Pharmacological treatments of fibromyalgia: Do complex conditions need complex therapies?

doi:10.1016/j.drudis.2008.01.004

Drug Discovery Today

Volume 13, Issues 7–8, April 2008, Pages 333-340

https://doi.org/10.1016/j.drudis.2008.01.004 Get rights and content

Fibromyalgia (FM) is a chronic pain condition, with auxiliary symptoms, such as sleep disturbances and fatigue. Although many of the mechanisms of action targeted by the drugs used to treat FM have been focused to the management of single symptoms, drugs (e.g. pregabalin, duloxetine) have now been identified that demonstrate a multidimensional effect. However, such drugs often fail to demonstrate acceptable efficacy in the majority of the patient population. Thus, the mechanisms of action of the drugs studied as treatments for FM are either identifying subgroups within the pathophysiology of the condition or suggesting that a mechanism of action that will offer universal efficacy has, as yet, to be identified.

Introduction

Fibromyalgia (FM) is a common chronic diffuse pain condition [1]. Patients with FM typically present with allodynia and hyperalgesia, in addition to experiencing many auxiliary symptoms, such as sleep disturbances, chronic fatigue and cognitive difficulties 1, 2, 3. Localized or regional pain in most patients with FM precedes the widespread pain, which could suggest the latter develops from the former. Although pain is a predominant feature of FM, pathophysiology related to the alteration in pain processing does not, however, clearly explain other commonly experienced symptoms, such as fatigue and sleep disturbances. Classification of FM is often further complicated by the presence of co-morbid conditions (Figure 1). It is estimated to affect 2–4% of the general population, increasing to greater than 7% of those over 70 years of age [4]. The management of FM is complicated by the lack of understanding of whether the pathophysiological mechanisms proposed are causal or consequential and overlap with symptoms of other health conditions (e.g. chronic fatigue syndrome, myofascial pain, systemic lupus erythematosus). It is generally assumed to be a complex and difficult to treat disorder, which usually requires a multidisciplinary approach, using both pharmacological and non-pharmacological interventions 5, 6.

Several hypotheses have been proposed regarding the pathophysiology of FM, which include a dysfunction of pain modulatory systems within the central nervous system (CNS), neuroendocrine dysfunction and dysautonomia 7, 8, 9, 10. This article will consider the value of potential drug targets for treatment of FM and how this information can offer insight into the pathophysiology of the condition. The predominant mechanisms of action, which this review will focus on, by which drugs have demonstrated efficacy in patients with fibromyalgia or are currently in clinical trials are summarized in Table 1.

Section snippets

Central sensitization

FM is often described as a condition of heightened generalized sensitization to pain, which is associated with spatially distributed allodynia and hyperalgesia. A lack of underlying peripheral structural damage and inflammatory signs suggests that little peripheral stimulation is required 7, 56. This is supported by the failure of anti-inflammatory medications, such as the non-steroidal anti-inflammatory drugs, naproxen and ibuprofen, and prednisone to be effective treatments of FM 57, 58, 59.

NMDA antagonism

NMDA receptor antagonists are not widely accepted as treatments of chronic pain, because of a lack of specificity and thereby associated adverse effects. Nevertheless, ketamine and dextromethorphan have demonstrated efficacy (pain score) as anti-hyperalgesics in the treatment of FM 30, 31, 32. Selective antagonists of the NR2B subunit-containing NMDA receptor, for example ifenprodil, are antinociceptive in preclinical pain models, with much lower side effect profiles compared with other NMDA

Descending pain-modulating pathways

The endogenous descending pain-modulating system links the periaqueductal grey and the rostal ventromedial medulla with the spinal cord. Evidence suggests that in FM there is a failure to modulate pain, that is a consequence of noxious stimuli, because of dysfunction in the descending inhibitory pathways 74, 75, 76. Serotonergic and noradrenergic neurons are involved in the inhibitory mechanisms of the descending pain-modulating pathways in the brain and spinal cord [7]. Thus, enhancement of

Bioamine reuptake modulators

First-line pharmacological therapies for FM are often antidepressants, particularly tricyclic antidepressants (TCAs), such as amitriptyline and dothiepin 5, 77. The analgesic effects of TCAs could be explained by inhibition of the reuptake of serotonin and noradrenaline into the neuronal terminal modulating the descending tracts, influencing the dorsal horn neurons. In addition, low-dose TCAs have been significantly effective in the management of sleep and fatigue in patients with FM 6, 11, 12,

Dopamine

In addition to noradrenaline and serotonin being involved in the spinal descending inhibitory pathways, dopamine plays a role at the supraspinal level of the thalamus, basal ganglia and limbic cortex 93, 94, 95, 96. A reduction of presynaptic dopamine metabolism in FM, as demonstrated by positron emission tomography, supports a disruption of dopaminergic neurotransmission being involved in the pathophysiology of FM [97]. In addition, it has been reported that patients with FM have an abnormal

α₂δ ligands

The α₂δ-subunit of voltage-gated calcium channels is responsible for calcium influx into nerve terminals and the subsequent release of neurotransmitters, such as glutamate and substance P, that play a role in pain processing 99, 100. Thus, ligands of the α₂δ-subunit that block presynaptic calcium channels will decrease the release of multiple neurotransmitters and attenuate abnormal hyperexcitability of neuronal networks as that associated with chronic pain. The α₂δ-subunit ligand, gabapentin,

Gamma-aminobutyric acid (GABA)

Gamma-hydroxybutyrate (GHB) is a precursor to GABA and exhibits agonist activity at both the GHB-specific receptor and GABA_B receptor [102]. Sodium oxybate, the sodium salt of GHB, provided significant improvements in the major symptoms of FM (i.e. pain, tenderness, sleep quality and fatigue) during an 8-week study 39, 40. The benefits of sodium oxybate in FM have been largely attributed to its capacity to consolidate and improve deep sleep. A significant correlation (r = 0.55, p < 0.001) was

Hypothalamic–pituitary–adrenal (HPA) axis

Research suggests that the pain-processing pathways may not be the only part of the CNS involved in the pathophysiology of FM, but may also include the HPA axis and the autonomic nervous system.

In some patients with FM the HPA axis is disturbed with elevated cortisol levels lacking diurnal fluctuation and blunted cortisol secretion in response to stress 7, 10. This is consistent with the HPA axis being underactivated and some patients with FM exhibiting a subnormal adrenocortical function.

Future directions

Although drugs as treatments of FM are being identified that demonstrate efficacy against multiple domains (e.g. pain and function) of the condition, such agents are identifying refractory subgroups of patients. In addition, because the pharmacological properties (bioamine modulation, calcium channel blockade) of these treatments are similar to those of currently available medications, the potential of long-term (years rather than months) adverse effects to which patients with this chronic

Conclusion

FM is a complex and difficult to treat disorder, which usually requires a multidisciplinary approach using both pharmacological and non-pharmacological interventions. Many of the mechanisms of action targeted by the drugs used to treat FM have been focused to the management of single symptoms rather than the condition. Drugs (e.g. pregabalin, duloxetine and sodium oxybate) have now been identified that demonstrate a multidimensional effect in this condition. However the relationship of their

References (109)

D.L. Goldenberg
Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain
Best Pract. Res. Clin. Rheumatol.
(2007)
L.M. Arnold
A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with FM with or without major depressive disorder
Pain
(2005)
L.M. Arnold
A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia
Am. J. Med.
(2002)
A.A. Patkar
A randomized, controlled trial of controlled release paroxetine in fibromyalgia
Am. J. Med.
(2007)
U.M. Anderberg
Citalopram in patients with fibromyalgia – a randomized, double-blind, placebo-controlled study
Eur. J. Pain
(2000)
T. Graven-Nielsen
Ketamine reduces muscle pain, temporal summation and referred pain in fibromyalgia patients
Pain
(2000)
S.P. Cohen
The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients
J. Pain
(2006)
J. Quijada-Carrera
Comparison of tenoxicam and bromazepan in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial
Pain
(1996)
R.Q. Skrabek
Nabilone for the treatment of pain in fibromyalgia
J. Pain
(2008)
K.G. Henriksson
Is fibromyalgia a distinct clinical entity? Pain mechanisms in fibromyalgia syndrome. A myologist's view
Baillieres Best Pract. Res. Clin. Rheumatol.
(1999)

B.A. Chizh

NMDA receptor antagonists as analgesics: focus on the NR2B subtype

Trends Pharmacol. Sci.

(2001)

P.B. Wood

A reconsideration of the relevance of systemic low-dose ketamine to the pathophysiology of fibromyalgia

J. Pain

(2006)

R. Staud

Effects of the N-methyl-d-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects

J. Pain

(2005)

N. Julien

Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition

Pain

(2005)

R. Staud

Temporal summation of pain from mechanical stimulation of muscle tissue in controls and subjects with fibromyalgia syndrome

Pain

(2003)

E. Kosek et al.

Modulatory influence on somatosensory perception from variation and heterotropic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects

Pain

(1997)

J.A. Mico

Antidepressants and pain

Trends Pharmacol. Sci.

(2006)

B.C. Shyu

Neurophysiological, pharmacological and behavioural evidence for medial thalamic mediation of cocaine-induced dopaminergic analgesia

Brain Res.

(1992)

E.H. Chudler et al.

The role of the basal ganglia in nociception and pain

Pain

(1995)

A. Lopez-Avila

Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulated cortex

Pain

(2004)

P.B. Wood

Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with PET: a pilot study

J. Pain

(2007)

M.J. Millan

Descending control of pain

Prog. Neurobiol.

(2002)

D.J. Dooley

Ca²⁺ channel alpha2delta ligands: novel modulators of neurotransmission

Trends Pharmacol. Sci.

(2007)

F. Wolfe

The American College of Rheumatology (1990) criteria for the classification of fibromyalgia. Report of the multicenter criteria committee

Arthritis Rheum.

(1990)

D.J. Clauw

Fibromyalgia: more than just a musculoskeletal disease

Am. Fam. Physician

(1995)

A.K. Jain

Fibromyalgia syndrome: Canadian clinical working case definition, diagnostic and treatment protocols – a consensus document

J. Musculoskelet. Pain

(2003)

D.S. Rooks

Fibromyalgia treatment update

Curr. Opin. Rheumatol.

(2007)

L.M. Arnold

Biology and therapy of fibromyalgia. New therapies in fibromyalgia

Arthritis Res. Ther.

(2006)

P. Mease

Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment

J. Rheum. Suppl.

(2005)

A.M. Abeles

Narrative review: the pathophysiology of fibromyalgia

Ann. Intern. Med.

(2007)

L. Arendt Neilsen et al.

Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain inhibition

Best Pract. Res. Clin. Rheumatol.

(2007)

P. Sarzi-Puttini

Increased neural sympathetic activation in fibromyalgia syndrome

Ann. N. Y. Acad. Sci.

(2006)

F. Tanriverdi

The hypothalamic–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

Stress

(2007)

S. Carette

Comparison of amitriptyline, cyclobenzaprine and placebo in the treatment of fibromyalgia

Arthritis Rheum.

(1994)

L.M. Arnold

A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder

Arthritis Rheum.

(2004)

O. Vitton

A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia

Hum. Psychopharmacol.

(2004)

R.M. Gendreau

Efficacy of milnacipran in patients with fibromyalgia

J. Rheumatol.

(2005)

K. Sayar

Venlafaxine treatment of fibromyalgia

Ann. Pharmacother.

(2003)

F. Wolfe

A double-blind placebo controlled trial of fluoxetine in fibromyalgia

Scand. J. Rheumatol.

(1994)

D.L. Goldenberg

A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia

Arthritis Rheum.

(1996)

http://clinicaltrials.gov/ct2/show/locn/NCT00357825?intr=%22Reboxetine%22&rank=7 (accessed 12 January...

Dinan, T. and Daly, P. Neurocure Ltd. Use of pharmaceutical compositions of lofepramine for the treatment of ADHD, CFS,...

M. Palangio

Treatment of fibromyalgia with sibutramine hydrochloride monohydrate

Arthritis Rheum.

(2002)

A.J. Holman et al.

A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications

Arthritis Rheum.

(2005)

A.J. Holman

Treatment of fibromyalgia with the dopamine agonist ropinirole: a 14-week double-blind, pilot, randomized controlled trial with 14-week blinded extension

Arthritis Rheum.

(2004)

http://www.ucb-group.com/research_and_development/product_pipeline/902.htm (accessed 12 January...

M. Späth

Treatment of fibromyalgia with tropisetron – dose and efficacy correlations

Scand. J. Rheumatol. Suppl.

(2004)

S.R. Clark et al.

Supplemental dextromethorphan in the treatment of FM. A double blind, placebo controlled study of efficacy and side effects

Arthritis Rheum.

(2000)

http://www.evotec.com/en/our_pipeline/evt101.aspx (accessed 12 January...

L.M. Arnold

Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial

Arthritis Rheum.

(2007)

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^☆: Disclosure: Dr Kim Lawson has served in an advisory capacity to, and received honoraria from, Eli Lilly, Boehringer Ingelheim, Pfizer Ltd., Propagate Pharma Ltd., Brintnall & Nicolini Inc., Lazard Capital Markets Inc., Decision Resources Inc., RTI Health Solutions and IMS Health UK.

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ReviewPost ScreenPharmacological treatments of fibromyalgia: Do complex conditions need complex therapies?☆

Introduction

Section snippets

Central sensitization

NMDA antagonism

Descending pain-modulating pathways

Bioamine reuptake modulators

Dopamine

α2δ ligands

Gamma-aminobutyric acid (GABA)

Hypothalamic–pituitary–adrenal (HPA) axis

Future directions

Conclusion

Best Pract. Res. Clin. Rheumatol.

Pain

Am. J. Med.

Am. J. Med.

Eur. J. Pain

Pain

J. Pain

Pain

J. Pain

Baillieres Best Pract. Res. Clin. Rheumatol.

Trends Pharmacol. Sci.

J. Pain

J. Pain

Pain

Pain

Pain

Trends Pharmacol. Sci.

Brain Res.

Pain

Pain

J. Pain

Prog. Neurobiol.

Trends Pharmacol. Sci.

The American College of Rheumatology (1990) criteria for the classification of fibromyalgia. Report of the multicenter criteria committee

Arthritis Rheum.

Fibromyalgia: more than just a musculoskeletal disease

Am. Fam. Physician

Fibromyalgia syndrome: Canadian clinical working case definition, diagnostic and treatment protocols – a consensus document

J. Musculoskelet. Pain

Fibromyalgia treatment update

Curr. Opin. Rheumatol.

Biology and therapy of fibromyalgia. New therapies in fibromyalgia

Arthritis Res. Ther.

Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment

J. Rheum. Suppl.

Narrative review: the pathophysiology of fibromyalgia

Ann. Intern. Med.

Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain inhibition

Best Pract. Res. Clin. Rheumatol.

Increased neural sympathetic activation in fibromyalgia syndrome

Ann. N. Y. Acad. Sci.

The hypothalamic–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

Stress

Comparison of amitriptyline, cyclobenzaprine and placebo in the treatment of fibromyalgia

Arthritis Rheum.

A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder

Arthritis Rheum.

A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia

Hum. Psychopharmacol.

Efficacy of milnacipran in patients with fibromyalgia

J. Rheumatol.

Venlafaxine treatment of fibromyalgia

Ann. Pharmacother.

A double-blind placebo controlled trial of fluoxetine in fibromyalgia

Scand. J. Rheumatol.

A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia

Arthritis Rheum.

Treatment of fibromyalgia with sibutramine hydrochloride monohydrate

Arthritis Rheum.

A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications

Arthritis Rheum.

Treatment of fibromyalgia with the dopamine agonist ropinirole: a 14-week double-blind, pilot, randomized controlled trial with 14-week blinded extension

Arthritis Rheum.

Treatment of fibromyalgia with tropisetron – dose and efficacy correlations

Scand. J. Rheumatol. Suppl.

Supplemental dextromethorphan in the treatment of FM. A double blind, placebo controlled study of efficacy and side effects

Arthritis Rheum.

Review
Post Screen
Pharmacological treatments of fibromyalgia: Do complex conditions need complex therapies?☆

α₂δ ligands