________________________________ Chronic Pain Syndromes: Current Concepts and Treatment Strategies
COMMON CLINICAL CHARACTERISTICS OF FIBROMYALGIA
System
Contributory Factors
Autonomic
Decreased heart rate variance, a tendency for syncope, altered cutaneous capillary responsiveness Hypothalamic-pituitary-adrenal axis dysfunction, including blunted cortisol response, and abnormal growth hormone regulation Consistently elevated levels of the pro-nociceptive neurotransmitters substance P, glutamate, nerve growth factor, brain-derived neurotrophic factor, and serotonin 2a/3a Consistently decreased levels in pain-ameliorating neurotransmitters serotonin 1a/b, norepinephrine, and dopamine Typically normal endogenous opioid system, helping explain the lack of benefit from opioid analgesics Central amplification of pain and/or reduced anti-nociception (central sensitization, abnormalities of descending inhibitory pain pathway function) Strong familial aggregation for fibromyalgia; evidence of polymorphism in the genes encoding serotoninergic, dopaminergic, and catecholaminergic systems in fibromyalgia etiology
Neuroendocrine
Neurotransmitter
Neurosensory
Genetic
Source: [325; 326; 327]
Table 13
CLASSIFICATION In the absence of definitive laboratory tests for fibromyalgia, diagnosis relies on patient history and symptom self-report, physical examination, and manual tender point examination, in accordance with the 2010 standardized criteria established by the ACR. (The ACR criteria were further revised in 2016 to exclude patients with regional pain syndromes [325].) With the diverse symptoms and often vague presentation, the typical patient with fibromyalgia fails to receive an accurate diagnosis for an average of five years [324]. Further complicating the diagnostic process is the considerable symptom overlap with other syndromes such as lupus and rheumatoid arthritis [325]. Fibromyalgia is a diagnosis of exclusion, and patients should be thoroughly evaluated for the presence of other disorders that could be the cause of symptoms before a diagnosis of fibromyalgia is made [324; 325]. TREATMENT The treatment goal in fibromyalgia is to decrease pain and associated symptoms and to improve function and quality of life. No cure is available from any single therapy. The overall treatment effects of single interventions are modest at best, and the management approach with greatest evidence involves pharmacologic therapy combined with nonpharmacologic approaches such as education, exercise, and cognitive-behav- ioral therapy [325; 326]. The atypical nature of fibromyalgia is underscored by it being the only chronic pain syndrome that may be effectively treated with SSRIs [133]. Because the high doses required often cause adverse effects that are poorly toler- ated, SSRIs have largely been replaced by dual serotonin/nor- epinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, levomilnacipran, milnacipran, or duloxetine [325]. Only milnacipran and duloxetine are approved for use in fibromyalgia [36].
An interdisciplinary pain rehabilitation program that empha- sizes behavioral or cognitive-behavioral interventions com- bined with conditioning exercise is recommended for patients with partial or substantial disability due to fibromyalgia-related chronic pain [133]. Advances in the understanding of pain transmission help to explain the effective pharmacotherapies for fibromyalgia ( Table 14 ). The efficacy of TCAs is thought to occur through inhibition of serotonin and norepinephrine reuptake in spinal neurons, increasing their synaptic concentration and resulting in descending pain pathway mediation of analgesia. Low-dose TCAs have demonstrated short-term efficacy in patients with fibromyalgia [325]. A systematic review and network meta-analysis that compared the TCA amitriptyline with pregabalin, duloxetine, and milnacipran concluded that amitriptyline was not significantly different from placebo for relief of depression but showed higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes [328]. Adverse effects (e.g., dry mouth, drowsiness, weight gain) often limit patient acceptance or and tolerance for TCAs. A useful combination is a TCA (e.g., amitriptyline, nortriptyline) in low dosage at bedtime plus a first-generation SSRI (e.g., fluoxetine, paroxetine), which allows for improved efficacy with lower dosing that can help prevent adverse effects. However, patients taking combinations of serotonin- active drugs should be closely monitored for the development of serotonin syndrome, and all patients taking antidepressants should be carefully monitored for worsening depression or the emergence of suicidal thoughts [325]. Use of amitriptyline for fibromyalgia is off-label [36].
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