Fibromyalgia is a complex disorder that affects 1% to 5% of the population and can occur at any age. Fibromylgia presents as a widespread chronic musculoskeletal pain without physicalor laboratory signs of any specific pathologic process. Most patients also experience fatigue, memory problems, sleep disturbance, depression, and anxiety. Similar to other chronic pain disorders, prevalence rates of fibromyalgia are higher in females than in males. The underlying mechanisms for the continued pain in fibromyalgia are still beign explored. A substantial amount of research evidence supports that a low threshold to pain is caused by central sensitization and disordered pain regulation at the spinal cord and supraspinal levels. lncreased reactviity of paan-processing cells in the spinalcord or brain evokes hyperexcitability of pain pathways combined with decreased activity of inhibitory pathways. Thus, the imbalance bewteen the amount of excitation and inhibition results in alterations of central nervous system (CNS) nociceptive processing. An important mechanism at the spinal cord level is the interaction bewteen the peripheral mechanoreceptors and deep spinalcord neurons. The evedience shows that in chronic conditions, peripheral sensory neurons and axons show synaptic remodeling in the spinal dorsal horn, resulting in nociceptive hypersensitivity that is dependent on the activity of the N-methyl-D-aspa rtate receptor (NMDAR). As such, low-level non-noxious stimuli are preceived as pain. because of the increased sensitivity of deep spinal cord neurons that transmit sensory information and amplified trafficking of pain signals. At the supraspinal level, chronic pain is associated with the changes of sesnory regions in the brain responsible for nociceptive processing. Specific brain structures that display greater activation include the secondary somatosensory cortex, insula, and anterior cingulate cortex. Functional neuroimaging studies in patients with fibromyalgia compared to normal individuals showed higher brain activation in the thalamus, primary and secondary sometosensory cortices, insula, and cingulate cortex with pressure, heat, or nociceptive stimuli. Patients with fibromyalgia also showed impairement of the descending inhibitory pain pathways that resulted in decreased activation in the anterior cingulate cortex and thalamus, as well as a significant imbalance in connectivity within the pain network during rest. The greater activation of some regions and the inhibition of others likely result in changes in the neurotransmitter levels in the brain. A decrease in serotonergic and noradrenergic activities of the inhibitory monoaminergic pain control pathways has been proposed as one of the mechanisms in underlying chronic pain.
Further clinical treatment that stimultaneously increases serontin and norepinephrine levels has been successful in restoring descending inhibitory activity in fibromyalgia. Alterted
dopaminergic and GABAergic neurotransmission may also contribute to the augmented central processing of pain in patients with fibromyalgia. Brain imaging in patients with fibromyalgia has shown elevated glutmate levels in pain-related brain regions such as the posterior cingulate gyrus, posterior insula, ventrolateral prefontal cortex, and amygdala. Patients with fibromyalgia also show increased Blutemate and glycine in cerebrospinalfluid. When patients are treated with pregabalin, elevated glutamate levels in the insula and functional connectivity bewtween the default mode network and insula decrease with both clinical and experimental pain. The pathogenesis of fibromyalgia appears to have a strong genetic component. A genome-wide linkage study confirmed a potential inherltance mechanism by showing a 13.6-fold increased risk of developing the syndrome in first degree relatives. Gene research suggests that fibromyalgia is potentially associated with ploymorphisms in the serotoninergic, dopaminergic, and catecholaminergic systems, predisposing an individual to an insufficient analgesic response. Two potential susceptilbility candidate genes are the serotonin transporter gene (SLC64A4) and the transient receptor potientialvanilloid channel 2 gene (TRPV2)on chromosomes 17p71.2-q11.2. Polymorphism of SLC64A4 and TRPV2 has been linked to endogenous pain modulation in
patients with fibromyalgia. Two additonalgenes are the myelin transcript factor 1 like gene (MYf1L), responsible for neuronal differentiation and congnitive ability, and the neurexin 3 gene (NRXN3), a receptor in the nervous system and a cell adhesion molecule. However, no single nuceleotide polymorphism has acheievd the genome-wide significant threshold. The NMDAR mediates the excitatory glutmatergic synaptic transmission in the spinalcord and brain that is strongly implicated in the amplification of pain signals and central sensitization in fibromyalgia. Consequently, NMDAR antagonists such as ketamine may be used to reduce the excessive nociceptive input and central pain sensitization. ln clinical pratice, ketamine [2-(2-chloro phenyl)-2-(methyla m ino)cyclohexa nonel is primarily used for anesthesia and perioperative analgesia. Ketamine acts as a non-competitive inhibitor that binds an intrachannel NMDAR site, resulting in decreased channel opening time. ln clincal use, the S (+) stereoisomer of ketamine is the most potent form of NMDAR antagonist. Because ketamine blockade of NMDARS has the potentialto reduce the induction of synaptic plasticity in central and peripheral neurons and prevent functional chnages responsible for the main-tenance of chronic pain states, ketamine's use for chronic pain mangement has increased since 1995. Ketamine also interacts with other receptors and channels in the CNS, including monoaminergic receptors, opioid receptors, nicotinic and muscarinic acetylcholine receptors, and voltagesensitive sodium signaling. Ketamine binds with high affinity to dopamine D2 receptors.
Suppression of the normal activity of dopa mine-releasing neurons within the limbic system is hypothesized to contribute to pain in fibromyaglia. Because dopamine plays a dominant role in natural analgesia, potentiation of dopamine signaling may contribute to ketamines's analgesia. The potential of ketamine to enhance endogenous antinociceptive systems results in potentiation of the descending serotoninergic inhibition pathways. Further, ketamine may also reduce susbatnce P receptor-med iated pain and restore altered brain-derived neurotrophic factor (BDNF) expression. Ketamine also has an anti-inflm matory effect, modulating the production of different proinflammatory mediators that are implicated in the pathogenesis of fibromyalgia. Therefore, in addition to ketamine's effet on NMDAR, functional chnages in neuroplasticity in chronic pain may relate to multiple neuronal pathways that are implicated in fibromyaglia pain physiology. Because the same neurotransmitters that control pain also regulate sleep, cognition, energy, and emtional networks in the brain, these functions/neural networks may improve in patients with fibromyalgia. Besides having analegesic properties, ketamine is an effective treatment for severe major depressive disorder, a condition that has a high prevalence in patients with fibromyalgia. Based on ketamine's robust antidepressant effect, the US Food and Drug Administration approved a nasal spray formulation in March 2019 for the management of treatment-resistant depresiion. The evidence of ketamine's effectiveness in fibromyalgia is evolving.
This information obtained after review Ochsner Journal 21:387-394, 2021
@2021 by author(s); Creative Commons Attribution License (CC BY)
DOI : 10.31486/toj.21.0038