Charles J Malemud*
Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio USA
Received Date: May 02, 2013; Accepted Date: July 20, 2013; Published Date: July 25, 2013
Citation: Malemud CJ (2013) Regulation of Pain in Fibromyalgia by Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibition. Int J Phys Med Rehabil 1:144. doi: 10.4172/2329-9096.1000144
Copyright: © 2013 Malemud CJ. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Fibromyalgia is a chronic pain processing disorder primarily affecting the musculoskeletal system. Fibromyalgia is often accompanied by chronic fatigue, dyscognition and altered sleep architecture. One mechanism widely recognized as contributing to chronic pain in fibromyalgia involves musculoskeletal tenderness in response to innocuous mechanical stimuli also known as allodynia. However, the recently performed re-analysis of the clinical criteria for the diagnosis of fibromyalgia proposed that physicians should also take into account a patient’s overall symptoms deemphasizing the tender point count. It is generally agreed that the cellular basis for the chronic musculoskeletal pain of fibromyalgia involves abnormalities in ascending and descending pain pathways resulting from heightened central nervous system sensitization. Of note, the results of studies employing animal models of chronic pain substantiate such a mechanism. Importantly, the co-morbidities characteristic of fibromyalgia patients also suggests a genetic component presumably involving biogenic amines and single nucleotide polymorphisms in the serotonin transporter protein and dopamine transporter and receptor genes. By all indications the 5-hydroxytryptamine/5-hydroxytryptamine receptor pathway appears to be an appropriate target for therapeutic intervention. Indeed, selective-serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibition have now been added to antidepressant medicines and pregabalin as clinically efficacious drugs for fibromyalgia. It is now thought that antidepressants such as amitryptiline and pregabalin act via high-voltage activated Ca2+ channels and the Kv1 family of K+ channels and/or by modifying defective serotonergic circuitry exemplified by abnormalities in serotonergic receptor-mediated events. Selectiveserotonin and serotonin/norepinephrine reuptake inhibitors such as duloxetine and milnacipran, respectively, act through a G-protein-coupled mechanism involving the 5-hydroxytryptamine/5-hydroxytryptamine-(2A) receptor which leads to activation of cyclic AMP-dependent protein kinase A and Ca2+/calmodulin kinase IV. However, more recent evidence indicated that this drug class also activates Janus kinase-3, extracellular signal-regulated kinase 1/2 and the Src/Phosphatidylinositide-3-kinase (PI3K)/Akt/Glycogen Synthase Kinase-3/mammalian target of rapamycin signaling pathway.
Allodynia; Central nervous system desensitization; Chronic fatigue; Fibromyalgia; Hyperalgesia; Serotonin; Serotonin/ norepinephrine; Selective-serotonin/serotonin-norepinephrine reuptake inhibition
Henricksson proposed that the fibromyalgia syndrome (FMS) now be considered a multisystemic disease rather than a syndrome  because the chronic pain of FMS is widespread. FMS is functionally characterized by a generalized mechanical hypersensitivity or hyperalgesia to innocuous pain stimuli also known as allodynia  and according to the American College of Rheumatology the diagnosis of FMS should no longer merely rely on an assessment of hyperalgesia produced by the physical manipulation of at least 11 tender points among a specific group of 18 anatomic sites defined in the 1990 American College of Rheumatology criteria for the diagnosis of FMS . Instead, the new criteria for clinically assessing FMS  proposed that the relative weight given to the number of tender points be significantly minimized in favor of placing a greater emphasis on an individual’s overall clinical symptoms. In the long-term this change in emphasis for the diagnosis of FMS might be expected to increase the frequency of FMS because in each case, what is predicated is that the generalized hypersensitivity response to innocuous pain stimuli would not be solely limited to those anatomic sites with tender points . However, the results of a recent study  demonstrated that the modified 2010 ACR criteria  for the diagnosis of FMS did not result in higher numbers of patients being diagnosed with the disorder. Instead, the results supported the contention that FMS and scores on the polysymptomatic distress scale employed to aid in making the diagnosis of FMS was largely dependent on the severity of somatic symptoms.
FMS is predominately diagnosed in middle-aged women . However, although the persistence in pain must be continuous over a period of at least 3 months for FMS to be considered in the differential, the persistence in pain criteria was shown to be gender-independent . Although FMS is classified as a chronic musculoskeletal pain disorder, it is also characterized by bouts of chronic fatigue and dyscognition .
Co-morbid conditions associated with FMS
Several co-morbid conditions are often associated with FMS  including functional dysautonomia and obesity. Importantly, dysautonomia can aid in helping physicians discriminate FMS from other musculoskeletal pain disorders such as osteoarthritis and the peripheral neuropathy of chronic diabetes mellitus II. FMS patients may also present with clinical evidence of paresthesias, chronic headache, irritable bowel disease, diffuse myalgias and generalized anxiety disorder . In addition, a significant increase was found in the frequency whereby FMS patients demonstrate abnormal sleep quality patterns [9-12]. In a recent study, sleep quality, but not age, depression, anxiety or FM symptoms was shown to be related to the deficit in inhibitory conditioned pain modulation . Importantly, the severity of clinical FMS correlated with thermal pain perception. FMS patients often complain of sexual dysfunction . These patients can also manifest major depressive disorder, panic attacks, and posttraumatic stress disorder [15,16] as well as exhibiting the symptoms common to Raynaud’s phenomenon .
Even though central nervous system (CNS) desensitization is considered the primary mechanism at the root cause of chronic pain in FMS, evidence of the many co-morbid conditions associated with FMS has strongly suggested that other factors, including genetic abnormalities, some involving biogenic amine dysfunction , single nucleotide polymorphisms in the serotonin transporter gene, SCL6A4, and dopamine transporter and receptor genes [19,20]. Altered allelic frequencies between FMS patients and controls were also found in the genes encoding γ-aminobutyric acid A receptor β3 (GABRB3), trace amine-associated receptor-1 (TAAR1) and interferon-induced guanylate-binding protein-1 (GBP1) . In the same study, associations were found in a replication cohort for TAAR1, regulator of G protein signaling-4 (RGS4), central cannabinoid receptor-1 (CNR1), and glutamate receptor-4 (GRIA4). Of note, expression of the TAAR1, RGS4 and CNR1 genes are associated with the normal function of pain pathways or G-signaling.
FMS has also been associated with distressful lifestyle , hormonal imbalances exemplified by impairment in the hypothalamic/ pituitary/adrenal axis and the growth hormone/insulin-like growth factor-1 paracrine axis [15-23], neuroendocrine immunologic dysfunction and defective cell-mediated immunity [24-29] all of which may be viewed as contributing to the pathophysiology of FMS.
Abnormal neutrotransmitter activity
The hyperalgesia and allodynia characteristic of the clinical presentation in patients with FMS is likely to result from deficient serotonergic and noradrenergic, but not opioidergic-deficient transmission in the CNS descending inhibitory pain pathways [6,30]. In FMS neurochemical and receptor levels associated with signal transduction in ascending pro-nociceptive pathways were shown to be increased whereas these levels were decreased in the descending anti-nociceptive pathways . Moreover, increased neurotransmitter levels were found in the cerebrospinal fluid (CSF) of FMS patients which was indicative of an elevated level of signaling in the pro-nociceptive pathways. Examples of those neurotransmitters that were generally associated with increased ascending input were substance P, nerve growth factor, and brain-derived neurotrophic factor which were found at higher levels in the CSF of patients with FM compared to healthy controls. In addition, glutamate and other biogenic amines were shown to be higher in both CSF and in brain of FMS patients. Glutamate is a known activator of a central pain pathway regulated by the interaction of glutamate with the N-methyl-D-aspartate (NMDA) receptors. This interaction results in amplification of central pain following repeated painful stimulation and may be a pertinent mechanism underlying the development of hyperalgesia and allodynia. In summary, several types of neurotransmitters which have been implicated in regulating central pain were shown to be elevated in the CSF and brain tissue of FMS patients, whereas other neurotransmitters which inhibit pain were decreased .
Pregabalin, amitryptyline and paraxotine alter neutrotransmitter activity
The overall contribution of defective neurotransmitter homeostasis and the view that certain drug classes could be employed to treat specific pain pathways is supported by the relatively strong clinical efficacy of pregabalin  and amitryptyline [32,33] for treating FMS. These drugs act by engaging high-voltage activated Ca2+ channels and the Kv1 family of K+ channels as well as by modifying defective serotonergic circuitry exemplified by abnormalities in serotonergic receptor-related events which appear to be the basis for therapy of FMS with serotonin-specific reuptake inhibitors (SSRIs) such as paroxetine . Furthermore, implicating the serotonin-norepinephrine pathway as a relevant mechanism for pain modulation is likely the rationale why serotonin-norepinephrine reuptake inhibitors (SNRIs) have now been added to the pharmacotherapeutic armamentarium for FMS [35-37]. However, recently, Choy et al.  suggested that since pregabalin and the SNRIs appear to act through different pain-controlling and sleep-improving mechanisms, the treatment of FMS patients could possibly be improved by combination therapy. For example, the doses of pregabalin approved for treatment of FMS resulted in a significantly greater improvement in sleep, measured by Medical Outcomes Study Sleep Scale, when compared with milnacipran
Animal models of experimentally-induced chronic pain have been successfully employed to determine the underlying mechanism(s) as to how SNRIs might act to modulate pain pathways in FMS. In that regard, imipramine and milnacipran were shown to yield significant anti-nociceptive effects in a model of chronic pain in rodents induced by formalin injection  and in the same study, venlaxafine, a dual reuptake inhibitor, prevented the development of a form of neuropathic pain induced by chronic constriction injury of the sciatic nerve. Of note, milnacipran and duloxetine decreased pain sensitivity whereas, the SSRI, fluoxetine did not. In another study, Ivengar et al.  showed that duloxetine (5-30 mg/kg) was a more effective drug compared to venlaxafine and milnacipran because duloxetine had increased efficacy in reversing mechanically-induced allodynia in the L5/L6 spinal ligation model of chronic pain in the rat. However, duloxetine produced minimal effects on modifying the tail-flick response which were typically found to accompany acute nociceptive pain in rats. These results suggested that inhibition of serotonin and norepinephrine reuptake involves separate pain pathways in this rat model. Similar conclusions were gleaned from the results of studies which studied the effects of duloxetine in various models of pain in the rat . Thus, duloxetine, could reverse or prevent acetic acid-induced writhing and duloxetine also showed efficacy in reversing carrageenanand capsaicin-induced hyperalgesia and allodynia at doses that had limited effect on acute nociception in the tail-flick and hot plate tests with little change in normal motor function. However, Jones et al.  showed using the carrageenan-induced pain model in the rat that dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or combinations of SSRIs and SNRIs were efficacious in producing a synergistic analgesic response. More recently, Ohnami et al.  showed that milnacipran inhibited C-fiber-mediated nociceptive synaptic transmission activity in the adult rat spinal dorsal horn in a model of neuropathic pain evoked by activation of 5-hydroxytryptaminergic and noradrenaline-mediated pathways. Taken together, the results of these studies using animal models of chronic pain indicated that inhibition of serotonin and norepinephrine reuptake was responsible for the modulating analgesic effect of this drug class on chronic pain.
An understanding of the mechanism(s) at the level of cells that underlie the clinical efficacy of antidepressants such buproprion, for dampening neuropathic pain, or SSRIs and SNRIs that show efficacy for reducing the chronic pain of FMS appears essential for future pain drug development. Thus, evidence accumulated over the past 15 years have indicated that these drugs exert their pain-reducing effects, in part, by activating the G-protein signaling cascade [44-47], and by increasing serotonin and norepinephrine levels in blood which causes activation of several intracellular signaling pathways . These drugs by working through these signaling pathways also have the capacity to regulate downstream transcription of genes encoding hypothalamic hormones, serotonin receptors, components of the non-serotonergic systems, neurotrophic factors, and inflammatory mediators .
Importantly, SSRIs act primarily at the 5-hydroxytryptamine (5-HT)/5-HT receptor transporter protein level and have limited, if any, interaction with other neurotransmitter signaling systems. In that regard, SSRIs can bind to the transporter protein directly while blocking the reuptake process so that more serotonin remains in the synaptic cleft where it is free to combine with receptors both distal and proximal from the primary transporter protein receptors. Additionally, serotonin and norepinephrine can directly interact with plasma membrane serotonin transporters (SERTs) and plasma membrane norepinephrine transporters (NETs) [18,50,51] which will also cause serotonin and norepinephrine levels in a synaptic cleft to increase. However, what remains controversial is the extent to which all SSRIs bind to identical SERTs domain as do serotonin or act through more indirect mechanisms.
In addition to the well-characterized components of the 5-HT signaling system which defined the role of the serotonin G-proteincoupled receptors [44,52], activation of cyclic AMP-dependent protein kinase A (PKA), phosphorylation of cyclic AMP responsive element binding protein  and activation of Ca2+/calmodulin kinase IV , the results of recent studies have added to the complex nature of 5-HTreceptor- mediated cellular events. Thus, these results showed that 5-HT/5-HT (2A) receptor binding could activate Janus kinase-2 (JAK- 2)/Signal Transducers and Activators of Transcription-3 (STAT-3) and extracellular signal-regulated kinase 1/2 (ERK1/2) in human placental choriocarcinoma cell cultures . 5-HT/5-HT (2A) and dopamine have also been shown to activate the Src/Phosphatidylinositide3-kinase (PI3K)/Akt/Glycogen Synthase Kinase-3(GSK3)/mammalian target of rapamycin (mTor) [PI3K/Akt] pathway [54-56] through G-coupled signaling . However, what remains conjectural is whether activation of JAK-2/STAT-3, ERK1/2 or PI3K/Akt which had been proposed as a mechanism pertinent to neuroprotection in depressive disorders  was also critical for blunting chronic pain in FMS.
Traditional antidepressants have previously been proposed as inhibitors of neuroinflammation . In that regard, SSRIs were shown to suppress inflammation biomarkers in activated microglia through an interferon-γ-mediated regulation of intracellular calcium . In addition, several SSRIs and venlafaxine were also reported to suppress the production of nitric oxide and tumor necrosis factor-α induced by lipopolysaccharide in cultured microglia [59-64]. Therefore, a further exploration of the extent to which neuroinflammatory mechanisms play a salient role in the progression of FMS is warranted.
The SNRIs, mainly duloxetine and milnacipran, have been successfully employed to reduce the chronic pain of FMS with improved quality of life. In that regard, the results of five well-designed double-blind placebo-controlled or double-blind extension studies with milnacipran support its continued use for treating patients with severe FMS (Table 1).
|Trial Design||Dose(S)||Primary Outcome(S)||Reference|
|Db-Pc1||Flexible Dose Escalation Up To 200 mg/Day||Pain Reduction:
50% Milnacipran; 14% Placebo (P<0.05)
75%Milnacipran; 38% Placebo (P<0.01)
|Db-Pc1||100 mg/200 mg/Day||Pain: Global
100 mg And 200 mg/Day
|Db-Pc1||100 mg/200 mg/Day|| ↑ In Fms Pain Response
Compared To Placebo
And In Multiple Sf-36
|Db-Pc1||100 mg/200 mg/Day||↑Composite Responder
Rate And Improved Pain Score Compared To Placebo – Pooled Doses
|Db3 For 3 Months Followed By 1 Year Extension||100 mg/150 mg/200 mg/Day||1 Yr Result:
Improvement From Baseline In
Sleep And Quality
1double Blind-Placebo Controlled
2Sf-36 Is Physical Component Summary-36
Table 1: Results of Clinical Trials Involving Milnacipran Treatment of Fms.
Arnold et al.  were the first group to report on the clinical efficacy of duloxetine in subjects with primary FMS with or without concurrent major depressive disorder. Pain scores were reduced in FMS patients after duloxetine therapy as assessed by the Fibromyalgia Impact Questionnaire and the ‘Brief Pain Inventory’ pain severity score instrument when compared to pain scores using these outcome measurements in patients in the placebo arm. Pain reduction also correlated with significantly greater improvement in mean tender point pain threshold. Furthermore, pain was reduced in the FMS patients from the duloxetine arm as measured by several different clinical improvement outcome measurements regardless of baseline major depressive disorder index.
In another clinical study duloxetine (60 mg/day), was compared to placebo in two 12- and 15-week phase III studies . Treatment with duloxetine was associated with a reduction from baseline in the ‘Brief Pain Inventory’ average pain severity score and greater improvement in the patient-rated global impression of improvement scale in patients with FMS, regardless of the whether FMS patients has been also been given a diagnosis of major depressive disorder. The results of this clinical trial also showed that duloxetine therapy of FMS was long-lasting with improvement in pain scores maintained over a 52-week period. However, patients with FMS who failed to respond to duloxetine during the initial phase of this study failed to derive any benefit from duloxetine even when the drug was increased from 60 mg/day to120 mg/day compared to those FMS patients who were maintained on the same drug dose during the subsequent 52-week, double-blind phase. The mechanism underlying the initial lack of responsiveness to duloxetine remains to be completely understood.
The results of a recent clinical investigation by Skljarevski et al.  extended the pain-reducing efficacy of duloxetine in FMS to other disease states characterized by chronic pain, including, diabetic peripheral neuropathy, osteoarthritis and back pain. The results of this study also implied a common mechanism for the action of duloxetine in the reduction of pain intensity as well as for improving physical functioning. Both pain reduction and improved physical functioning were consistently found to have been positively affected by duloxetine treatment over a wide-range of pain-involved diseases.
Five clinical trials, encompassing 4138 subjects, were analyzed to determine the clinical efficacy and side-effects of another SNRI, milnacipran, in the therapy of neuropathic pain in FMS patients . From this analysis, the authors concluded that milnacipran at either the 100 mg/day or 200 mg/day dose was effective in only a minority in FMS patients. Thus, milnacipran provided moderate pain relief (defined as at least a 30% improvement), to about 40% improvement (1655 subjects) compared to about 30% showing improvement by subjects receiving placebo. However, the power of this study was apparently insufficient to determine the extent to which pain relief exceeded at least 50%. Furthermore, by employing the ‘use of last observation carried forward technique’ it was likely that the results overestimated the efficacy of milnacipran in the FMS subjects. Of note, FMS patients in the milnacipran arm manifested an increased incidence of adverse events compared to placebo, which was primarily, nausea, headache and constipation. Moreover, the number of adverse events was significantly greater at the higher dose level of milnacipran. Thus, the results of this analysis temper conclusions regarding the efficacy of milnacipran therapy from individual clinical trials in treating the chronic pain of FMS Patients (Table 1).
Finally, Napadow et al.  used resting-state functional magnetic resonance imaging and measurements of intrinsic brain conductivity to show that non-pharmacologic intervention reduced pain in FMS subjects. Importantly, the results of this study suggested the possibility that intrinsic brain conductivity could potentially be employed as an objective research and clinical assessment tool for measuring pain reduction in FMS patients treated with SSRIs or SNRIs. Such an analysis could be additive to assessing the effect of non-pharmacologic interventions such as cognitive behavior modification focusing on learning pain-coping techniques.
Central nervous system (CNS) desensitization is now considered to be the primary mechanism accounting for the chronic pain in FMS. Low levels of serotonin and norepinephrine in the peripheral circulation appear to correlate with chronic pain syndromes. Thus, increasing and/or maintaining higher levels of these neurotransmitters through inhibition of selective-serotonin or serotonin/norepinephrine reuptake were proposed as the rationale for the efficacy of SSRIs or SNRIs as treatment strategies for managing the chronic pain of FMS. The results of several studies using small animals in models of chronic pain have elegantly defined several of the pain pathways altered by these drug classes. The results of these studies support the utility of these animal models for future testing of chronic pain-remitting drugs. Importantly, the results of well-designed clinical trials in subjects with FMS in which SSRIs and SNRIs have been analyzed demonstrated that these drugs were adequately tolerated. However, milnacipran was only moderately effective in reducing neuropathic pain in FMS. Furthermore, milnacipran was associated with more adverse events and withdrawals compared to placebo.