Chronic pain and depression - Pathos

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Chronic pain and depression

Dolore cronico e depressione
Short review
Pathos 2021, 28; 1. Online 2021, Jun 30
Davide Cristina
Mental Health Dipartiment ASP 7
Ragusa (Italy)
Summary  Chronic pain is a major public health problem worldwide, recent studies have found that the role of neuronal plasticity is at the root in the development of chronic pain and depression. Both pathological condition share neurophysiological mechanism and neurotransmitters, which has implications for treating both simultaneously.
Riassunto  Il dolore cronico è un grave problema di salute pubblica a livello mondiale, recenti studi hanno accertato che il ruolo della plasticità cerebrale è alla base nello sviluppo del dolore cronico e della depressione. Entrambi i quadri patologici condividono percorsi biologici e neurotrasmettitori, il che ha implicazioni per il trattamento di entrambi.
Key words  chronic pain, depression, neuroplasticity, antidepressants.
Parole chiave  dolore cronico, depressione, neuroplasticità, antidepressivi.

Chronic pain is a major public health problem, with epidemiological studies report that nearly one in five people in the world suffer from moderate to severe chronic pain and that one in three people are not self-resiliant due to pain. Epidemiological data from developed countries has shown that up to 50% of the general population may be affected by chronic pain.1 Acute pain induces mood deflection while chronic pain is known to initially induce demoralization and subsequently depression. Depression can also adversely affect pain symptoms and treatment response. Pain and depression independently induce long-term plasticity in the central nervous system (CNS).2 The coexistence of depression and chronic pain creates a difficult treatment for depressive disorder imagining depression as either pre-existing or pain-induced.

Pain includes both the perceptive component (nociception) and the affective-emotional experiential component. Chronic pain has a duration of more than 3 months and involves a complex regulation of the algogenic signal at the spinal level: a reflected signal returns to the source of the algogenic stimulus and through anafferent neuron reaches the brain after processing, the response returns via an efferent neuron to its interneuron which has a modulation function. Chronic pain can lead to peripheral sensitization, a condition characterized by a decrease in the activation threshold and an increase in membrane excitability and the phenomenon of central sensitization, an amplification of afferent signals at the CNS level, so as to make it remain in a state of high reactivity and with greater perception of pain.3 Chronic pain is associated with profound changes in personality and lifestyle and creates a vicious circle of suffering with a deterioration in the quality of life.

Cerebral pain network
The physiological response to pain is activated by algogenic signals capable of stimulating the terminations of pain-receptive neurons (nociceptors) that transmit the stimulus to the neurons of the posterior horn of the spinal cord, from which originate five ascending pathways to the thalamus and the cerebral cortex: spino-thalamic, spino-reticular, spino-mesencephalic, spino-hypothalamic, cervico-thalamic. The thalamic nuclei mediate the transmission of information to the cerebral cortex, which directly participates in the processing of painful sensations. These ascending pathways correspond to some main locations in the periaqueductal gray, in the nucleus of the raphe magno, in the reticular formation of the bulb and the midbrain including the parabrachial area that emits afferents up to the limbic structures such as the amygdala which modulates emotional behavior. The nociceptive information reaches other areas of the brain stem: serotoninergic (nuclei of the raphe), noradrenergic (locus ceruleus) and dopaminergic that give rise to direct projections to the diencephalon and telencephalon and to pathways descending to the spinal cord (the latter instead play a role in modulating pain connected to the hypothalamus, the midbrain and the bulb control the spinal neurons that transmit nociceptive impulses).
Projections of the anterior and frontal cingulate cortex in association with the limbic system would be important for processing the affective and cognitive dimension of pain. In imaging studies, the most commonly activated areas in pain were observed to include the primary and secondary somatosensory cortex, anterior cingulate cortex, insular cortex, prefrontal cortex, thalamus, nucleus accumbens and amygdala. Activations of the primary and secondary somatosensory cortices contribute to the sensory-discriminative dimension of pain. The anterior, prefrontal, insular cingulate cortex, the nucleus accumbens and the amygdala, meanwhile, have been implicated in the affective component of pain.2,4
It has been shown, in fact, that the pathways responsible for the transmission of algogenic stimuli share the same brain regions involved in the management of mood, including the insular cortex, the prefrontal cortex, the thalamus5 and the anterior cingulate cortex (the latter believes that it integrates sensory impulses with emotional states). The association between pain and depressive disorders becomes stronger as the severity of both conditions increases.
Several studies with magnetic resonance imaging (MRI) have confirmed the central role of the insula in the processing the painful stimulus, as well as the function of processing and integrating the sensory/discriminative aspects of pain and the sensory/cognitive components of pain perception, respectively.6
A recent study reports that in patients with chronic pain who manifest depressive symptoms, a new brain pathway has probably been identified, formed by 5-hydroxytryptamine projections consisting of a bundle of serotonergic neurons that from the dorsal raphe nucleus (5-HTDRN area responsible for regulating mood as it is rich in serotonergic neurons) connects to the interneurons that express somatostatin in the central nucleus of the amygdala. From the central amygdaloid nucleus the somatostatinergic interneurons connect to the lateral abenula, an area also closely involved in depressive syndrome as well as nociception. The inhibition of this pathway (tract of the dorsal core of the raphe - amygdaloid nucleus) on the male mouse model suffering from chronic pain produced a depressive-like behavior. The subsequent activation of the same pathway with pharmacological and optogenetic approaches reduced the depressive-like behavior previously induced. Similarly, it was observed from magnetic resonance imaging of patients with depressive comorbidity that the connection between the dorsal raphe nucleus and the central nucleus of the amygdala was reduced compared to patients suffering only from chronic pain. The new pathway could mediate some aspects of depressive symptoms by being less active in patients with depressive comorbidity.7
The role of neuroplasticity
Neuroplasticity is the ability of the SNC to modify its structure and consequently the functions of its neurons, in response to external stimuli related to harmoful events or pathological conditions and in relation to the development process of the individual.8 We talk about adaptive plasticity when the change is positive with respect to noxa. On the other hand, maladaptive plasticity is defined if the modification due to certain stimuli leads to pathological alterations. Many studies show that chronic pain and depression can result from neuroplasticity mechanism, which are an important condition for the onset and aggravation of both disorders. The condition of maladaptive neuroplasticity, can therefore be considered a disease state.9 These mechanism are also triggered in the sensory conduction pathways from the peripheral nervous system (sprouting) which consists of neurochemical alteration and sometimes anatomical modifications that contribute to the onset, development and maintenance of chronic pain.10,11 Brain Derived Nerotrophic Factor (BDNF) is an endogenous neurotrophic protein that has greater expression in the adult mammalian brain and is involved in the activation of neuronal receptor tyrosine kinases (Trk) via intracellular signaling pathways that mediate action neurotrophic on synapses, on neurogenesis, on neuronal differentiation and on neuroplasticity also in response to stress at the level of the prefrontal cortex and dentate gyrus.12,13 It was lowers BDNF levels in the blood, and play a key role in the onset and development of pain. BDNF appears to have different serum levels depending on the underlying disease associated with chronic pain.14,15 Chronic pain is known to cause depression; in fact, environmental stresses increase the plasma concentrations of glucocorticosteroid leading to an hypoproduction of BDNF, perhaps at the basis of the onset of reactive depressions.16.17 Depression, on other hand, has a negative affect on both painful symptoms and the response treatment. Depression and chronic pain independently induce long-term plasticity in the CNS.2
A recent review presents on one side the prevalence of pain in cohorts of depressed patients and, on the other side, the prevalence of depression in cohorts of pain patients whith chronic pain. There is therefore a higher incidence of this combination than when these conditions are esamined individually. The presence of pain makes it difficult to recognize and treat depression. When the pain is moderate to severe, it is associated with more pronounced symptoms (poor quality of life, less work functioning and increased use of health care). Likewise, depression in pain patients is associated with greater ailments and greater disability. Patients with major depression and painful symptoms have lower response and remission rates than those whitout painful symptoms; the times required to achieve remission are longer. The treatment must be incisive.18 Since depression and pain share neurophysiological mechanisms and pathways, there is a fall in the treatment when both are present at the same time.19 Since changes in neuroplasticity occur during the experience of pain and depression involving monoamines, many studies have been carried out in recent years focusing on the application of antidepressants (AD) in the management of chronic pain.17

Neurotransmitters and the role of antidepressants
The classic monoamine hypothesis proposes that depression is caused by the reduced availability of neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in the CNS. Antidepressants selectively act on some subtypes of 5-HT and NA receptors to block its reuptake and increase their concentrations in the synaptic space, improving neurotransmission and having an antidepressant effect.17,20 Monoamine neurotransmitters take part in the onset and development of pain, in fact the efficacy of AD 5-HT reuptake inhibitors (SSRI) and NA-5HT (SNRI) in patients with chronic neuropathic pain is used.21,22 In Italy, ADs indicated for painful states are amtriptyline, clomipramine (tricyclics), duloxetine and trazodone. Other ADs, such as venlafaxine, bupropion, citalopram, fluoxetine and paroxetine, despite being only indicated for depression, anxiety disorder and some for obsessive compulsive disoerder in our country, are used offlabel in chronic painful states (neuropathies and fibromyalgia). The guideline of neuropathic pain (Amorin et al. 2016) brings nortriptyline, amitriptyline, imipramine at a therapeutic dosage (DT) of 25-150 mg / day as first-line treatment regarding the use of ADs, tricyclics (TRC) for 6-8 weeks, duloxetine at a DT of 30-120 mg/day for 4 weeks and venlafaxine at a DT of 37.5-225 mg/day for 4-6 weeks. In third-line treatment the use of AD such as citalopram, and paroxetine at DT of 10-40 mg/day for 4 weeks.23,25
TCR drugs are of old generation; the mechanism of action is characterized by the inhibition of reuptake of 5-HT and NA in the synaptic space.20 Venlafaxine and duloxetine are two SNRIs. Venlafaxine has an AD efficacy similar to imipramine and, since at low doses it mainly inhibits the reabsorption in the synaptic space of 5HT, the efficacy on pain is obtained at higher doses capable of also inhibiting the NA transporter (NET). SNRI have similar efficacy to TRC but with fewer side effects. These molecules have given good results, in several clinical trials, in the treatment of neuropathic pain, in the treatment of diabetic polyneuropathy, in HIV neuropathy and in oncological neuropathic pain. Bupropion has NET and dopamine transporter (DAT) inhibitory properties and primarily inhibits dopamine reuptake, with a benefit in some forms of neuropathic pain.24 Duloxetine has a direct modulating effect on the descending pathways of pain with an inhibiting effect on the NA system of the Locus Cereuleus and on that of the 5HT of the Nucleo del Rafe.25 Milnacipran is a SNRI, with stronger action on the NET than the transporter serotonergic (SERT). Data suggest that this AD may be effective for pain in fibromyalgia. Milnacipran is not approved in Italy.26 TCR and SNRI are the most used ADs in the treatment of neuropathic/fibromyalgia pain.27
In addition to AD, mood stabilizers and analgesics have an important function in the treatment of chronic pain. The contribution of appropriate psychotherapy in the treatment of chronic pain-induced depression is important, as confirmed in many clinical investigations.28

Chronic pain and depression are closely related and share the same neurophysiological areas and mechanisms of CNS. Some ADs are first-line drugs in neuropathic pain, especially TRCs and SNRIs which, in addition to performing an analgesic function, also act as antidepressants. Chronic pain and depression independently induce long-term plasticity in the CNS. Maladaptive neuroplasticity therefore appers to be one of the main causes of chronic pain and/or major depression and of the different combinations of the two conditions.

Conflict of interests
The author declares that the article is not sponsored and was drafted without conflict of interest.
30th June 2021
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