EDITORIAL
Chronic Pain and Neurodegenerative Processes in Elderly People There is an increasing interest in the relationship between anatomo-physiological modifications of the nervous system and chronic pain, especially in the elderly. Apparently, contradictory data have been reported, as in the high incidence of chronic pain in the older population despite a significant elevation in the pain perception threshold in the same age group.1,2 Those data, also confirmed by the fMRI,3 might be related to the progressive hypofunctionality of Ad fibers.4 Nevertheless, the tolerance to pain seems unaltered or even reduced with age.1,5 Data indicate a hyposensitivity to low intensity stimuli and a hypersensitivity to high intensity stimuli. In other words, it seems that the elderly perceive pain later, but once perceived the pain becomes rapidly intolerable. This reduced early sensitivity might in part be responsible for the high incidence of accidents and thus contributes to the high prevalence of chronic pain reported in the elderly.6 Additionally, there are other important modifications of the pain perception system in this age group. For example, there is a clear reduction in the descending inhibitory capacity7,8 with an associated increase in central sensitization.9 These epiphenomena can be postulated to be the consequence of yet other anatomo-physiological modifications coincident with aging. There are many experimental data clearly showing the importance of cells in the nervous system other than neurons, such as mast cells and microglia. In older people, the production of factors essential for normal function of the stromal cells, also present in the nervous system, is compromised.10 However, the production of mast cell precursors is not affected.10 Moreover, mast cells in many tissues of the elderly are hypersensitive to inflammatory mediators and show an increased capacity for degranulation.11,12 In other tissues, the mast cell density is significantly DOI: 10.1111/papr.12254 © 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume , Issue , 2014 –
increased with age.13,14 In the endoneural compartment, such an increase might also be caused by progressive neuronal damage. The increased endoneural number of mast cells and their progressive hyper-reactivity with age play a major role in the determination of the altered functionality of the pain receptors and the pain primary fibers. Moreover, hyper-reactive endoneural mast cells seem to be responsible for the progressive deterioration of the Ad fibers via the uncontrolled release of enzymes.4 Like the mast cells, the microglia (which are arguably the most important immune cells of the central nervous system [CNS]) are functionally very much modified with age.15 In normal conditions, microglia are present in the CNS in a physiological branched form. When stimulated, they become immediately activated or proinflammatory. This modification is responsible for the rapid reduction of the neuroinflammation and a rapid restoration of the neurohomeostasis. In elderly people, microglia are present in a primed phenotype,16 which is responsible for a more intense and long-lasting response. This abnormally exuberant reaction seems to be a main cause for persistent neuroinflammation and irreversible neuronal damage.16 The primed microglia present at spinal cord level and in the thalamus, because of an excessive response to peripheral painful stimuli, seem to facilitate the initiation of chronic and neuropathic pain. Moreover, direct action on second- and third-order neurons in the pain pathway seems to be responsible for the neuronal hyperexcitability (central pain).17 Proinflammatory cytokines over-released by activated microglia may also damage the integrity of the white substance and the ultrastructure of the myelin sheath. In fact, a reduction in myelin proteins has been related to the increased glial activation.18 These data implicate deep modifications in Ad fibers with age as major contributors to chronic pain states, as opposed to alterations in the integrity of C fibers.4 The altered reactivity of mast cells and microglia in the older people is increasingly emerging as a cofactor, if
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not a primary factor, in the origin of chronic pain: the so-called low-grade inflammation or nonresolving inflammation, which is typical for chronic diseases, including the chronic pain.19–21 Pain, as chronic pathological condition is associated with perisistent inflammation frequently of low intensity. It is characterized by the elaboration of proinflammatory substances including TNF-a, IL-1, and IL-6 among others.22 The proinflammatory mediators influence the somatosensory receptors, but also increase the permeability of the hematospinal barrier, allowing toxic substances to penetrate in the spinal tissues. These substances may directly activate the microglia, amplifying the pain transmission (central sensitization), favoring the spinal neuroinflammation, initiating and perpetuating neurodegenerative processes. As with chronic pain, chronic disease states that are characterized by low-grade inflammation may be associated with mood modifications (anxiety and depression) and neurodegenerative changes leading to neurocognitive disturbances.23,24 The latter cognitive alterations are a clear obstacle to the diagnostic evaluation of pain patients; hence, they impede correct treatment and pain reduction.25,26 Pain reduction in the elderly has been associated with significant improvement in multiple quality of life measures.27 Further, patients with chronic pain, including those without neurological disturbances, frequently have cognitive deficits, which also interfere with the normal social life. Many of the cognitive dominions, such as attention, concentration capacity, elaboration speed, memory, psychomotor ability, and other capacities are negatively influenced by pain. Moreover, chronic pain syndromes are negatively associated with the attention and memorization processes.28 Therefore, in the diseases characterized by chronic pain and neurocognitive disturbance, the low-grade inflammation of the nervous system is clearly a connecting element that reciprocally amplifies the two conditions. In fact, persistent activation of the immune system not only damages the peripheral, spinal, and supraspinal somatosensorial neurons, but also the neuronal populations responsible for the most common neurodegenerative diseases.19 This neurobiological process, certainly involved in the transmission between the classical pain ascending and descending routes of the nervous system, might also be responsible for many of the chronic painful conditions where there is a direct synaptic connection between the first and the third neurons, as in cranial nerves (eg, trigeminal neuralgia). Unfortu-
nately, this issue has been very poorly investigated, at least till now. Giustino Varrassi, MD, PhD, FIPP*; Mariella Fusco, PhD†; Stefano Coaccioli, MD, PhD‡; Antonella Paladini, MD, PhD§ *Paolo Procacci Foundation, University of L’Aquila, L’Aquila, Italy; † Scientific Information and Documentation Center, Epitech Group, Padova, Italy; ‡ Internal Medicine, University of Perugia, Perugia, Italy; § Anesthesiology and Pain Medicine, University of L’Aquila, L’Aquila, Italy E-mail:
[email protected]
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