controlled trials of cognitive-behavioural therapy and behaviour therapy for chronic pain in adults. It was concluded that the studies provide sufficient evidence to claim that cognitive behavioural therapy and behavioural therapy in adults with chronic pain is effective.

There has been a growing interest in the use of formal self-management training programs for FM. Sandstrøm and Keefe [75] reviewed studies that have tested the efficacy of two types of programs, those emphasising training in coping skills, and those emphasising training in physical exercise. Taken together, the studies reviewed suggested that formal self-management programs such as coping skills training or exercise may play an important role in the control of FM symptoms. However, it was also concluded that not all individuals with FM responded to such programs. Additional research is clearly needed to explore fully how cognitive-behavioural therapy best should be applied in order to achieve optimal effects.

4. Drug therapy

Due to incomplete understanding of the aetiopathogenetic processes of FM, convential drug therapy is mostly based on empirical research [76]. However, the evolving contours of the pathogenic mechanisms of FM have encouraged an increased use of drugs applied in other medical conditions. Several experimental studies have already been done and may hopefully initiate a new generation of drugs for FM. An overview over studies in which convential drugs are applied in the treatment FM is given in table I [77-105]. Most of the studies are presented in more detail in the following text.

4.1 Convential treatment

Unfortunately, the results from empirical research are rather discouraging, as only a few drugs have proved partly effective. Drugs frequently administered in FM are non-steroid anti-inflammatory agents (NSAIDS), analgesics, sedatives, antidepressants and serotonin-reuptake-inhibitors. Opioids are only occasionally applied in severe cases, and only poorly studied in this context. As there is a large body of evidence that fibromyalgia is a central pain state, this medication should be studied in the context of fibromyalgia patients. However, as opioids have a considerable abuse potential, treatment involving such drugs should be individualised and avoided in patients with prior history of substance abuse. Systemic glucocorticoids are also sometimes employed and convential medication treatment also comprises triggerpoint injections.

4.1.1. Non-steroid anti-inflammatory agents (NSAIDS)
The possible pain reducing effects of NSAIDS in FM have been tested in several placebo controlled studies [77-80]. Neither naproxen, ibuprofen nor tenoxicam proved to be more efficient than placebo. These negative results are hardly surprising, as inflammatory mechanisms do not appear to be involved in the pathogenesis of FM.

4.1.2 Analgesics

Surprisingly, rather few controlled trials of the use of analgesics to control pain in FM have been undertaken and to our knowledge only two studies of acetaminophen[81, 82] and no studies of acetyl acid have been undertaken. Tramadol, a newcomer among analgetics, is a combined opioid analogue, norepinephrine inhibitor and serotonin releasing drug. One study was done in 1998 by Biasa and co-workers [83] in which 12 patients received injections with tramadol 100 mg or placebo. The results gave no clear information of the possible effects of this drug. Another study of tramadol concluded that tramadol provided pain relief in FM patients who tolerated the drug [84]. Further studies are awaited.

4.1.3 Sedatives and anxiolytics

Cyclobenzaprine hydrochloride is a commonly prescribed centrally acting muscle relaxant which is structurally similar to tricyclic antidepressants (TCAs) and differs from amitriptyline by only one double bond [106]. In 1988, Bennett and co-workers found significantly reduced pain in FM patients after administration of cyclobenzaprine [85]. However, the majority of later studies, were unable to demonstrate the same beneficial results [79-80, 86-88], except for the combination of alprazolam and ibuprofen that demonstrated a small beneficial effect.

Due to the high risk of abuse and marginal effects, these drugs should not administered as a first choice medicament, and only after carefully considerations in each individual case. The short acting non-benzodiazepine sedatives zolpidem and zopiclone improved sleep but failed to reduce pain in three studies [89-91], and may thus be administered in cases with severe sleep disturbances. Their lack of analgesic effects, however, limits their role in the therapy of FM.

4.1.4 Glucocorticoids

In 1985, Clark and co-workers [92] entered 20 patients with FM in a double-blind crossover study to compare the effects of prednisolone versus placebo. VAS scales for pain, morning stiffness, fatiguability, sleep disturbances and TP examination were assessed at baseline, end of week 2 and end of week 4. Overall there was no improvement while taking prednisolone, indeed most measured variables showed a trend towards deterioration. This study is of a special importance, since it clearly demonstrated that corticosteroids should not belong to the therapeutic spectrum of FM. In cases of FM responding favourable to steroids, the diagnosis should be thoroughly reconsidered.

4.1.5 Monoamine oxidase inhibitors

In 1998, Hannonen and co-workers [93] compared moclobemide with AMI and placebo. Moclobemide is a reversible inhibitor of the mono oxidase A and inhibits the deamination of serotonin, norepinephrine and dopamine in the synaptic cleft. It acts as an anti-depressiva drug. The response criteria in this study were weak and 74% of the AMI treated group responded, while 49 and 54% responded favourable to placebo and moclobemide, respectively. There appears to be no good reason for prescribing this drug for FM patients.

4.1.6 Serotonin reuptake inhibitor (SSRI)

As this drug group also interferes with the serotonin metabolism, several clinical trials to explore their possible effect on FM have been undertaken. Two double blind, placebo controlled studies with two different agents have been conducted. Wolfe and co-workers [94] tested fluoxetine (FL) against placebo, while Nörregaard and co-workers [95] explored the possible effects on pain of citalopram. Both studies failed to reveal any significant pain reduction in FM patients. Cantini tested FL in combination with cyclobenzaprine (CYC) and amitriptylin (AMI) [96]. In contrast to single treatment, the combination of CYC and FL was superior to CYC alone. In a double-blind crossover design with four arms (AMI; FL; AMI and FL, placebo) there was a statistically significant improvement compared with the placebo treated group, for both AMI as well as FL.

When used in combination, AMI and FL produced significantly better results than either drug alone, as measured by the Fibromyalgia Impact Questionnaire and by visual analogue scale of pain, global well-being and sleep [97]. Citalopram 20-40 mg alone did neither show any effect [98], while sertraline in combination with AMI 25 mg showed improvement in all parameters (VAS pain, sleep, fatigue, stiffness and TP) [99]. Thus, SSRI does not have a place as a single drug treatment in FM patients. In depressed FM patients, however, it may have a role applied in combination with AMI. Tricyclic-antidepressants

Tricyclic agents like AMI, clomipramine, dothiepin and doxepin inhibit the re-uptake of serotonin and norepinephrine at the neuronal terminals. The prevailing hypothesis is that mechanisms involving serotonin and norepinephrine mediate clinical analgesia through descending systems originating in the brainstem and influence the dorsal horn of the spinal cord.

Several double-blind controlled studies of AMI versus placebo have been undertaken. The first study was published in 1986 by Carette and co-workers [100] who found that both AMI and placebo improved significantly morning stiffness and pain compared to baseline scores.

Goldenberg and co-workers [77] likewise found AMI superior compared to placebo in a 6-week trial using outcome parameters such as patient and physician global assessment, pain, sleep problems, fatigue on awaking and TP score. These favourable results of AMI therapy were confirmed by Scudds in 1989 [101] and by Jaeschke in 1991 [102]. In 1994, Carette and co-workers followed 208 patients over six months who were treated with AMI and cyclobenzaprine (CYC). Due to a higher than expected placebo response, long term efficacy could not be demonstrated [88].

In conclusion, the beneficial short-term effects of AMI appear well documented and at the present it may represent the drug of choice in FM. Moreover, further long-term studies are warranted before the role of AMI in FM is finally defined.

4.1.8 Trigger-point treatment

Trigger point injection may reduce pain originating from concomitant triggerpoints in selected FM patients who also suffer from myofascial pain syndrome. A triggerpoint is a localised painful spot in a taut band of muscle fibre producing localised and referred pain on palpation. These triggerpoints may be injected with lidocaine or be manipulated with dry needling, spray and stretch techniques [107]. Less postinjection soreness may be achieved by applying lidocain instead of dry needling [103]. Hong and co-workers [104] performed a study comparing injections with spray and stretch. They found injections more favourable as the patients still had significant pain relief two weeks after injection. This method has clear limitations as a high number of FM patients possess several triggerpoints. This treatment ought to be reserved for patients with pronounced triggerpoints of which the most bothersome should be chosen for injection. The results are optimal when combined with stretching and physical therapy [105].

4.2 Future aspects of drug therapy

This category comprises both drugs already in use, but in other therapeutical fields and experimental drugs. An overview is given in table II [108-129].

4.2.1 Anti-epileptic drugs (AED)

Antiepileptic drugs (AED) have for a long time been administered in different chronic pain conditions [108]. To our knowledge, there exists no study designed to evaluate the possible effects of such drugs in FM patients. Several newer AED with an improved tolerability have recently been introduced. Gabapentin shows the greatest potential in the management of chronic pain and may exert an indirect effect via a second order neurone, such as Wide Dynamic Range neurones. No published double-blind, placebo-controlled trials have evaluated gabapentin in the treatment of pain syndromes.

4.2.2 Salmon calcitonin

Salmon calcitonin has analgesic properties and is commonly used to treat osteoporotic fractures. Besette and co-workers performed a study in FM patients applying 100 IU s.c. calcitonoin compared to placebo. After four weeks there was no significant differences between the two groups [109].

4.2.3 S-Adenosylmethionine (SAM-e)

S-adenosylmethionine is an anti-inflammatory drug with analgesic and anti-depressant effects. Jacobsen and co-workers [110] investigated the efficacy of 800 mg orally administered s-adenosylmethionine daily versus placebo for six weeks in 44 FM patients. Significant improvements were observe for pain at rest and fatigue. Pain during physical activity, quality of sleep and overall well-being did not show any improvement. Although Volkmann and co-workers [111] were unable to show pain reduction (600 mg i.v. for only 10 days), the potential effect of SAM, should be further delineated in FM.

4.2.4 5-Hydroxytryptophan (5-HTP)

5-HTP is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosyntesis of serotonin, and is well absorbed from an oral dose. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including FM [130]. A double-blind, placebo-controlled study of the efficacy and tolerability of 5-HTP was conducted in 50 FM patients. All the clinical parameters studied were significantly improved by treatment with 5-HTP [ 112]. Some of the same authors published a 90-day study with the same promising results. In addition, the efficacy was to maintained throughout the whole period of treatment [113]. Further controlled studies are required to define properly the value of 5-HTP in FM patients.

4.2.5 Botulinum

Botulinum is applied to ease spasms. Recently, it has been shown that botulinum also may relieve pain, before relieving spasms [131]. Relja studied the efficacy on pain in 10 patients with tension-type headache [114]. There was a significant decrease in muscle tenderness that lasted up to eight weeks. This preliminary study demonstrated that injection of botulinum may be an effective treatment for patients with chronic tension-type headaches. It’s potential effects on pain in FM need to be investigated.

4.2.6 Capsaicin

Capsaicin is a depletor of Substance P (SP) and desensitises the neuronal cell membrane, resulting in inhibition of synthesis and release of SP [132]. McCarty and co-workers [115] investigated efficacy and safety in a double-blind, vehicle-controlled study of 0.025% capsaicin cream in 45 FM patients. Capsaicin-treated patients reported significantly less tenderness in TP and a significant increase in grip strength. However, there were no statistical significant differences in the visual analogue scale of pain. The most common adverse effect was transient burning or stinging at the application site. Before recommending this drug in FM, additional confirmative studies are needed.

4.2.7 Gamma-hydroxybutyrate (GHB)

GHB is a naturally occurring metabolite of the human nervous system, with the highest concentrations in hypothalamus and basal ganglia. Scharf and co-workers [116] evaluated the possible effect of GHB in 11 patients with FM. There was a significant improvement in both fatigue and pain, with an increase in slow wave sleep and a decrease in the severity of the ?-anomaly (the protrusion in slow wave sleep). This is a drug of interest with a potential place in the treatment of FM. Further controlled studies are, however, needed to finally establish the clinical improvement and the polysomnographic changes observed.

4.2.8. Growth hormone (GH)

Bennett et al [117] investigated the possible efficacy of GH in FM patients with low levels of insulin-like growth factor using the Fibromyalgia Impact Questionnaire, the TP score and the global improvement. The study lasted nine months and there was a significant improvement in all the examined parameters. Thus, although being rather expensive, the drugs appear promising.

4.2.9 Nerve-growth-factor (NGF)

NGF is reported to regulate the sprouting of sensory axons into neighbouring denervated territory and there exists selective expression of high-affinity NGF receptors (trkA receptors) on nociceptive afferents. NGF may thus function as a mediator of some chronic pain conditions including FM. This assumption is supported by the work of Giovengo and co-workers who has measured higher concentrations in cerebrospinal fluid of NGF in FM patients compared to controls [133]. McMahon and co-workers [118] have used a synthetic protein trkA-IgG to sequester endogenous NGF and block the survival effects of NGF on cultured sensory neurones. In this study it was shown that administration of this molecule produces a sustained thermal and chemical hypoalgesia and leads to a down-regulation of the sensory neuropeptid calcitonin gene-related peptide. Antagonists of NGF may therefore be of clinical use. So far no clinical studies have been undertaken.

4.2.10 NMDA-receptor antagonists

A probable pathogenic mechanism of chronic pain is sensitisation within the central nervous system that in part is mediated by the excitatory amino acids glutamate and aspartate binding to N-methyl-D-aspartate receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but the substances are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphen, and ketobemidone are also antagonists at the NMDA-receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptors antagonists may represent a new class of analgesics and may have co-analgesic properties when used in combination with opioids [134].

Quite a few trials on the effect of these types of drugs have been undertaken in patients with neuropathic, post-traumatic and other types of chronic pain. The results are variable. Several studies have shown substantial pain relief by administration of the drug [135-141], while other studies have shown no or little beneficial effect [142-144]. A serious problem still to be resolved is the side- effects.

In a randomised controlled trial of oral ketamine in patients with chronic pain [124], only 14% of the patients had an extra analgesic response. The majority of patients complained of serious side-effects. However, the disease spectrum of the patients in this study was highly heterogeneous, encompassing cases with multiple sclerosis and post-stroke pain. An experimental study in 17 patients showed reduced muscle pain, temporal summation, and referred pain in FM patients [123]. To our knowledge, only one clinical study on the effect of ketamine-antagonists has been undertaken in FM [125]. The conclusion was that dextromethorphan added to tramadol may have a therapeutic role in a small subset of fibromyalgia patients. Thus, NMDA receptor antagonists should be evaluated in more studies including FM.

4.2.11 5-HT 3 receptor antagonists

Recently, clinical studies with 5-HT 3 – receptor blockers have been performed in FM patients. The 5-HT 3 – receptor is a ligand-gated cation channel located in the central and peripheral nervous system. The antagonists are potent and highly selective competitive inhibitors. They are rapidly absorbed and penetrate blood-brain barrier easily. Half-lives in healthy

subjects vary from 3 – 4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT 3 – receptors are present exclusively on peripheral and central neurones. In the periphery the receptors are located on pre- and postganglionic autonomic neurones and on neurones of the sensory and enteric nervous system. A high density of 5-HT 3 – receptors are located in the brain stem, cortex and dorsal horn ganglia. The central receptors are thus concentrated in regions that are involved in integration of the vomiting reflex and pain processing. Clinical efficacy was first established for chemotherapy-induced emesis.

Serotonin receptors interact with other neurotransmitter systems to play an essential role in pain processing and endogenous pain suppression as a component of the monoaminergic descending inhibitory system with projections from the brain stem to the dorsal horn. The role of the 5-HT 3 – receptors in this context is still not fully understood. Overall, the findings relating to the effect of stimulation or blockade of 5-HT 3 – receptors on pain reactions are inconsistent and not yet convincing [145].

A prospective, multicenter, double-blind, parallel-group, dose-finding study exploring efficacy and tolerability of 5, 10 and 15 mg tropisetron in 418 FM patients was undertaken [127]. A bell-shaped dose-response curve appeared with the highest efficacy of 5 mg once daily. Treatment was well tolerated and prolonged clinical benefits were seen.

Haus and co-workers [128] compared a 10 days and a 28 days randomised study. The pain reduction was most pronounced after 10 days with further improvement up to day 28. Psychometric tests showed significant improvements in depression and anxiety score, and functional symptoms improved with prolonged tropisetron treatment. In a pilot study, Müller and Stratz investigated intravenous administration of tropisetron versus oral treatment [129].

Following a single i.v. injection, a more rapid and profound reduction in pain was achieved than with 5 mg oral tropisetron per day. In individual cases, patients who had previously experienced no reduction of pain after 10 days of 5 mg oral tropisetron daily responded to i.v. therapy. A more favourable and persistent effect on pain, combined with a simultaneous significant improvement in various vegetative and functional symptoms was achieved with five days treatment with 2 mg tropisetron i.v. per day. Thus, 5-HT3 receptor antagonists are promising as pain relievers in FM. Tropisetron was first reported to be generally well tolerated, except for the not infrequent occurrence of headache and obstipation. New studies are in progress, but lately fatal cases of obstipation have been reported, which unfortunately may retard new research in this otherwise promising area.

Hopefully we will still know much more about the possibilities of these drugs during the next few years

5. Conclusions

FM is still an enigmatic condition with unknown aetiology and a pathogenesis that only begins to be understood. Moreover, it is most probably a heterogeneous condition, with several pathways to the final stage of chronic pain and fatigue. The wide spectrum of treatment modalities mirror the complexity of the condition. Traditional pharmacological treatment alone, is has so far been rather discouraging. Tricyclic antidepressants and to a certain extent selective serotonin reuptake inhibitors are the most efficacious drugs so far with respect to improvement of pain, while zopiclone has an effect on sleep disturbances. A new analgeticum, tramadol, seems promising in relieving pain, and further studies are awaited with interest.

On the other hand, the development of new drugs is now in progress, represented by 5-HT3 – and NMDA-receptor antagonists, growth hormone, nerve-growth-factor and possibly gamma-hydroxybutyrate. Unfortunately the two first drugs mentioned have serious side-effects, while growth-hormone is very expensive. Hopefully further studies in these fields will lead to a new generation of pain-modulating medicaments suitable for FM. Due to the probable multifactorial aetiology, a combination of several drugs will possibly be useful in the future.

Most non-pharmacological trials treatments were associated with significant improvement in coping and also with some pain reduction. When compared, non-pharmacological treatment appears to be more efficacious in improving self-report of FM symptoms than pharmacological treatment alone. The optimal intervention for FM in the future would possibly include appropriate medication as needed for sleep and pain combined with non-pharmacologic treatment such as specific exercise, instruction in relaxation techniques, attending support groups including participation in patient education programs and cognitive-behavioural therapy.


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