Background: Elderly patients in general exhibit a higher incidence of chronic and neuropathic
pain conditions. This group poses a particular clinical challenge due to age-related pharmacokinetic
and pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and
cognitive decline. Poor control of pain has consistently been identified as an issue for older people.
The identification of safe and efficacious treatments for chronic pain remains a critical public health
concern, especially considering the progressive increase of the world’s elderly population.
Objectives: This narrative review deals with the principal alterations of the somatosensory system
together with changes in non-neuronal cells in the course of aging. The possibility to control chronic
pain based on an innovative strategy which addresses non-neuronal cell dysregulation control will
also be discussed.
Study Design: Narrative review.
Results: Peripheral nerves display functional, structural, and biochemical changes with aging that
mainly involve Aδ fibers. Alteration in the responses to heat pain in the middle insular cortex and
primary somatosensory cortex are also observed in the elderly. In general, pain threshold increases
with age while the threshold of pain tolerance remains unchanged or decreases. Additionally,
other important modifications of the pain perception system in this age group consist in a clear
reduction in the descending inhibitory capacity with an associated increase in central sensitization.
Furthermore, different changes concern immune system cells, such as mast cells and microglia, that
with age show an increase in their sensitivity to noxious stimuli and a decreased capability to be
regulated by homeostatic endogenous systems. Since these cells are the primary interlocutors for
pain neurons, their alterations lead to changes that promote persistent neuroinflammation, thereby
impacting pain neuronal cell functionality.
Limitation: This review is not an exhaustive review for the current evidence supporting the role
of immune cells in influencing pain somatosensory neuron functions. It is also important to stress
the small number of studies designed to determine the efficacy and safety of anti-pain therapies in
elderly patients.
Conclusion: Non-neuronal cells of immune system origin such as microglia and mast cells, along
with astrocytes, are capable of influencing pain somatosensory neuron functions. These nervous
system non-neuronal cells may thus be viewed as innovative targets for persistent pain control. Among
therapies aiming at preserving the functionality of non-neuronal cells, palmitoylethanolamide, with
its high efficacy/risk ratio, may be an excellent co-treatment for the ever-growing elderly population
with chronic pain.
Key words: Elderly, chronic and neuropathic pain, mast cells, glial cells, neuroinflammation,
micronized and ultra-micronized palmitoylethanolamide
Importance and challenges of neuropathic pain
