Pain: from physiopathology to bio-psycho-social model - Pathos

There are a large number of pathologies characterized by pain, but the pathogenetic mechanisms underlying them can be traced to a few basic cases:

It has been demonstrated that physiological, high-threshold nociceptive pain, which is caused by thermal, chemical and mechanical stimuli of high intensity, has a protective effect. This is also the response that occurs in the event of an injury, for example, of a traumatic nature.

While skin nociceptors are particularly sensitive to thermal stimuli, nociceptors in deep somatic tissues, such as joints and muscles, are especially sensitive to mechanical stimuli.

A noxious thermal stimulus is detected by TRPV1 receptors (40 to 43 degrees Celsius)3-5 The application of heat results in a conformational change within the non-selective cation (Ca²⁺) channel of TRPV1, which causes a local depolarization. This is then propagated by the opening of voltage-dependent sodium channels, generating an action potential that travels to the higher centers.6

Inflammatory pain can affect various structures and is characterized by the activation of peripheral nociceptors.

Acute pain is still within a physiological range, inflammation is the body's normal response to tissue damage caused by the presence of pathogens such as viruses, bacteria, fungi and parasites.

Physical trauma, burns, radiation and frostbite are other possible causes of inflammation, such as corrosive chemicals such as acids, alkalis and oxidizing agents.

Symptoms of acute inflammation include swelling, redness, fever and/or pain. Pain is caused in part by tissue distortion due to swelling, but also by certain chemical mediators of inflammation such as bradykinin, serotonin and prostaglandins.

Neutrophils are the first and predominant cells in the acute phase of inflammation. Neutrophils contain granules rich in lysozyme, matrix metalloproteinases and myeloperoxidases, which are released on the foreign or self-antigen and cause its destruction. Neutrophils also destroy the antigen by phagocytosis, release of reactive oxygen species and cytokines such as IL-1, IL-6 and TNF-α.

Lymphocytes, T-lymphocytes and B-lymphocytes constitute the subsequent line of defence and play a pivotal role in mediating inflammation through a multitude of intricate mechanisms, including cytokine secretion, lymphocyte costimulation and the production of antibodies and immune complexes.7

In this context, pain is associated with a reduction in the nociceptive threshold, resulting from the influence of inflammatory mediators, particularly prostaglandins. In the event of persistent pain, cytokines become involved.

Proinflammatory agents, via their receptors, induce biochemical alterations at the nociceptive terminal. To illustrate, the TRPV1 receptors, which normally open at 43°C, undergo phosphorylation due to prostaglandin- and cytokine-activated kinases, leading to activation at 37°C. This body temperature is sufficient to elicit pain. As the threshold is reduced, innocuous stimuli at the site of inflammation cause pain, a phenomenon known as allodynia.

These impulses reach the central synapse, which in turn is modified by the opening of glutamate-sensitive MNDA receptors. Calcium is the second messenger that activates kinases that go into the nucleus of the nerve cell and modify its gene expression. In short, as we move towards chronicity, there is a profound change in the pain pathway: inadequate resolution of inflammation or inadequate control of inflammation can lead to a persistent inflammatory state.

The aim of anti-inflammatory therapies is therefore primarily to reduce peripheral sensitization by blocking the synthesis of prostaglandins and cytokines.

Neuropathic pain (NP) is a direct consequence of an injury or pathology affecting the somatosensory system, whether peripherally or centrally.

It may result from specific endocrine dysfunctions (painful diabetic peripheral neuropathy), viral infections (post-herpetic neuralgia), trauma (spinal cord injury) or as a consequence of various treatments (chemotherapy-induced peripheral neuropathy). Additionally, neuropathic pain has been linked to various other conditions, including cancer and neurological disorders such as multiple sclerosis, stroke, and centralized pain syndromes.

It is often the case that neuropathic pain has a compressive origin or is related to the injury of a nerve fibre.

In the vicinity of the lesion site of peripheral afferent nerves, which represent the primary site of neuropathic pain, the presence of immune cells has been observed. This is followed by a prolonged release of cytokines and multiple alterations in gene expression.

At the site of the lesion, there is also a functional reorganization of the fiber, with the expression of sodium channels of a different type (embryonic) and a decrease in potassium channels that normally confer electrical stability to the neuron. This results in the formation of an ectopic site (pain does not originate from the periphery) with a high discharge frequency, either spontaneous or evoked, depending on the pathology.

Inhibitory drugs that reduce the discharge of voltage-dependent sodium channels are a potential avenue for treatment.

The spinal cord represents the initial integrating station for nociceptive stimuli originating from the periphery, and is implicated in the pathogenesis of both inflammatory and peripheral neuropathic pain.8

The increased activity of the N-methyl-D-aspartate (NMDA) receptor in the spinal cord plays a pivotal role in the induction of central sensitisation, which is a crucial process in the development and maintenance of pain hypersensitivity.9

Under physiological conditions, NMDA receptors are blocked by magnesium.

However, under pathological conditions, the magnesium blockade of NMDA receptors is removed and NMDA receptor activation increases by several mechanisms, including phosphorylation of the same.10

Recent studies have also highlighted an interaction between NMDA receptors and TRPV1 receptors at the level of the spinal cord in guinea pigs, which appears to be involved in the transmission of inflammatory and neuropathic pain.

TRPV1 is present at both presynaptic and postsynaptic spinal levels and is associated with the mechanisms of neuropathic pain exacerbation.11 Furthermore, persistent glutamate-mediated hyperexcitability also contributes to the impairment of GABAergic inhibitory tone in the dorsal horn of the spinal cord (DH).

Additionally, the early increase in oxygen free radicals due to oxidative stress has been observed to cause a reduction in GABAergic neurotransmission. This occurs through the modulation of GABAA chloride channels, which in turn attenuates inhibitory synaptic transmission in the superficial dorsal horn.12

The rostral ventromedial medulla (RVM) plays a pivotal role in supraspinal analgesia, particularly in the context of opioid-induced analgesia, by acting as a key mediator at higher centres. In this region of the brainstem, two distinct types of physiologically definable neuronal cell structures have been identified that are responsive to opioid action. The "off" cells, which are activated by morphine and inhibit the transmission of nociceptive signals, and the "on" cells, which play a pronociceptive role when their activity is depressed, are two distinct types of neuronal cell structures in the rostral ventromedial medulla (RVM).14

Furthermore, opioids interact with additional regions of the brain, including the periaqueductal grey (PAG) and the locus coeruleus, which collectively influence the final passage of nociceptive information to the dorsal horn of the spinal cord.15

There are several key players in the processing of pain:

In contrast, the amygdala plays a pivotal role in affective pain, which is a subcortical region that shapes the emotional components of pain. Given the presence of opioid receptors in the central nucleus (CeA) of the amygdala, it has been postulated that this area also contributes to pain control through opioid mechanisms.

However, the positive expectation associated with the placebo unifies the various stimuli, including sensory and social stimuli, within the broader psychosocial context in which we exist. The evidence suggests that positive verbal suggestions play a significant role in inducing positive expectations in patients and have an analgesic effect.

Verbal suggestions have been observed to activate not only opioid receptors (mu receptors, specific for morphine), but also CB1 endocannabinoid receptors, the cyclooxygenase pathway (aspirin-NSAIDs) and dopamine receptors. This is achieved with a duration, variability and magnitude of effect that may be less than that of drugs.20

Given that words and drugs both emerged during the course of evolution, it is more accurate to suggest that drugs operate via the same mechanisms as words.

Furthermore, in this field of enquiry, it is noteworthy that recent studies employing magnetic resonance imaging have demonstrated a correlation between thalamic activation and functional thalamus-PAG connectivity and the formation of positive memories.

The authors observed that the thalamus plays a pivotal role in the functional link between nostalgia and pain. This indicates the potential for a memory-induced analgesic modulation mechanism. The results demonstrated that the nostalgia paradigm markedly diminished the perception of pain, particularly in the case of noxious thermal stimuli.21

The effect of reducing the perception of pain was linked to the viewing of nostalgic images, including those of a bicycle used during childhood, scenes from childhood such as the old schoolyard, a candy that was popular among children at the time, or an old game from the days when they were children. The smell of childhood biscuits was also used. The researchers induced the secretion of substances that lowered the perception of pain, including serotonin, noradrenaline and endorphins.

Given its predominantly positive valence, nostalgia therefore performs an analgesic function by activating neuronal pathways that have been shaped by evolutionary processes.

Pain modulation is influenced by social factors.22

Socio-familial and ethnic context have been identified in the literature as relevant factors in the determination of pain perception.

The relational-familial context in which a child lives has been identified as a significant factor influencing the perception of pain threshold.23 It has been observed that the pain and fear experienced by children during venous punishment are related to the parents' ability to regulate emotions.

Indeed, the latter enact a series of behaviours that direct the child's attention towards the procedure and inadvertently communicate anxiety, fear or their own concerns.

Thus, the factors that influence the child's perception of pain appear to be related, in various ways, to parental behaviour according to their ability to regulate emotions, with the effect of amplifying or reducing the perception of paediatric pain.24

Pain perception and response can be strongly influenced by cultural and ethnic differences.

Some populations, for example the Zulu and Aboriginal communities (South Africa and Australia) are better able to tolerate pain and especially to experience less of it.

Their expectation towards back pain and towards pain in general is positive.

They therefore have a completely different approach to pain than the peoples of the western world, who tend to stay at rest and be afraid to move around, and reject pain as a disease.25

We then see how social determinants can positively or negatively influence the perception of pain.

In an integrated statistical analysis of 1,191 women with early-stage breast cancer treated at a large cancer centre in Memphis, Tennessee, it was observed that pain is the most common side effect of breast cancer.

The study showed that adequate pain management is crucial to support treatment tolerance.26-27 Patients' quality of life is therefore an important element in improving cancer treatment.27 Pain among women with breast cancer was observed to be significantly associated with stress.28 Socially isolated patients had a higher risk of breast cancer mortality than socially integrated patients.29-30

Social determinants also showed a significant association with pain perception.31

Women who lived in poorer neighbourhoods were likely to have undertreated pain.

It could be deduced from these studies that both the management of post-diagnosis pain in the breast cancer patient and the patient's own care plan must take into account not only pathological factors but also social conditions that allow better pain and disease management.32

In particular, studies conducted by Wang et al. showed that the subjective experience of pain can be altered when an individual decides to help another person.

Neuroimaging studies have shown that prefrontal regions (e.g. the dorsolateral prefrontal cortex [DLPFC]) and areas associated with the affective processing of pain (the amygdala) modulate the effects of pain anticipation on subjective evaluations.33-35

Furthermore, the PAG is widely recognized for its role in modulating pain in this type of social feedback situation.

The act of helping others, whether by donating resources to a stranger or the bearing someone else's suffering, has been found to have a beneficial outcome.

At the neural level, the altruistic condition (as opposed to the control condition) led to a reduction in the response to painful stimuli in pain-related brain areas.40