Central Role of Dopamine in Fibromyalgia
Fibromyalgia is a common disorder known chiefly for its association with chronic widespread pain and tenderness to light palpation. A diagnosis of fibromyalgia in the clinical setting is based on the classification criteria established by the American College of Rheumatology, published in 1990.1 While historically considered a disorder of the musculoskeletal system, included within the greater symptom complex that comprises the so-called ‘fibromyalgia syndrome’ are a striking number of neurological phenomena that include dysautonomia,2 nondermatomal paresthesias,3 temporospatial dysmetria,4 and restless legs syndrome.5 Patients also frequently complain of cognitive dysfunction (commonly referred to as ‘fibro fog’) characterized by impaired concentration and short-term memory consolidation, impaired speed of performance, inability to multi-task, and frequent cognitive overload.4,6
Given the absence of readily demonstrable peripheral tissue pathology, fibromyalgia research in the last two decades has focused increasingly on the central nervous system as a potential source of symptoms. Indeed, among the more recent hypotheses regarding the pathophysiology of the disorder is that fibromyalgia represents a state of dopaminergic hypo-function that develops subsequent to changes in limbic function following exposure to chronic stress.7 This proposition was originally drawn from three key observations:
- fibromyalgia has been characterized as a ‘stress-related’ disorder due to its frequent onset and apparent exacerbation of symptoms in the context of stressful events8;
- the experience of chronic stress results in the disruption of dopaminergic activity in otherwise healthy organisms9; and
- dopamine plays a dominant role in natural analgesia within multiple brain centers such as the basal ganglia,10 ventral striatum,11 thalamus,12 and limbic cortex.13,14
Evidence Of Disrupted Dopaminergic Neurotransmission In Fibromyalgia
The first hint in the medical literature of a connection between fibromyalgia and dopamine was provided by Russell et al, who in 1992 reported lower concentrations of metabolites of dopamine, norepinephrine, and serotonin in the cerebrospinal fluid (CSF) of fibromyalgia patients in comparison to matched controls.15 As noted above, an increased incidence of restless legs syndrome (RLS) among fibromyalgia patients has also been described.5 While the exact etiology of RLS remains poorly understood, there is mounting evidence from both neuroimaging studies16 and from patient response to pharmacological intervention17 to indicate a role of central dopamine in the pathogenesis of RLS.
There exist several lines of pharmacological evidence for dopaminergic dysfunction in fibromyalgia. For example, indirect evidence is provided by the result of a study by Malt et al., who reported that fibromyalgia patients demonstrate augmented prolactin release in response to a single 60-mg challenge dose of buspirone in comparison with controls.18 Given that the release of prolactin in response to buspirone has been related to the medication’s putative activity as a partial dopamine antagonist,19 the authors concluded that fibromyalgia may be characterized by increased sensitivity or density of dopamine D2 receptors, which would be in keeping with a functional denervation hypersensitivity.
A series of studies performed in Scandinavia have demonstrated that a large subset of fibromyalgia patients respond to systemic administration of sub-dissociative levels of ketamine with reductions in experimental pain, referred pain, and muscle tenderness.20-22 While ketamine has traditionally been conceived of primarily as an n-methyl-d-aspartate (NMDA) receptor antagonist, recent reevaluation of its pharmacological activity has demonstrated that at the low doses typically used in analgesic (versus anesthetic) applications, ketamine acts largely as a dopamine D2 receptor agonist.23,24 Thus, the positive response to systemic low-dose ketamine among responders may be interpreted as providing evidence for the role of dopamine in the alleviation of fibromyalgia pain.
Alternatively, NMDA receptor antagonists have also been demonstrated to increase dopamine synthesis, which presumably contributes to their efficacy in the treatment of Parkinson’s disease. Presynaptic NMDA receptors on dopaminergic terminals have also been proposed to promote the non-stimulated release of extra-synaptic dopamine which, in turn, inhibits phasic reactivity of dopamine neurons in response to stimulation.25 By opposing the activity of these presynaptic receptors, NMDA receptor antagonists may promote phasic dopamine release in response to environmentally relevant stimuli and may, therefore, have utility in the treatment of fibromyalgia. Indeed, the observation that fibromyalgia patients who respond to systemic low-dose ketamine (a putative dopamine D2 receptor agonist) likewise respond to oral dextromethorphan (a clinically available NMDA receptor antagonist) lends credence to this proposition.26
“Compared with the placebo group, patients receiving pramipexole experienced significant improvement in measures of pain as reflected by an average 36% decrease in VAS pain across the active treatment group, with 42% of these achieving >50% decrease in pain...”
Sodium oxybate (Xyrem, Jazz Pharmaceuticals) is the sodium salt of the naturally occurring neurotransmitter gamma-hydroxybutyrate (GHB) and numbers among the molecules whose therapeutic utility in fibromyalgia has shown considerable promise.27-29 While the benefits of sodium oxybate have been largely attributed to the molecule’s activity as a GABA receptor agonist and consolidator of deep sleep—which is disrupted in fibromyalgia—it is intriguing to note that GHB also exerts substantial influence over dopaminergic neurotransmission. Specifically, GHB appears to decrease the threshold for phasic burst firing of dopaminergic neurons, which has been proposed to represent the analgesic aspect of dopaminergic neurotransmission. Moreover, GHB also increases DA synthesis30,31 while simultaneously reducing extrasynaptic (“tonic”) DA concentrations that activate inhibitory autoreceptors,32 thereby limiting dopamine synthesis and phasic release during stimulated burst firing. Consequently, sodium oxybate’s therapeutic benefit in fibromyalgia may stem from increased phasic reactivity of dopaminergic neurons in response to painful stimuli. Formal trials of sodium oxybate for the treatment of fibromyalgia are currently on-going.33