Fibromyalgia syndrome (FMS) is mainly characterized by pain, fatigue. The etiology of fibromyalgia is still unclear and its management often difficult. Pain associated to FMS is not controlled with analgesic drugs, instead it seems to partially relieved by neuropathic pain drugs. In our experience, among the available therapies, Cannabis (THC) associated with cannabidiol is the only one that showed to be the most efficacious, however the central psychotropic effects associated to its administration limits its use.
Our observations reveal that the fibromyalgic patients occasionally displayed stress-induced painful relapses and other nociceptive pain, distinct from fibromyalgic pain. These pain conditions were responding to the NMDA (N-methyl-D-aspartate) glutamate receptor inhibitors, while common analgesics shown to be efficacious for the second.
Palmitoylethanolamide (PEA) is an endogenous N-acylethanolamine that indirectly potentiates the activity of endocannabinoid system without inducing central psychotropic effects. This prompt us to consider PEA for pain control in FMS patients.
44 fibromyalgie patients received PEA for over 120 days in different combination with duloxetine, dextrometorphan and ketamine.
PEA addition improved the control of pain, showing a good efficacy both when used alone or in combination with NMDA inhibitors to manage the relapse due to stress, and with Duloxetine for the control of the depression, when present.
Palmitoylethanolamide in fibromialgia
Palmitoylethanolamide is a fatty acid amide congener of the endocannabinoid anandamide (AEA). Unlike the latter, PEA does not interact with CB1 receptors. PEA is able to reduce the release of histamine and pro-inflammatory factors from mast cells[20,21]. The activation of glial cells with consequent increase in intrathecal levels of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia.
In the study of Katedoff, patients with fibromyalgia displayed high concentrations of serum and cerebrospinal interleukin-8, but not interleukin-1β. This profile is consistent with the symptoms of fibromyalgia, where sympathetic activity induced by stress rather than by mechanisms associated with prostaglandins is involved. These data support the hypothesis that glia are activated in response to pain mechanisms, ands also explain the lack of response to NSAIDs. Furthermore, and in agreement with Kadetoff, a decreased function of β-adrenergic receptors (down-regulation) has been found, which is characteristic of a state of chronic stimulation.
Glia acts dynamically to modulate neuronal and synaptic communication and, by releasing neurotransmitters, neuromodulators, pro-inflammatory cytokines and chemokines affects the course of pathological pain.
Abnormal afferent activity can cause plastic changes in the CNS, altering the pain matrix (brain areas that register emotion and memory of pain).
Glutamate released by neurons binds to receptors on adjacent astrocytes, generating a calcium wave which propagates to other astrocytes via electrical synapses. The wave is generated by the formation of a gradient of calcium between endoplasmic reticulum and cytoplasm. Electrical synapses, unlike chemical synapses allow direct communication between two excitable cells. This type of synapse is characterized by transmission that occurs without delay and through channels that offer low current resistance. These channels are called gap junctions, and are formed by six intermembrane protein subunits (connexins) arranged to form a connection.
In addition to destroying pathogens by phagocytosis microglia also release a variety of cytotoxic substances that can damage cells directly and lead to death of the neurons. Microglial proteases catabolize proteins and cause direct cellular damage, while cytokines such as interleukin-1 promote axon demyelination. Finally, microglia can damage neurons by release of glutamate and aspartate which activate NMDA receptors. Although intended to eliminate infected neurons, viruses and bacteria, this process can also cause collateral damage to healthy neurons. Consequently, a chronic inflammatory response can lead to widespread neuronal cell damage, because microglial cells deteriorate the brain in an attempt to eliminate the infection. Neurogenic inflammation and subsequent neuronal damage are followed by repair mechanisms with reconstruction of new synapses and subsequent remodeling that may be characteristic of maladaptive plasticity[25,27]. In fact, fibromyalgia is characterized by a reduction of gray matter in the left parahippocampal gyrus, bilateral middle-posterior cingulate gyrus, insula and left medial frontal cortex.
PEA in fibromyalgia: pilot study in 44 patients
To evaluate the efficacy of PEA in controlling pain associated with FMS, 44 patients (4 male, 40 female) between the ages of 20-76 years (median = 52±14) and affected by FMS were recruited.
Diagnostic criteria were:
a. Diffuse and persistent musculoskeletal pain;
b. Presence of at least 11 of 18 TPs;
c. Absence of response to analgesics (this factor is very important in the diagnosis of neuropathic pain).
PEA was administered throughout the study duration.
In Italy, researchers give priority to the development of intelligence linguistics at the expense logical-mathematical intelligence. Thus, we chose to evaluate the results by simplified PGIC (Patient Global Impression of Change scale) rather than with the VAS (Visual Analogic Scale) or the NRS (Numeric Rating Scale ). The pain improvement was rated by a 4-point PGIC scale (0= unchanged or worsened patient; 1= a light but not noticeable improvement; 2= patient with better and definite improvement that has made a real or worthwhile difference, treated with PEA + NMDA; 3= patient with better and definite improvement that has made a real or worthwhile difference, treated with PEA. An initial evaluation was performed within 20 days of PEA administration searching only the first signs of improvement. After 120 days positive results were recorded considering only cases with marked improvement (no pain or occasional pain intensity not exceeding a NRS of 2).
Within 20 days, 84% of the patients responded positively to therapy with: marked improvement in 30%, noticeable improvement in 54%, and 16% unchanged. At 120 days the percentage with marked improvement increased to 54% without showing, however, a significant difference in comparison to a previous study in which patients were treated with a combination of pregabalin/duloxetine.The patients distribution based on PGIC rates was assessed by the Kruskal Wallis test. The number of patients, grouped into the categories according to their rate of improvement, appear to be different between the day 20 and the day 120.
This difference by the Kruskal Wallis test is statistically significant (p< 0,0149); in fact the number of patients with substantial improvement increases over time while the number of patients unchanged or slight improved decreases. One very important point is the action exerted by pregabalin against the psychotropic effects of cannabinoids, found previously on a case of CRPS in which phytocannabinoids had been taken for recreational purposes. Pregabalin is an anticonvulsant that binds to the regulatory subunit α2δ of voltage-gated calcium channels in the CNS, thereby reducing entry of Ca2+ at presynaptic terminals which leads to inhibition of release of glutamate, noradrenaline and substance P.
Postsynaptic NMDA receptor activity is needed to prevent degranulation of presynaptic vesicles. It may be that NMDA receptor activation leads to nitric oxide production which then acts on presynaptic neurons, allowing vesicular modifications induced by pregabalin, although the presence of presynaptic NMDA receptors cannot be ruled out. Apart from a yet-to-be-clarified direct or indirect interaction between pregabalin and NMDA receptors, interaction with cannabinoids may also occur. Rated with the PEA, there was also an antagonism towards the analgesic action.
Thanks to the therapeutic effect of PEA we have been able to better understand the various manifestations of pain in fibromyalgia.
The pain of FMS, while maintaining its basic “algic” background is erratic, alternating with spontaneous remissions that make it difficult to assess therapeutic efficacy. A reduction in NRS of only a few points or short (several weeks) evaluation period cannot provide a reliable interpretation. In the course of studying pain evolution for several months we noticed that exist spontaneous remissions and peak of pain usually caused by stressful moments such as physical fatigue, night work or particularly heavy work, fever or simple infections, surgery or psycho-physical trauma (hand pain being often mistaken for compression of the median nerve in the carpal tunnel, resulting in many patients being inappropriately subjected to surgery and resulting aggravation of the syndrome)), all conditions that increase sympathetic activity play a role, in agreement with the studies of Kadetoff and Light[22,23,29]. In these instances pain does not respond to PEA, phytocannabinoids or analgesics, but only to ketamine[32,35,38].
Fibromyalgia may be associated also with other painful degenerative diseases such as osteoarthritis or sciatica which can complicate the underlying pain. One needs to learn how to distinguish these: the latter are not generalized pain, but rather focal and asymmetrical and sensitive to NSAIDs. The key to treating FMS is to identify the type of pain and choose the appropriate method, to prevent spikes triggered by stressful events and establish a rescue therapy for unpredictable cases.
Conclusions: PEA useful in fibromyalgia
In the attempts to alleviate the pain in FMS ineffective and, at times harmful drugs are often used. This underlies the inevitable side effects of therapeutic inefficacy.
Findings from the present observational study propose the following opportune actions:
• suspend ineffective drugs;
• suspend α2δ ligands, that show interference with cannabinoids;
• substitute benzodiazepine, selective serotonin reuptake inhibitors and selective norepinephrine uptake inhibitors with duloxetine, which has proven effective in reducing anxiety-depression in FMS and contributes to reduction of neuropathic pain;
• administer PEA (1200 mg daily);
• in the presence of painful outbreaks (which often occur during stressful events) it would be advisable to administer dextromethorphan (30 mg bid or tid) or, in refractory cases, one-hour continuous infusions of ketamine (6-10 mg) weekly or bi-weekly, repeated 5-6 times to achieve sustainable efficacy;
• in refractory cases administration of phytocannabinoids at customized doses may be efficacious.
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