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12 Articles in Volume 7, Issue #8
A Clinical Guide to Weaning Off Intrathecal Opioids
Avoiding the Pitfalls of Opioid Reversal with Naloxone
Central Role of Dopamine in Fibromyalgia
CES in the Treatment of Insomnia: A Review and Meta-analysis
Combined Phrenic Nerve Palsy and Cervical Facet Joint Pain
Dextrose Prolotherapy for Unresolved Neck Pain
Low Level Laser Therapy - Part 1
Mistakes Made by Chronic Pain Patients
Near-infrared Therapeutic Laser and Pain Relief
Patulous Eustachian Tube: Part 2
The “Promise” of Pain Medicine: Profession, Oaths, and the Probity of Practice
Three Dimensional Imaging of the Foot

Central Role of Dopamine in Fibromyalgia

A review of the evidence that fibromyalgia is associated with a disruption of dopaminergic neurotransmission together with a discussion of its therapeutic implications.

Scientific research has revealed neurotransmitter links to fibromyalgia, including elevated levels of substance P and depleted levels of serotonin. Dr. Patrick Wood recently uncovered the possibility of dopamine deficiency as a major contributor to fibromyalgia symptoms. This timely article gives insights into his work and offers new treatment opportunities for fibromyalgia patients.

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:

  1. 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;
  2. the experience of chronic stress results in the disruption of dopaminergic activity in otherwise healthy organisms9; and
  3. 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

The most direct pharmacological evidence of a role for dopamine in fibromyalgia has been provided by Holman and colleagues, who have reported the results of several studies that investigated the utility of dopamine agonists in the treatment of fibromyalgia.34-38 The best known of these is the report of a controlled trial of the dopamine D2/D3 agonist pramipexole (Mirapex, Boehringer-Ingelheim) in the treatment of fibromyalgia, which appeared in the journal Arthritis and Rheumatism.38 The primary outcome in this 14-week study was improvement of pain as indicated on a 0-10 cm visual analog scale (VAS); secondary measures of efficacy included subjective tenderness and quality of life. 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 (as compared to 17% of those on placebo). A number of other measures, such as fatigue and global well-being, likewise showed significant symptom improvement.

Finally, two recent studies that utilized positron emission tomography (PET) have provided direct evidence of a disruption in dopaminergic neurotransmission in patients with fibromyalgia. The first of these utilized 6-[(18)F]fluoro-L-DOPA (FDOPA) to determine the presynaptic activity of dopaminergic neurons in female fibromyalgia patients in comparison with matched controls.39 While the small sample size was a limiting factor, a significant reduction in uptake was nonetheless demonstrated in the dopaminergic centers of the mid-brain (i.e. ventral tegmental area and substantia nigra) and in multiple regions of the pain neuromatrix, including the thalamus, insula and cingulate cortex, where dopamine plays a role in natural analgesia. A subsequent PET study demonstrated a dramatic disruption in the dopaminergic reactivity to a tonic painful stimulus within the basal ganglia as demonstrated by 11C-raclopride, a radio-ligand with specificity for dopamine D2 receptors.40 In control subjects, the amount of dopamine released in response to tonic pain correlated with subjective ratings of pain intensity, while no such relationship was demonstrated in fibromyalgia patients. Taken together, these neuroimaging studies provide the most compelling evidence to date of the involvement of dopamine in the pathophysiology of fibromyalgia and strongly suggest that maneuvers to enhance dopaminergic activity are physiologically relevant to the disorder.

“...several lines of evidence support the proposition that a disruption of normal dopaminergic neurotransmission plays a role in the pain of fibromyalgia. ...such a disruption may ostensibly contribute to the expression of many of the bizarre and seemingly unrelated symptoms that characterize the greater ‘fibromyalgia syndrome.’”

In summary, several lines of evidence support the proposition that a disruption of normal dopaminergic neurotransmission plays a role in the pain of fibromyalgia. Given the diverse activities in which central dopamine is active, such a disruption may ostensibly contribute to the expression of many of the bizarre and seemingly unrelated symptoms that characterize the greater ‘fibromyalgia syndrome.’ Fibromyalgia’s heritage as a musculoskeletal disorder has led to a number of comparisons between fibromyalgia patients and those with rheumatoid arthritis — the archetypal rheumatologic disorder — ultimately highlighting the dramatic distinction between these two populations.

On the other hand, one would reason that if fibromyalgia is indeed a disorder in which a depression in dopamine synthesis and reactivity plays a central role, then a more appropriate ‘archetype’ may be found in Parkinson’s disease, a disorder that is likewise associated with a broad spectrum of non-motor symptoms that impact a variety of bodily systems. When seen from this perspective, the overlap in phenomenology between the two disorders is striking and includes such symptoms as parasthesia, dysautonomia, genitourinary and gastrointestinal dysfunction, sleep disturbances, frequent psychiatric involvement and, perhaps most intriguingly, mysterious musculoskeletal pains.

Therapeutic Implications Of Altered Dopaminergic Neurotransmission

Dopamine acting at post-synaptic receptors has been demonstrated to be analgesic in a variety of settings. Within the basal ganglia, the majority of evidence suggests that the analgesic capacity of dopamine is primarily due to stimulation of post-synaptic dopamine D2 receptors,10,11 while in the insular cortex and thalamus, evidence suggests that activation of dopamine D1 receptors engage neurons involved in descending inhibition at the spinal level.12,14 One would, therefore, predict that pharmacological interventions that either mimic the activity of dopamine at post-synaptic receptors or promote the biosynthetic capacity and phasic reactivity of dopaminergic neurons would have therapeutic utility in the treatment of fibromyalgia.

As noted above, Holman and Myers have published the report of a successful controlled study of the dopamine D2/D3 agonist pramipexole in the treatment of fibromyalgia.38 The study was unique for a number of reasons, not the least of which was that pramipexole was added to what were the subjects’ best-yet medical regimens. While it may be argued that this strategy obfuscates the interpretation of subject responses, a counter argument would be that regardless of what agents these subjects may have been taking, their regimen was not biologically relevant to their underlying pathophysiology as witnessed by the observation that they continued to meet inclusion criteria for a study of primary fibromyalgia. In addition, there were two exclusion criteria for participation that the authors maintain were critical to subject selection, the first being the presence of untreated sleep apnea and the other being evidence for intermittent cervical cord compression (i.e. cervical myelopathy) as determined by pain on cervical extension, e.g. gazing up at the stars or sitting in a dentist’s examination chair. The reasoning behind these exclusions is that each represents an independent source of autonomic activation, which the authors reasoned may interfere with response to treatment with this class of agent based on clinical experience.

Given that the use of this agent for the treatment of fibromyalgia has been considered controversial,41 it is noteworthy that the European League Against Rheumatism (EULAR) has recently endorsed the use of pramipexole for the treatment of the disorder.42 When employing pramipexole, starting doses of 0.25 to 0.5 mg at bedtime have been used, with weekly dose titration by 0.5 mg to a target range of 3 to 4.5 mg. This dosing strategy is considerably different from the doses used in either Parkinson’s disease, in which patients take medication three times a day, or in RLS, in which nightly dosing at lower levels is used. Again, given that post-synaptic activation confers analgesic activity, the relatively high dose used in fibromyalgia may be necessary to achieve post-synaptic activity. In contrast, it may be conjectured that the efficacy of therapeutic strategies used in Parkinson’s disease, i.e. lower doses and more frequent administration, may stem from changes in the synaptic environment, which is likely radically altered owing to massive loss of dopaminergic neurons.

Trials to-date of ropinirole have met with less remarkable success than those utilizing pramipexole, although this may ostensibly be related to either statistical considerations or a mismatch in the dosing strategy. A failed study presented by Holman was based on a small sample size, which likely amplified placebo response,36 while a European study conducted by GlaxoSmithKline that failed to demonstrate benefit used relatively small doses of a proprietary long-acting formulation.43 The relative strength of pramipexole to ropinirole is roughly 1:5, therefore a patient who responds to 3 mg of pramipexole would be anticipated to require 15 mg of ropinirole. Indeed, preliminary data and this author’s clinical experience have demonstrated utility of this agent in the treatment of fibromyalgia.

Side effects are relatively common with these medications. Nausea may be treated with either relatively high-dose proton pump inhibitors (PPI), as was done in the pramipexole study. Alternatively, this author has had success using trimethobenzamide hydrochloride (Tigan) at doses of 300 mg two to three times a day as needed for nausea associated with dopamine agonists. Insomnia is also not uncommon, nor is temporary activation, which may be countered using sedative hypnotics or low-dose benzodiazepines (e.g., lorazepam or clonazepam). Patients may also experience weight loss. Practical considerations in the use of dopamine agonists pramipexole and ropinirole are summarized in Table 1.

Table 1. Practical Considerations for the Use of Dopamine Agonists in Fibromyalgia*
Medication Dosages Notes

Pramipexole (Mirapex®)

Start 0.25–0.5 mg nightly; increase as necessary or as tolerated by side-effects in 0.5 mg increments weekly to target of 3–4.5 mg nightly.
Rule out OSA prior to initiation of therapy; if present, ensure adequate treatment prior to commencement.
Rule out intermittent cervical cord compression/cervical myelopathy prior to initiation of therapy. (Does patient have pain on cervical extension, e.g. looking up at the ceiling or sitting in a dentists chair?)

Ropinirole
(ReQuip®

Start 0.5–1 mg nightly; increase as necessary or as tolerated by side-effects in 0.5–1 mg
increments weekly to
target dose of 10–15 mg nightly.
Monitor for development of obsessive behaviors (e.g. gambling, internet shopping) or excessive/unpredictable sleepiness. Also, monitor for weight loss.

Medication strategies to consider for the treatment of side-effects:

Nausea

  • PPI (e.g. lansoprazole, pantoprazole)*: may require up to 3x normal strength
  • Trimethabenzomide (Tigan)* 300 mg two to three time a day as needed.†

Insomnia

Activation

Pramipexole is somewhat easier to titrate due to scored tablets, which may be split, while ropinirole tablets have a unique shape that makes splitting difficult. Pramipexole may be somewhat more efficacious due to concomitant alpha2 receptor agonism, while ropinirole may have fewer side-effects.†

  • Zolpidem* 2.5–10 mg at bedtime
  • Lorazepam (Ativan)* 0.25–1 mg
  • Clonazepam (Klonopin)* 0.25–2 mg at bedtime
    • Clonazepam (Klonopin)* 0.25–2 mg two to three times a day†
    • Propranolol* 30 mg twice a day†
* These agents are not approved by the US Food and Drug Administration for the treatment of fibromyalgia and therefore represent “off-label” use.
Consider obtaining informed consent prior to initiating therapeutic trial.
† Author’s clinical experience
Abbreviatons: OSA — obstructive sleep apnea; PPI — proton pump inhibitor; mg — milligrams

In addition to the foregoing, an additional dopamine agonist has recently become available in a patch form, i.e., rotigotine transdermal (Neupro, Schwarz Pharma). A Phase II “proof of concept” trial of rotigotine transdermal for the treatment of fibromyalgia sponsored by the manufacturer was launched in March 2007 and is currently underway44; however, no clinical data regarding the utility of this agent in the treatment of fibromyalgia are currently available. In light of the failed trial of controlled-release ropinirole, it remains to be seen whether long-acting agents will prove as effective as nocturnal dosing with short-acting formulations.

Conclusions

Dopamine is a catecholaminergic neurotransmitter that plays a prominent, albeit historically lesser known, role in natural analgesia within the central nervous system. Indeed, it has been demonstrated that the analgesic capacity of classical analgesics (i.e., mu-opioid receptor agonists, such as morphine) is derived in large part from their capacity to activate dopaminergic neurons.11 An increasing body of evidence suggests that fibromyalgia is associated with dysfunctional dopaminergic neurotransmission as demonstrated by neuroimaging studies that have revealed both a reduction in dopamine synthesis at baseline39 and a disruption of dopamine release in response to tonic painful stimulation.40 Together, these observations provide a reasonable explanation for post-synaptic hypersensitivity of dopamine receptors suggested by increased prolactin release in response to buspirone challenge.18

Many of the symptoms that comprise the greater ‘fibromyalgia syndrome’ may also be related to a disruption of normal dopaminergic activity, including RLS, dysautonomia, dysphoria and cognitive dysfunction. Strategies aimed at enhancing dopaminergic activity, therefore, represent a rational approach to the treatment of fibromyalgia — a proposition lent credence by the observation that several of the agents that have demonstrated an ability to alleviate fibromyalgia symptoms have prominent effects on dopaminergic neurotransmission, as reviewed above. Pramipexole, a dopamine agonist currently indicated for the treatment of Parkinson’s disease and RLS, has been demonstrated by a placebo-controlled, double blinded trial to be effective at alleviating pain and other symptoms of the disorder38—resulting in its endorsement by EULAR for the treatment of fibromyalgia.42 There also exist a number of other medications whose mechanisms of action likewise impact dopaminergic parameters that may eventually demonstrate utility in the treatment of this complex disorder.

Disclosures

Dr. Wood has received consulting fees of less that $10,000 from Boehringer-Ingelheim and Jazz Pharmaceuticals. In addition, he has received research support from GlaxoSmithKline and performed research under contract with Cypress Bioscience/Forest Laboratories and Orphan Medical.

Last updated on: January 24, 2012
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