A proposed framework for sub-types within the greater ‘fibromyalgia construct’ addresses the heterogeneous fibromyalgia population and moves toward a rational, mechanistic approach to therapy.

A growing body of evidence supports the proposition that patients with fibromyalgia represent a heterogeneous population both in terms of objective physiologic findings and neuropsychiatric constitution.1,2 This heterogeneity likely explains the inconsistency seen in laboratory testing and, clinically, the response to trials of various medications. A greater understanding of the potential differences in the pathophysiologic processes that may contribute to the development of the fibromyalgia phenotype (i.e. chronic widespread pain and tenderness) stands to inform clinical management and, ultimately, improve the lives of patients. The three sub-types proposed are: 1) dopamine deficiency, 2) neuronal hyperexcitability, and 3) dysautonomia.

The purposes of this overview are:

to propose a hypothetical framework for sub-types within the greater ‘fibromyalgia construct’

to explore possible elements of the clinical phenotype associated with each

to discuss potential pharmacological strategies to address them

Dopamine Deficiency

Abnormalities in dopamine synthesis and release have been proposed as a primary cause of fibromyalgia symptoms.3 This proposition was originally derived from several key observations, which include: 1) the onset of fibromyalgia and exacerbation of symptoms frequently occur in the context of stressful events4; 2) exposure to chronic stress disrupts dopaminergic neurotransmission in otherwise healthy animals5; and 3) dopamine plays a dominant role in natural analgesia in multiple regions of the central nervous system (CNS) including the limbic cortex, basal ganglia, thalamus, and spinal cord.6 Other potential causes of attenuated dopaminergic neurotransmission include genetic variations governing the activity of enzymes that participate in the dopamine synthetic pathway.7

In addition to its role in pain processing, dopamine also plays a role in other functions that appear to be involved in fibromyalgia, including motor control and coordination, regulation of the autonomic nervous system, cognition, and normal sleep physiology. Thus, a list of potential clinical manifestations of abnormal dopamine activity would include restless legs, sleep bruxism, stiffness, poor coordination, depressive symptoms and/or apathy, dysautonomias (e.g., orthostatic intolerance, constipation, over-active bladder), poor concentration, and disturbed sleep. Clinical signs of hypodopaminergia have not been rigorously documented, but the astute clinician should look for telltale elements of the physical examination such as increased muscle tone, mild resistance to passive extension/flexion of the elbow and wrist (more prominent with distraction), evidence of dyscoordination, and poor suppression of the blink reflex on glabellar tap.

Several therapeutic strategies might be considered to address low dopamine levels and are derived largely from the treatment of RLS and Parkinson’s disease. For example, stimulation of dopamine synthesis may be accomplished through utilization of metabolic precursors, such as L-tyrosine or L-phenylalanine. In my clinical practice, I often recommend supplementation with DL-phenylalanine (DLPA), given that there is evidence that d-phenylalanine has activity as an enkephalinase inhibitor, which might ostensibly provide additional analgesia based on evidence from pre-clinical models.8 I have refrained from recommending levodopa given the observation that this agent has the potential to produce symptom augmentation in RLS. One of the mechanisms governing dopamine synthesis and release is activation of inhibitory presynaptic dopamine D2 autoreceptors by extracellular dopa-mine.9 Thus, antagonism of these receptors by microdose dopamine antagonists (e.g., perphenazine in the range of 0.5-4mg) may counteract this inhibition.10 There is a commercially available combination of perphenazine/amitriptyline that was previously marketed under the brand names Etrafon™ and Triavil™ that comes in a variety of dose ranges (e.g., perphena-zine/amitriptyline 2-10, 2-25, 4-25, 4-50mg).

An alternative strategy to address low dopamine is through the use of dopamine agonists. A controlled trial of pramipexole in fibromyalgia patients taking concomitant medications reported that 45% of patients on active medication responded with >50% reductions in pain among those on active treatment.11 Trials of ropinirole have been less spectacular, but this may be due in part to weaknesses in study design, including insufficient dosing and limited patient recruitment.12 In addition, evidence suggests that many drugs typically conceptualized as n-methyl-d-aspartate (NMDA) receptor antagonists have activity as D2 receptor agonists, including ketamine,13 amantadine,14 and memantine.15 Ketamine has been shown in a series of studies to produce robust effects on fibromyalgia pain when administered systemically at low dose.16-18 While no commercial formulation is currently available for clinical use, compounding pharmacies can elaborate oral slow-release formulations or solutions for intranasal use. In fact, a proprietary formula is currently undergoing evaluation for the treatment of acute pain.19 With regard to amantadine, there is neuroimaging data in humans demonstrating that, in addition to acting as both a direct and indirect D2 agonist, it also cause up-regulation of D2 receptor expression, which would make target neurons more susceptible to dopaminergic activity.20 Indeed, this may contribute to its efficacy in the treatment of Parkinson’s disease. Both amantadine21,22 and memantine23,24 have shown promise in treating chronic pain, although no data exist concerning their utility in fibromyalgia.

Still other strategies to increase dopamine activity include inhibition of dopamine reuptake, e.g., with bupropion, a mixed dopamine-norepinephrine reuptake inhibitor and targeted inhibition of monoamine oxidase-B (MAO-B), which increases dopamine availability by preventing its degradation. Selegiline has specificity for MAO-B, which is preferentially involved in dopamine catabolism, when used at doses lower than 10-15mg/day. It is available in tablet and capsule form in 5mg doses. A transdermal formulation is approved for the treatment of major depression.

Neuronal Hyperexcitability

The absence of a readily demonstrable peripheral pathology to explain fibromyalgia pain has lead to the conclusion on the part of many investigators that fibromyalgia represents a form of ‘central sensitization’ characterized by increased neuronal responsiveness to stimulation.25,26 Evidence in support of this proposition comes from several lines of research, including poly-modal sensitivity,27,28 increased activation of cortical neurons in response to painful and non-painful stimulation,29,30 decreased thresholds for nociceptive flexion reflex,31 and abnormal brain activity characterized by alpha-wave arousals during stage III/IV sleep (i.e. ‘alpha-delta’ sleep).32 Thus, while seizure disorders are characterized by neuronal hyperactivity primarily in the motor cortex and, less commonly, the limbic cortex/temporal lobe, it is conceivable that a sub-type of fibromyalgia embodies hyperactivity within sensory cortices. The chief excitatory neurotransmitter in the CNS is glutamate, while the primary inhibitory neurotransmitter is gamma-aminobutyric acid (GABA). In addition to these, there are a host of factors that affect that balance between neuronal excitation and inhibition, an imbalance of which could ostensibly produce neuronal hyperexcitability.

“Gabapentin is another agent that has shown some promise in treating fibromyalgia by controlled trial.”38

Anatomical problems are also a consideration. For example, the phenomenon of descending inhibition whereby higher brain centers modulate the response of spinal neurons to painful stimulation depends on neuronal tracts within the spinal cord.33 Accordingly, anatomical conditions that compromise the function of neurons participating in descending inhibition (e.g., cervical stenosis, a hypoplastic posterior fossa) would be anticipated to contribute to increased sensitivity.34,35

In the clinical realm, distinguishing neuronal hyperexcitability from other potential fibromyalgia sub-types may represent a challenge, especially when attempting to parse supraspinal vs. spinal contributions. Elements of the patient’s history may be most telling, particularly a history of head or neck trauma, which may provide clues to the presence of abnormal cervical anatomy. Another clue may be pain on cervical extension. When present, consider obtaining a cervical MRI with views obtained in cervical extension and flexion.36 In clinical practice, I also look for evidence of poly-modal sensitivity such as brush allodynia, hyperacusis/ phonophobia, and photophobia.

Several strategies exist to counteract neuronal hyperexcitability. Anti-epileptic medications (AEDs) are commonly used to treat pain, ostensibly by attenuating the release of excitatory neurotransmitters. Notably, the first medication to win FDA approval for the treatment of fibromyalgia (i.e. pregabalin) is a newer generation AED that binds to the alpha-2-delta site on neuronal calcium channels, thereby attenuating neuronal activation by inhibiting the influx of calcium ions.37 Gabapentin is another agent that has shown some promise in treating fibromyalgia by controlled trial.38 In clinical practice, I have had success using extended-release valproate (i.e. Depakote ER) in doses starting at 250mg and titrated as necessary to 500-1000mg. Limitations to valproate’s utility include the potential for weight gain and hair loss and the need to monitor liver enzymes.

An alternative strategy to address neuronal hyperexcitability is to boost GABAergic function. GABA receptors come in two main varieties. GABA-A receptors form ion channels that when activated allow influx of chloride ions, which inhibit neuronal activation. They may be targeted directly through separate binding sites specific for benzodiazepines and barbiturates. In contrast, GABA-B receptors act through inhibitory G-proteins and are sensitive to baclofen. Regarding benzodiazepines: they may be broadly divided into two main categories, i.e. hypnotics and anxiolytics. Given that fibromyalgia is frequently associated with anxiety and an increased incidence of anxiety-related disorders, treatment with anxiolytic benzodiazepines (e.g., alprazolam, diazepam, clonazepam) versus those with more specific activity as hypnotics (e.g., temazepam, triazolam) might represent a more elegant strategy. A liability associated with GABA-A agonists, including benzodiazapines and barbiturates, is their potential for lethality in overdose. Chronic activation of the GABA-A receptor also results in desensitization owing to receptor down-regulation, a phenomenon that can produce psycho-physiologic dependence. While the use of barbiturates in clinical practice has largely been relegated to history, there is one agent—namely carisoprodol (Soma©)39—that is indirectly related to barbiturates that may have some utility in addressing neuronal hyperexcitability as a cause of fibromyalgia, although prudence dictates it be reserved for consideration only in those patients who are refractory to other classes of medication. The chemical name for carisoprodol (N-isopropylmeprobamate) provides a clue to its nature as a pro-drug for meprobamate (Milltown), a Schedule IV barbiturate with significant abuse potential.

Baclofen is a central acting muscle relaxant with specific activity as a GABA-B agonist. While mainly used for the treatment of spasticity related to spinal cord injury or stroke, clinical experience suggests it has meaningful utility in the treatment of a subset of fibromyalgia patients. An alternative strategy to target the GABA-B receptor is through the use of sodium oxybate, a salt of the naturally occurring neurotransmitter gamma-hydroxybutyrate (GHB). GHB is the metabolic precursor of GABA, and the effects of GHB on the central nervous system occur both through GHB-specific receptors as well as GABA-B receptors.40 Sodium oxybate is a potent hypnotic that has been demonstrated to consolidate stage III/IV sleep. It is currently indicated for the treatment of cataplexy associated with narcolepsy and with excessive daytime sleepiness. Controlled trials of sodium oxybate for the treatment of fibromyalgia have demonstrated improvements in multiple domains, including pain reduction and improved sleep.41,42 Given this agent’s potential for abuse, the manufacturer has established a unique distribution system in which patients in the United States can only get prescriptions filled through a central pharmacy.

As noted above, a variety of neurotransmitters can affect that balance between neuronal excitation and inhibition, including serotonin, norepinephrine, dopamine, and histamine. Given that these agents have a variety of functions within the CNS, a patient’s clinical presentation may provide clues as to which to target through rational pharmacotherapy. For example, serotonin is known to play a role in affect and sleep; therefore, a person with melancholic depression (vs. atypical depression), which is characterized by heightened arousal and insomnia, may benefit by measures to increase serotonin, including supplementation with metabolic precursors (i.e. 5-HTP) or serotonergic antidepressants. Two caveats bear mentioning. First, those agents with greater specificity for serotonin reuptake are generally less effective for the treatment of fibromyalgia in comparison with mixed serotonin-norepinephrine inhibitors.43 Thus, preferential consideration should be given for trials of agents such as duloxetine or venlafaxine. In addition, serotonergic antidepressants are associated with suppression of dopaminergic neurotransmission, which may be manifested by such side effects as restless legs or sleep bruxism.44 If a person’s clinical profile is informed by low dopamine as discussed in the preceding section, then the use of serotonergic antidepressants may be particularly problematic.

Finally, ovarian steroids also produce profound effects on cortical activity, with estradiol producing pro-excitatory effects and progesterone and its metabolite allopregnanolone producing inhibition through allosteric modulation of GABA-A receptors.45 There is evidence that female fibromyalgia patients in general may be characterized by increased rates of abdominal surgeries including hysterectomy with oopherectomy.46 Current standard of care in such patients involves replacement of estrogen (to prevent hot flashes and bone loss) in the absence of progesterone supplementation — a situation that ostensibly promotes increased neuronal excitability. In my clinical practice, I address this situation through the judicious use of low-dose natural progesterone, which is profoundly different than synthetic progestogens (e.g., medroxyprogesterone acetate) in terms of pharmacology and metabolic effects.47,48 Given its calming effects, natural progesterone can be used as a sleep aid when unopposed estrogen therapy is suspected of contributing to insomnia or irritability. Natural progesterone is available through compounding pharmacies in individualized doses that can be titrated against a patient’s response to therapy. A commercial formula is available as Prometrium®.

Dysautonomia

Several lines of evidence suggest that fibromyalgia is associated with dysautonomia variously characterized by sympathetic hyperactivity, decreased sympathetic activation in response to challenge, and low parasympathetic tone.49 The primary components of the autonomic nervous system are the sympathetic (“fight or flight”) nervous system and the parasympathetic (“rest and digest”) nervous systems. The activity of the central nervous is modulated in part by elements of the central nervous system, including the locus ceruleus, which is the primary nucleus of the central noradrenergic system, as well an neurons that produce corticotrophin-releasing hormone, which stimulates the locus ceruleus. The primary effector of parasympathetic tone is the vagus nerve, which supplies cholinergic innervation to a variety of organs including the heart, liver, spleen and gut. Clinically speaking, dysautonomia may manifest in a variety of way according to the affected organ, including such symptoms as heightened arousal and insomnia, increased baseline heart rate and/or a tendency for palpitations or tachycardia, orthostatic intolerance, changes in perspiration (either increased or decreased), sicca-like symptoms (e.g., dry eyes, dry mouth), changes in bowel motility and bladder symptoms. In addition, animal models demonstrate that dysautonomia related to either excessive norepinephrine or vagal compromise can produce hyperalgesia.50

There are several potential sources of dysautonomia in fibromyalgia. For example, exposure to chronic stress has been demonstrated to increase sympathetic activity while simultaneously suppressing the activity of vagal afferents.51 Given the role of dopamine in modulating autonomic activity, changes in dopaminergic neurotransmission as detailed above might also contribute to changes in autonomic function. Indeed, this likely makes substantial contribution to the common occurrence of dysautonomia among patients with Parkinson’s disease.52

Strategies aimed at reversing imbalance between sympathetic and parasympathetic tone would be predicted to address symptoms related to dysautonomia—whether by reducing sympathetic hyper-activity, promoting parasympathetic activity, or a combination thereof. For example, the impact of sympathetic activity on target organs may be blunted through the use of beta-adrenergic antagonists (i.e. beta-blockers). The impact of excessive adrenergic tone at the supraspinal level may be likewise addressed by beta-blockers able to penetrate the CNS, including pindolol and propranolol. An open trial of pindolol for the treatment of fibromyalgia demonstrated a positive effect on multiple clinical domains, including clinical pain, tenderness, and stiffness.53 The impact on cardiovascular parameters (i.e. heart rate, blood pressure) was not clinically significant, although decreased dizziness was also noted, suggesting patients may have benefitted from improved orthostatic tolerance. Preliminary data from other centers have reported positive effects on pain related to temporomandibular joint disorder, which is a common comorbidity in fibromyalgia.54,55 In clinical practice, I typically prescribe either pindolol (start 2.5mg at bedtime, increase as necessary/tolerated to 10-15mg/night) or extended-release propranolol (i.e. Inderal LA 60mg/night). Because central-acting beta-blockers can interfere with melatonin synthesis, I typically recommend supplementation with over-the-counter preparations (e.g., melatonin 0.5-3mg at bedtime). Notably, concerns regarding side-effects of depression, fatigue, and sexual dysfunction associated with these medications appear unwarranted.56

An alternative means to address sympathetic hyperactivity is through the use of alpha-2 adrenergic agonists such as clonidine or tizanidine, the latter of which is used as a central-acting muscle relaxer. The rational behind using an alpha-2 agonist is to target inhibitory autoreceptors on adrenergic neurons of the locus ceruleus, thereby decreasing sympathetic tone. This class of medications’ well-known side effect of sedation makes them particularly well-suited for the treatment of insomnia when due to nocturnal sympathetic hyperactivity, although dry mouth can be problematic.

Strategies to boost parasympathetic activity include the use of pyridostigmine, a peripheral-acting acetylcholinesterase inhibitor.57 In clinical practice, I consider this strategy particularly in patients with dry eyes, dry mouth and constipation. It may also improve anxiety levels and sleep, ostensibly through the activity of vagal afferents, which affect higher cortical levels. There is also evidence that suggests dietary fat may increase vagal outflow.58 Given that the ‘inflammatory reflex’ numbers among the systems modulated by vagal activity, this may explain in part why omega-3 fatty acids have an anti-inflammatory effect. While dietary fat is typically seen as problematic in the typical American diet (especially omega-6 fatty acids and saturated fats, which are pro-inflammatory), I frequently recommend dietary supplementation with omega-3 fatty acid, typically with high-quality fish oil supplements at doses ranging from 1000mg two to three times a day.

Concluding Remarks

The purpose of this overview is to propose a series of hypothetical models to explain the physiological heterogeneity that characterizes fibromyalgia and suggest means by which to address elements of pathophysiology that may contribute to symptoms. While clinical experience has emphasized the utility of such an approach, the categories suggested have not been rigorously vetted according to strict standards of scientific inquiry. Several weaknesses are inherent to this model. To begin, there is a dense interplay between the various systems under consideration such that any given patient’s clinical presentation may be impacted by dysfunction due to a combination of factors. For example, dopamine participates in autonomic modulation and also exerts an inhibitory influence over neuronal activity by way of dopamine D2 receptor activity. Likewise, dopaminergic neurotransmission is modulated by excitatory drive from such cortical areas as the prefrontal cortex, hippocampus and amygdala such that an increase in neuronal activity in these areas (as suggested by the model) could attenuate dopamine synthesis and release.59,60 Finally, autonomic activity in the periphery may inform cortical activity and dopaminergic neurotransmission, which could explain the utility of vagal stimulation for the treatment of CNS conditions including epilepsy and depression.61 Thus, parsing the various contributions of each of these to an individual patient’s therapeutic management is a complex task. In addition, there are several other models of fibromyalgia subtypes that could be proposed based on available evidence, including an inflammatory subset (based on evidence of altered cytokine expression among some patients)62 as well as neuroendocrine model(s) variously characterized by low adrenal function,63 compromised growth hormone secretion,64 and even thyroid resistance.65

“The rational behind using an alpha-2 agonist is to target inhibitory autoreceptors on adrenergic neurons of the locus ceruleus, thereby decreasing sympathetic tone.”

Among the suggestions offered is the proposition that key elements of a patient’s clinical profile may inform decisions regarding individualized (i.e. N-of-1) trials of medication in a rational, systematic fashion.66 While the current front-runners under development by the pharmaceutical industry for the treatment of fibromyalgia emphasize two key mechanisms—namely, reduction in neuronal excitation and bioamine reuptake inhibition—several lines of evidence support the potential utility of alternate therapies, particularly with regard to use of dopamine agonist and central-acting beta-blockers. In general, more work is needed to determine whether physiological subtypes indeed exist within the greater ‘fibromyalgia construct’ and, if so, to elucidate the manner in which they might be appropriately addressed. The current work is therefore offered in hopes of stimulating these endeavors.

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 for Cypress Biosciences/Forest Laboratories and Orphan Medical.