Chronic pain represents a challenging condition, as it can be disabling, severe and intractable, causing both distress and suffering. Every year, European national health systems spend economic resources on drugs and therapies, often without any clear or permanent result [
16‐
19]. A precise diagnosis is arduous and medical doctors can only rely on patients’ descriptions of symptoms; this is why it is really hard to decide which is the best formulation, for the best antinociceptive efficiency, at different pain stages. Clinicians, before surgery, do not have guidelines to follow on the best biological formulation and dose; they usually have to choose between continuous analgesic treatment or on-demand opiod therapy. In fact, opioids are used in chronic pain therapy but the healing is overtaken by side effects, as well as respiratory and cognitive dysfunctions and immune impairment [
20‐
22]. In particular, opioid therapy is at the centre of a long debate because of its contrasting role in releasing pain and inducing, at the same time, tolerance and addiction [
23]. It can be reasoned that the problem lies in the lack of statistical data about the right dose for drug utilization and long-term efficacy. It is not clear whether different opioid formulations can lead to diverse effects, or whether the main goal in this field should be to achieve pain control or better rescue functional abilities. Moreover, the genetic and metabolic processes causing pain conditions are still not confirmed. The absence of objective tests and biological markers, to monitor risk factors and pain development, leads to a deceptive and negative consideration of opioid consumption. However, in this confused background, an excessive inflammatory response seems to have a key role in the pathophysiology of chronic pain, and different opioids or diverse opioids administrations show various effects on immune system, as well as immunosuppression or immunostimulation, or both [
24]. In particular, hyperalgesia can be considered the result of synergy across immune, nervous and peptidergic systems. Immune and immune-related cells, such as vascular endothelial cells and keratinocytes, secrete anti-inflammatory cytokine, opioid peptides and proresolution lipid mediators to block pain. Thus, the question is open: is this cooperating mechanism involved in pain defence or in enhancing damage? To answer the question, we must remember that each immune system cell type has a role in the process. For example, mast cells, which release vasodilator mediators, as well as histamine and bradykinin, have been found next to the primary nociceptive neurons and participate in nociceptor sensibilization. However, it is not clear which specific mediators regulate the event [
25‐
27]. Macrophages are normally recruited, in the site of injury, by inflammatory cytokines (i.e. TNF-α, IL-15) and contribute to mechanical allodynia. Thus, macrophages participate in the sensitization of nociceptors and neuropathic pain development, by releasing soluble mediators themselves (i.e. MIP-1α CCR1–CCR5) [
28]. Moreover, macrophage depletion partially reduces mechanical and thermal hyperalgesia without alteration of mechanical allodynia [
29]. Neutrophil migration to the site of damage is linked to inflammatory pain. These cells are recruited, influenced by afferent neurons during neurogenic inflammation and generate impulses, releasing P substance and calcitonin gene-related peptide. Neutrophil migration is also influenced by IL-1 [
30]. The complement system participates in inflammatory hyperalgesia and chronic pain; C5a anaphylotoxin, belonging to the complement cascade, acts as a potent attractant of neutrophils once linked to C5aR1 neutrophil receptors. In rodent models, C5a and C3a injection produces hyperalgesia; C5a and C3a
ex-vivo application sensitizes C fibres, facilitating neutrophil migration and hyperalgesia and C5a activates the spinal microglia during neuropathic pain [
31‐
34]. Considering lymphocytes, their role in the sensitization of nociceptors is not clear yet. There is evidence that T-helper 1 (Th1) and 2 (Th2) lymphocytes have different functions in the generation of pain: Th1 lymphocytes release pro-inflammatory cytokines (i.e. IFNγ, IL-2) facilitating neuropathic pain, Th2 lymphocytes release anti-inflammatory mediators (i.e. IL-4, IL-10, IL-13) inhibiting the process [
35]. Natural killer cells and B lymphocytes are also recruited during inflammation but there is no evidences of their involvement in the development of neuropathic pain, in animal models [
36‐
38]. However, human studies have shown that opioid therapy could functionality influence natural killer cells and B lymphocytes [
10,
11], and interferes with pain expression and pathological evolution in osteodegenerative syndrome [
39]. Moreover, studies suggest that opioids must be used with care in patients who are already immunosuppressed by disease or by other concurrently administered drugs, because opioid therapy (1.5–4 mg/day) increases μ-opioid receptor (MOR) mRNA levels in lymphocytes of 65% compared with controls and 47% compared with pre-treatment values. Even higher levels (an increase of 142% compared with controls and 135% with pre-treatment values) were observed in patients treated with morphine plus bupivacaine (0.2–0.4 mg/day). Elevation of MOR mRNA levels was confirmed in patients after 24 months of treatment and the percentage of natural killer cells was significantly decreased [
15].
At this point, the involvement of immune cells, cytokines, soluble mediators and their specific receptors in the pathophysiology of pain has to be considered as a starting point for a debate. Where does pain pathology take its origin? We could suppose that it is due to an incorrect release of such mediators by the blood cells. It could be possible that the quantity of released factors is not enough for defence. We could also hypothesize an over-release of mediators or an incorrect delivery. It could be possible that the specific receptors, on the target cells, are qualitatively or quantitatively expressed in a nonphysiological way, by producing a persistent sensitivity.
To verify our hypothesis, we will choose orthopaedic patients following opioid treatment for hip osteodegenerative pain and selected for hip replacement. This study protocol will help to set up the best therapy based on the lowest efficient dose and economy per patient, during the minimum time period, in order to bypass tolerance and addiction due to opioids. Our study presents an easy and noninvasive diagnostic plan, using peripheral blood samples, in which patients will not be overloaded by clinical tests and will be enlisted during routine clinical visits, by limiting stress, anxiety, costs and social problems.