Among the aspects that make the study of the relationship between chronic pain and depression interesting is the significant increase in its prevalence in recent years, becoming two of the main causes of consultation in outpatients.
As an example, the prevalence of low back pain can reach 45% in industrialized countries. In Chile, it is estimated that 5 million people suffer from chronic pain, with 28.8% of them having severe pain intensity. On the other hand, depression ranks third in disease burden worldwide.
The national health survey (ENS 2011) established that the prevalence of “depressive symptoms” in Chile reaches 17.2% in men and 25.7% in women. However, we do not have epidemiological data for both syndromes together.
The emotional component of pain is considered in its own definition.
The International Association for Study of Pain (IASP) defines it as “an unpleasant emotional and sensory experience, associated with actual or potential tissue damage, or described in terms of that damage.”
In the particular case of depression, the association with painful symptoms was identified early in the clinic and has received different names, such as “depressive equivalents” as a resemblance to anxious equivalents, or “masked depression,” which suggests that Pain would be a symptom that covers up or overlaps with emotional discomfort.
The usefulness of antidepressants , particularly tricyclics, in the treatment of chronic pain, even in non-depressed patients, has been known since the 1960s. These have been evaluated with positive results in headache, facial pain, peripheral neuropathies, among many others. . The effectiveness of these drugs on both depression and pain raised the question about the nature of this relationship.
The first observations of the response to tricyclics assumed a neurotransmitter deficit as a common basis; later studies found that selective serotonin reuptake inhibitors did not achieve the same effect, deducing that there are more components involved than serotonin deficiency.
| Epidemiology |
Among the limitations presented by existing population studies, we find the lack of homogeneity of the samples, the fact that different types of pain could have different causes that are related to depressive pathology (for example, inflammatory diseases increase the risk of depression in way independent of pain), the setting in which the patient is located (hospitalized, pain centers, psychiatry centers, etc.), the use of different pain and depression measurement scales, among others.
Taking into account the limitations described, we found a prevalence of painful symptoms in depressed patients that varies between 15% and 100%. In depressed primary care patients, the most frequently reported pain would be headache, abdominal pain, arthralgia, and chest pain. A cohort study with a 10-year follow-up found that depressed patients would be at greater risk of low back pain, shoulder and neck pain, and musculoskeletal symptoms.
Seen from the perspective of pain, the prevalence of depression in this group of patients in primary care reaches an average of 27% and can reach 56.8% if lifetime prevalence is considered. These results propose that the relationship between chronic pain and depression can not only be observed concomitantly, but can also occur over the years. Considering the origin of the pain, depression in patients with neuropathic pain is less common than in patients with pain without a known cause.
The association between these two conditions is also reflected in the prognosis.
In depressed patients who present pain at the beginning of their condition, it has been observed that the greater severity of the pain is associated with worse outcomes, including: more severe depression, greater functional limitation related to pain, greater unemployment, worse self-perception of health, increased use of opioids and outpatient medical visits. Meanwhile, low back pain is the most studied type of pain and it has been found that its association with depression is reflected in a worse prognosis.
| Physiology |
The first neurobiological findings about the relationship between pain and mood were seen when objectifying the analgesic effect of tricyclic antidepressants, which turns out to be independent of their effect on depressive symptoms. However, selective serotonin reuptake inhibitors did not have the same level of efficacy as tricyclics.
This situation generated the first suspicions of the role of norepinephrine (particularly its balance with serotonin) in the analgesic effect; however, the effect of serotonin and norepinephrine inhibitors does not reach the effectiveness of tricyclics. Given this dilemma, the blockade of NMDA receptors and calcium channels could be responsible for this difference.
With the development of animal models of chronic stress, especially with regard to the hypothalamic-pituitary-adrenal (HPA) axis, it was possible to understand and describe several changes in endocrine regulation, which have notable coincidences with the findings of neuroendocrine alterations in Studies of depression in humans, for example: an increase in central activation of the HPA axis, elevation of basal glucocorticoid concentrations, alteration of the circadian rhythm of adrenocorticotropin release, a slow suppression of the stress response and adrenal hypertrophy.
It is known that at least half of depressed patients have an elevated cortisol level.
Maladaptive changes in the Hypothalamic Pituitary Adrenal (HPA) axis prevent the regulation of cytokines, which is how the TNF that is normally found in the hippocampus will increase its concentration.
The increase in this cytokine has an impact on noradrenergic transmission, decreasing it through different pathways. On the one hand, it inhibits the release of norepinephrine, but it also activates presynaptic norepinephrine receptors (I2-AR), which increase its expression and sensitivity to Prolonged exposure to stress and pain, slowing the release of norepinephrine.
Under normal conditions, the release of norepinephrine exerts negative feedback on the TNFI, so the situation described previously favors a high level of TNFI in the hippocampus.
The increase in TNFI has been associated, for example, with the development of hyperalgesia, as well as depressive behaviors after microinfusions in the hippocampus in animal models. Increased cytokines also negatively affect neurogenesis.
Cytokines activate the immune system, including macrophages that release even more cytokines; This results in an alteration of the neuron-glia relationship, which under normal conditions is based on a bidirectional relationship where the glia modulate neurotransmitters, cytokines and neurotrophic factors and in turn, the neuron responds with neurotrophic signals. When this relationship is altered, it ends in neuronal atrophy and death. The previous phenomenon is also shared with depression.
For our purposes, the effect on supraspinal structures is of particular importance. Prolonged exposure to stress and pain increases the expression and sensitivity of I2 receptors and the expression of the norepinephrine transporter in locus ceruleus (LC) neurons. It is interesting to note that a study in an animal model demonstrated that these changes temporally correlate with the onset of anxious and depressive symptoms.
| Genetics |
Pain sensitivity has an important genetic component; this has been observed in both animal models and humans8. Recent studies in twins have linked some chronic pain conditions with anxiety and depressive symptoms, which could imply a common genetic basis.
Another interesting fact is that patients with chronic pain have more first-degree relatives who suffer from depression than the general population, even when they do not present depressive episodes.
| Conclusions |
Both pain and depression are highly common disorders, which can evolve towards chronicity or recurrence and which have a serious impact on various variables, both at the level of public health and at the level of the individual health of those who suffer from both pathologies together. Despite its importance, studies that refer to its comorbidity are scarce and have important limitations.
The presence of both diseases together is very common, and this could be due in part to the fact that each of them favors the appearance of the other and even more so, this comorbidity worsens the course of both diseases. As mentioned in this review, from a clinical point of view, the association between pain and depression has been observed for many years.
However, the study of the pathophysiology that could support this association is scarce. Among the first facts that should be highlighted is the clinical response of chronic pain with the use of tricyclic antidepressants, subsequently an attempt was made to reproduce this with Selective Serotonin Reuptake Inhibitor (SSRI), the result being a lower response, the above gave origin to the study of norepinephrine as an important neurotransmitter involved in this association.
On the other hand, the chronic stress model allowed the development of a hypothesis capable of accounting for this relationship. This hypothesis integrates different dysfunctions described in both pathologies, such as endocrine, inflammatory and neurotransmitter alterations. Vulnerability to present both conditions could also be mediated by genetic factors as has been proposed in population studies.
Some candidate genes are a mutation of the gene encoding BDNF, the serotonin transporter gene, and the gene encoding COMT. The review presents the evidence available to date, and even though there is clarity in the close relationship that exists between both conditions, the neurobiological bases of this interaction continue to develop. The optimal clinical approach to patients requires the management of both conditions simultaneously.
