Proposed Models of Fibromyalgia Sub-types
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
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.