Roles of immune cells and their mediators in Chronic Pain. Treatments and Interventions.

October 16, 2018February 4, 2022 Hospital Professional News

Chronic pain –a major debilitating condition difficult to treat– is defined as pain lasting longer than 12 weeks. It contributes to disability, fatigue, anxiety, depression, sleep disturbances, poor quality of life, and increases the healthcare costs. Chronic pain affects approximately one fifth of people worldwide, and increases as the population ages.

Regardless of aetiology and pathophysiological categorization –nociceptive, neuropathic, or idiopathic– the impact of chronic pain is broadly similar across many conditions. Inflammation, which causes inflammatory pain –rheumatoid arthritis (RA) and osteoarthritis (OA) account for ∼42% of the chronic pain patients in Europe; inflammatory bowel disease (IBD)–, nerve injury as a consequence of an operation or trauma, metabolic disorders –diabetic mellitus–, or auto-immune diseases –multiple sclerosis–, may cause neuropathic chronic pain. Cancer or cancer treatment –chemotherapy– may result in painful neuropathies.

Certain factors –including female gender, older age, lower socioeconomic status, geographical and cultural background, and genetics– can contribute to increase the risk of chronic pain. Other factors –smoking, alcohol, obesity, comorbidities, work-related factors, or physical activity level associated with chronic pain conditions– can be modified.

Clinical models of chronic pain –fibromyalgia syndrome, spinal pain, hand pain, irritable bowel syndrome– indicate a main role of classical conditioning in the development of pain-related disability.

Atypical neuronal activity –including peripheral sensitization of sensory neurons and sensitization of neurons in the central nervous system–, but also the immune system –microglia and macrophages– are involved in chronic pain regulation including neuropathic pain, cancer-induced bone pain and chronic inflammatory pain.

Depression and chronic pain

Chronic pain, as a stress condition, is one of the critical factors for depression, and –although their association remains unclear– their coexistence tends to further aggravate the severity of both disorders.

Chronic pain is an important risk factor for suicidality, and evidence suggests that individuals with chronic pain are twice as likely at risk of suicide. Thus, pain-related factors –sleep problems, depression, concurrent chronic pain conditions, and frequent episodes of intermittent pain–, are predictors of suicide risk. However, pain characteristics –type, duration, and intensity/severity– and disability have not been related to suicide risk.

Chronic pain and depression may share common neuroplasticity mechanism changes –that leads to a disruption of the function–, and may involve the same brain structures, neurotransmitters, and signaling pathways.

Brain regions –including the insular cortex, prefrontal cortex, anterior cingulate, thalamus, hippocampus, and amygdale –which are part of Injury sensory pathways of pain and mood management– form the histological structural foundation for the coexistence of pain and depression.

The molecular mechanism associated with chronic pain and depression might involve monoamine neurotransmitters –including serotonin (5-HT), dopamine (DA), and norepinephrine (NE)–, responsible for depression and pain when the level decrease; the decreased availability of brain-derived neurotrophic factor (BDNF) –involved in signalling pathways and regulation of neuroplasticity– is responsible for pain and depression; inflammatory signals in central nervous system can induce changes in neurotransmitter metabolism, neuroendocrine function, and neuroplasticity; glutamate and its receptor subtypes –N-methyl-D-aspartic acid (NMDA) receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–, have also been found to be involved in chronic pain and depression.

Immune cells and mediators

The immune system has been identified as an important contributor in the transition from acute to chronic pain, which appears to be a disorder of the nervous system. Immune cells and their mediators –which infiltrate damaged nerves, the dorsal root ganglia, spinal cord and tissues around free nerve endings– affect pain and pain control through different mechanisms, and have different roles in the initiation, maintenance and resolution of pain. Thus, it has been suggested that targeting some of these immune processes may modulate immune cells or immune mediators and therefore attenuate chronic pain.

Inflammatory mediators –bradykinin, histamine, adenosine triphosphate, neurotrophins and mainly cytokines– activate sensory neurons leading to pain and hyperalgesia, suggesting the involvement of these mediators in the initiation and maintenance of pain.

Evidence suggests that episodes of acute inflammation can induce sensory neuron plasticity –including changes in the expression of neurotransmitters, receptors, signalling cascades and ion channels causing long-lasting altered sensory response to subsequent inflammatory mediators– that may contribute to chronic pain development.

After nerve injury, both inteleukin-6 (IL-6) and its receptor (IL-6R) are upregulated, but not glycoprotein 130 (gp130). However, it has been suggested a role of this receptor component in pain, since depletion of gp130 in sensory neurons attenuates inflammatory, tumour, and arthritis pain.

Likewise, inhibition of IL-6 or IL-1β signalling by soluble gp130 or anakinra –a IL-1 receptor (IL-1R) antagonist–, or neutralization of tumour necrosis factor-alpha (TNFα) with TNFα antibodies or soluble TNF receptors attenuates the pain development in experimental arthritis models, involving both IL-1R and TNFα in the development of pain.

Other mediators include IL-15 –which contributes to the development of neuropathic pain by promoting infiltration of macrophages and T cells–, IFNγ –which induces spontaneous neuronal firing–, IL-18, IL-22 and IL-17.

On the other hand, administration of the anti-inflammatory cytokine IL-10 –an endogenous pain resolution pathway associated with decreased CD11b, an integrin family member, TNFα and IL-1β expression– reduces neuropathic pain. The fusion of IL-4 and IL-10 –instead of the combination of individual cytokines– is more effective in inhibiting pain, suggesting the use of anti-inflammatory cytokines as promising strategies for chronic pain. Resolvins –RvE1, RvD1– and neuroprotectin D1 (NPD1) –also called protectin D1 (PD1)–, all involved in the termination of inflammation, have strong analgesic actions too.

Myeloid cells –monocytes/macrophages are involved in the initiation, maintenance and resolution of neuropathic pain through the production of cytokines –IL-6, TNFα and IL-1β–, and the release of reactive oxygen species, with opposite effects in regulating macrophage phenotype by promoting polarization into anti-nociceptive or blocking pro-nociceptive phenotype. This regulation has a potential for new therapeutic strategies for chronic pain.

Research indicate a role of mast cells and granulocytes in the initiation of pain, and a potential role in maintaining pain, but no substantial role for neutrophils in pain induction. Mast cells –frequently found in close proximity to nerve endings– release cytokines, nerve growth factor (NGF), proteases, histamine and bradykinin that induce pain. Neutrophils can also release opioid peptides –β-endorphin, met-enkephalin and dynorphin-A– with anti-nociceptive effects through opioid receptors.

Evidence suggests that specific T-cells subtypes control the initiation of neuropathic pain, while the inflammatory mediator secreted determines whether T-cells have a pro- or anti-nociceptive role. T-cells –mostly CD4+ that produce IL-17 and IFNγ in a sex-dependent fashion– seem to be involved in the maintenance of pain, since depletion of CD4+ T-cells reduces hyperalgesia and allodynia, where the pain has developed. The increased IL-4 and IL-10 in the spinal cord would explain in an age-dependent way why children experience less neuropathic pain.

Autoantibodies against citrullinated antigens –(ACPAs) that bind to osteoclasts to induce the release of CXCL1, which activates sensory neurons and induces pain–, citrullinated fibrinogen, vimentin, α-enolase, collagen type-II, immunoglobulin-binding protein and histone-4 increase in patients with RA, showing the involvement of B cells in the initiation of pain.

Clinical studies show that targeting myeloid cell for treating neuropathic pain fail to reduce pain scores. Targeting B cells to prevent the production of autoantibodies –with anti-CD20– reduce arthritis disease onset, but does not improve pain.

Treatments and Interventions

The clinical management of chronic pain –mainly targeting the symptoms or neuronal signalling of chronic pain– is mostly palliative and has limited success.

Traditionally, chronic pain treatment included rest and inactivity, but evidence supports that exercise –key for cardiovascular and bone health– may have moderate benefits in reducing chronic pain and enhancing quality of life through improving both mental health –depression, headache or migraine, fibromyalgia– and physical functioning by increasing the production of endogenous opioids, leading to transient anti-nociception. Therefore, the general advice now is to keep active, particularly since physical activity and exercise is associated with minimal adverse effects in terms of medication interaction and abuse.

Among chronic pain patients, psychiatric comorbidity including major depression –as well as use of psychotropic medications–, is associated with increased risk for opioid misuse. Thus, codeine or tramadol –weaker opioids– are preferred to stronger ones like oxycodone or hydromorphone for pain management in these patients with past or present opioid addiction. Likewise, opioid agonist treatment with buprenorphine/naloxone or methadone has been showed to be effective in individuals with chronic non-cancer pain (CNCP) at risk of addiction.

Benzodiazepines have also demonstrated therapeutic effect in chronic neuropathic or inflammatory pain, and some studies suggest that they might be useful to treat chronic pain-induced depression. In adults, there is evidence supporting the use of some antidepressants –amitriptyline– to provide pain relief in certain CNCP conditions.

Additionally, some studies show that psychotherapeutic interventions approaches may reduce pain severity in patients with chronic pain.

Pharmacological interventions for children include antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol for CNCP and cancer pain.

The use of anti-inflammatory cytokines for pain treatment is a promising strategy, and targeting caspases –involved in microglia activation and maturation of pro-inflammatory cytokines in neuroinflammation–, particularly CASP1, CASP6, and CASP11 may offer a new therapeutic approach for chronic pain, but further studies are yet needed.

By Dr. Maria Benito

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