Calm pain signaling

Widespread pain from central amplification, not tissue damage. Defined by a dissociation stated plainly: the pain 'may not correlate with inflammation or structural damage', so anti-inflammatory logic can leave it untouched.

Joint comfort reduces it.

This link rests on the reviews of this outcome as a whole. No effect size specific to this arm has been reported, so it is shown at reduced weight. (from the reviews of this outcome).

Pain neuropeptide increases it.

Substance P as a nociceptive transmitter in central sensitization. PMC7005133

Brain adaptability reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Quiets overexcitation increases it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Calm reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Mood (serotonin) reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Alertness chemical modulates it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Motivation reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Nerve protection increases it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Brain inflammation increases it.

C. acnes promotes inflammation via TLR2 and TLR4; TLR signals induce NF-kB-dependent expression of NLRP3, pro-IL-18 and pro-IL-1beta. Androgens raise sebum secretion, triggering acne. doi 10.21037/atm-22-1362 · PMC2904443

Calms histamine response reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Inflammation signal (IL-6) increases it.

C. acnes promotes inflammation via TLR2 and TLR4; TLR signals induce NF-kB-dependent expression of NLRP3, pro-IL-18 and pro-IL-1beta. Androgens raise sebum secretion, triggering acne. doi 10.21037/atm-22-1362 · PMC2904443

Inflammation signal (TNF-α) reduces it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Headache peptide increases it.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It increases Pain neuropeptide.

It increases Daily energy.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It reduces Sleep.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It reduces Memory & focus.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It reduces Mood.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It increases Calm under stress.

Anxiety and depression are among the most frequent comorbidities of fibromyalgia, present in a majority of patients and associated with greater symptom severity. doi 10.1002/acr.24257 · PMC8582524

It reduces Physical performance.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It reduces Recovery.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

Ascendance (Nociceptive Volume Control) →