Perinatal pain-postpartum depression comorbid research and progression

Authors: Hu Li, Wang Chenyang, Feng Xiaojing, Wu Jing, Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Postpartum depression (PPD) is a common maternal psychiatric syndrome that includes mental, psychological, and physical disorders, and in severe cases, suicidal tendencies

Although a large number of studies have shown that there is a high comorbid and bidirectional regulatory relationship between chronic pain and depression, the relationship between perinatal pain and PPD has only attracted attention in recent years, and effective perinatal pain management may bring new light

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1.

It is generally believed that the high-risk period for PPD is 6 months after childbirth, but studies have shown that 27% of women with PPD are already symptomatic before pregnancy, and 33% of PPD are already symptomatic

Reports of the incidence of PPD vary from 6.

1.

The mechanism of perinatal pain is complex, and the characteristics of pain during childbirth and puerperium are different

Severe pain may cause nervousness, anxiety and fear in the mother, activate the body's sympathetic nervous system, and increase the level of adrenal cortical hormones and catecholamines in the

1.

There is a high degree of comorbidity between pain and depression, and a comorbid link between the two has been demonstrated in non-obstetric populations

In recent years, pain severity has also been shown to be closely related to the onset of maternal depression in the obstetric population, and perinatal pain is an important risk predictor of PPD

Women with severe postpartum acute pain have a 2.

2.

Although the high comorbidity of perinatal pain-PPD has been confirmed by a large number of clinical studies, and the comorbid mechanism of which has just started and is still unclear, the currently known comorbid research on chronic pain-depression can provide direction and enlightenment

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1 There is overlap between psychological pain and physiological pain in brain areas

There is a partial overlap between brain regions in the brain that involve psychological pain and the physiological pain network, and correctly identifying the associations between brain regions can help explore targeted interventions
.
The midbrain dopamine circuit is an important regulatory site for pain perception, pain-related anxiety and depression, in which the frequency of firing of dopaminergic neurons in the ventral covered area projected into different targets in the cortilial limb system exhibits heterogeneity, and plays an important role
in regulating different behaviors of depression and chronic pain.

Animal models have been used to confirm that the prefrontal cortex and the nucleus accumbens are important brain regions
in the regulatory network for depression and pain comorbidities.
The amygdala and mid-suture dorsal nucleus are also involved in
the regulation of pain and depression.
Zhou et al.
have found that persistent pain can induce depressive symptoms through "serotonin (5-HT) neurons of the amygdala - somatostatinergic neurons of the central amygdala - glutamate neural circuit of the lateral reins", leading to the occurrence
of depression.
The activation of this pathway can significantly improve pain and depression-like behavior, providing direction
for the treatment of pain and depression.

2.
1.
2 Hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal axis (HPA axis) is an important stress-related endocrine axis
.
The role of the HPA axis includes the integration of pain, memory, and emotional experiences
.
It has been found that the paraventricular nucleus of the hypothalamus receives projection from the hippocampus and amygdala, as well as the projection of 5-HT-capable neurons from the ventral lateral nucleus of the head of the medulla oblongata and norepinephrine (NE) neurons covered by the dorsolateral pontons, and the adrenocorticotropin-releasing hormone is regulated
by the above structures.
At the same time, glucocorticoids are fed back into the HPA axis and also back to the hippocampus, amygdala, and the ventral lateral nucleus of the head end of the
medulla oblongata.

Chronic pain as a constant stressor, resulting in the body in a long-term state of stress, elevated blood sugar leads to desensitization of glucocorticoid receptors, thereby interrupting its negative feedback regulation of the HPA axis, causing maladaptation
of the HPA axis.
The effect of depression or chronic pain on the HPA axis may be fed back into the systems associated with both through the HPA axis, leading to mutual promotion
of depression or chronic pain.

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3 Inflammatory factors

Inflammatory factors play an important role
in the comorbidities of neuropathic pain and depression.
Xie Zemin et al.
confirmed the elevated content of hippocampal pro-inflammatory cytokines IL-6 and TNF-α in neuropathic pain-induced rats by establishing a model of retained sciatic nerve injury in mice, and was inversely correlated
with depression severity.
Elevated levels of IL-6, TNF-α, IL-1β have also been found in the peripheral blood of patients with neuropathic pain and depression, and inflammatory factors may be involved in the comorbidities of neuropathic pain and depression through microglia activation, activation of tryptophan-hippocampindamine 2,3-dioxidase 1 pathway, glutamate receptor pathway, γ aminobutyric acid neuronal deinhibition effect, and activation of the HPA axis
。

2.
1.
4 Psychosocial factors

Pain-related cognition (e.
g.
, catastrophic cognition) and other pain-related beliefs (e.
g.
, beliefs about disability and medical cure) may play a mediating role
in the association between pain and depression.
Negative psychology may aggravate the severity of the two diseases, so psychological comfort
cannot be ignored while symptomatic treatment.

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2 Perinatal pain-comorbid mechanisms of PPD

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1 HPA axis abnormality

Perinatal women undergo significant changes in the endocrine system and may be associated
with the onset of PPD.
Perinatal pain is an important source of stress during childbirth, the HPA axis plays a regulatory role in stress responses as well as in many neuropsychiatric disorders, as an important neuroendocrine adaptation mechanism, and the low reactivity to stress may reduce susceptibility to adverse behaviors after childbirth; Pregnant women with PPD have a higher cortisol response to stress, suggesting that the stress response is too strong or fails to terminate in time may be involved in the development
of PPD.

2.
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2 Immune inflammatory mechanisms

Most women experience a certain degree of pain, anxiety, stress and other adverse emotions during the perinatal period, which in turn stimulates the secretion
of pro-inflammatory cytokines.
The introduction of the cytokine-glucocorticoid feedback loop provides a cornerstone
for the study of their role in the mechanism of PPD development.
Corwin and other studies have shown that changes in the interaction between the inflammatory response and the HPA axis affect the risk of PPD occurrence; The immuno-inflammatory response within a certain period of time after childbirth is not mediated by a single cytokine, and the balance of pro-inflammatory cytokines and anti-inflammatory cytokines may play a major role
.

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3 Psychosocial factors

Anxiety and fear of perinatal pain are common risk factors for PPD and may be associated
with a "catastrophic" psychological mechanism.
During childbirth, highly sensitive women may catastrophize pain and other physical sensations, amplifying physiological effects, resulting in more intense pain that the mother expects and actually experiences, and the degree of depression is significantly related
to the maximum delivery pain expectation.
The presence of depression increases the stigma of people with chronic pain, making them less likely to actively seek pain treatment, which can lead to longer and greater intensity of pain, which in turn exacerbates their depression
.

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4 Genetic factors

Studies have explored possible links between PPD and genetic factors from the perspective of single nucleotide polymorphisms, and by comparing the differences in candidate genes associated with pain or depression in patients with confirmed PPD and nonpregnant people, it was found that rs4633 is associated with persistent pain at 6 weeks postpartum, and rs11135349 and rs7548151 are associated with the maximum pain score experienced during childbirth, suggesting that genetic variation may be one of these factors
.

3.
Explore interventions for postpartum depression from the perspective of pain-depression comorbidities

3.
1 Prevention

From the perspective of perinatal pain management, PPD often delays early treatment due to difficulties in early identification and diagnosis, and the effect of later treatment is not ideal, and drug treatment may have an impact on aspects related to maternal and infant health, such as breast milk, and the choice is limited
.
Prophylactic treatment in high-risk patients may be more important
than pharmacotherapy.
From an intervenable point of view, pain is one of the many risk factors for PPD that can be effectively managed through existing medical means, so it is currently a feasible plan
to prevent the occurrence of PPD by effective analgesia during or after childbirth.

Epidural labor analgesia is one
of the most commonly used clinical methods of managing pain during childbirth.
Ding et al.
study divided 214 women who planned vaginal delivery into analgesia group for receiving epidural delivery and those who did not receive epidural delivery, and the results of the multivariate Logistic regression analysis showed that the use of epidural analgesia during delivery was significantly associated
with a reduced risk of PPD at 6 weeks postpartum.

A multicenter study conducted by Liu et al.
, which completed a 2-year follow-up of 580 first-born women, found that the use of intraspinal analgesia during childbirth was significantly associated
with a significant reduction in the risk of depression in the 2 years after childbirth, after correcting for confounding factors.
Although there is substantial evidence that effective intrapartum analgesia reduces the risk of PPD, little current research has addressed the relationship between
postpartum pain management and PPD.
Some studies have pointed out that postpartum acute and chronic pain is associated with PPD, Lim et al.
pointed out that the percentage of pain improvement within 6 weeks after childbirth is an important predictor of EPDS scores, and women with higher pain improvement have lower EPDS scores, but the use of postpartum analgesia is often limited
by mothers worried about the influence of drugs on their babies through milk.

At present, spinal analgesia also plays an important role
in the treatment of postpartum pain.
Clinical practice has shown that epidural analgesia is associated with a longer second stage of labour and the blockade of oxytocin release, which requires increased use of exogenous oxytocin to stimulate contractions
.
The use of exogenous oxytocin may work several weeks after delivery to protect the mother from PPD
.
Other studies have shown that breastfeeding at 6 weeks postpartum is more common for women who receive epidural analgesia, while mothers who do not take or adhere to breastfeeding are at higher
risk of PPD.
In addition, epidural analgesia can reduce the stress response during childbirth, reduce cortisol concentrations in the early postpartum period, and may reduce the incidence
of PPD.

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2 Treatment

PPD often requires comprehensive, multidisciplinary hierarchical management
due to the complexity of the pathogenesis and the degree of the disease.
For all women with PPD, once diagnosed, they need to be physically and mentally multi-faceted
, starting from their risk factors.
Self-care, psychosocial support, exercise, sleep improvement and other measures are applicable to all women with PPD
.

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1 Non-pharmacological therapy

The vicious circle between pain and depression involves cognitive, behavioral somatic responses (i.
e.
, pain), and emotions
.
Pain can not only cause physical discomfort to patients, but also affect cognitive, emotional and other psychological aspects, psychotherapy can alleviate pain
to a certain extent.

Cognitive behavioural therapy (CBT) and supportive psychotherapy are effective
in both depression and pain management.
The former helps patients correctly understand the negative effects of pain and guides patients to self-regulate, and then helps patients alleviate symptoms through some behavioral training to reduce the impact of pain and depression on
patients.
The latter obtains the trust of patients by eliminating their doubts about the disease, so that patients can feel the support of the outside world psychologically, and then exert the subjective initiative of patients to improve the treatment effect
.

A meta-analysis systematically assessed the effectiveness of psychological interventions CBT and interpersonal therapy (IPT) in primary care for women with PPD, and the results were significant and could avoid the potential side effects of the drug, gradually gaining favor
with more mothers.

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2 Medication

When PPD is severe or psychotherapy is not effective, antidepressant therapy may be added
.
Commonly used drugs for the treatment of PPD are selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), 5-HT/NE reuptake inhibitors (SNRIs) and the like
.

They exert antidepressant effects
by increasing the concentration of 5-HT and NE in the synaptic space.
The occurrence of depression is related to the decrease in the content of neurotransmitters such as 5-HT, NE, and dopamine in the central region and the decline in their receptor function, while 5-HT and NE play an important role in the downward pain regulation system, so antidepressants acting on 5-HT and NE can also block the transmission of pain signals to treat neuropathic pain
while antidepressing.
TCAs are suitable for the treatment of chronic pain and neuropathic pain, of which amitriptyline is the most widely used, and its analgesic onset concentration is significantly lower than its antidepressant concentration
.

SNRIs (such as venlafaxine and duloxetine) have an advantage
over TCAs because of their relatively small anticholinergic effects.
SSRIs (eg, sertraline, paroxetine, fluoxetine, citalopram, etc.
) can selectively inhibit 5-HT uptake without affecting norepinephrine reuptake, and the analgesic effect is relatively poor
compared with tricyclic antidepressants.
Because of the dual pharmacological mechanism of antidepressant and analgesic, antidepressants have broad
prospects for application in the treatment of patients with chronic pain and depression.
At the same time, there is growing evidence that the NMDA receptor antagonist ketamine also plays an important role in antidepressants, and since (S)-ketamine has a higher affinity for NMDA receptors than (R)-ketamine, (e.
g.
, esketamine) has also been developed as an antidepressant
.

Estromine has been approved for use in refractory depression, it is a new type of chiral cyclohexanone with strong analgesic effect, analgesic effect has been present in sub-anesthetic doses, esketamine produces good analgesic effect while also improving maternal postpartum depression
.
Gu Pan et al.
selected 300 pregnant women who had cesarean section under intraspinal anesthesia to explore the effect of esketamine PCIA on postpartum depression, and found that the incidence of PPD in postpartum 3d and 7d of the esketamine group decreased and decreased, and the remedial analgesia rate in different postoperative periods was also reduced
.

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3 Others

For women with severe and above PPD, SSRIs alone or with psychological interventions can be used; If SSRIs alone do not respond, change of antidepressants or increase dosages should be considered; If the mother has severe suicidal tendencies, psychosis, or resistance to treatment, electroconvulsive therapy (ECT)
may be considered.
ECT is one of the most effective treatments in psychiatry, and it is often thought to start acting faster than standard antidepressants and can significantly reduce symptom severity
.
It can therefore be used to treat severe PPD, especially in the case
of intractable suicidal or psychotic symptoms.

4.
Outlook

There is currently a lack of systematic research
on the mechanism of action between perinatal pain and PPD.
There may be important associations between antenatal depressive states, perinatal pain, and PPD, and antenatal mental status in pregnant women is rarely included in the study
.
Secondly, maternal perinatal pain management is not limited to drug analgesia, there are many non-drug methods, such as transcutaneous nerve stimulation, music therapy, Doula accompanying childbirth, etc.
, which can play an analgesic effect throughout the perinatal period, and whether it has a positive effect on the prevention and treatment of PPD needs to be further studied to clarify
。 In the future, it is necessary to further clarify the relevant mechanisms between perinatal pain and PPD and pain management and reducing the incidence of PPD, optimize the perinatal pain management plan, and also need more basic research on the mechanism of PPD occurrence to explore more targeted cause-related measures and strive to prevent the occurrence
of PPD from the source.

The discussion of the comorbid relationship between perinatal pain and PPD may increase the attention of women and the public to perinatal pain, thereby promoting the popularization of labor analgesia, and also putting forward higher requirements for anesthesiologists, such as the choice of analgesic timing, the type, dose, mode of administration and compatibility of analgesic drugs, the treatment of the relationship between analgesia and prolongation of labor, and
the management of pain after childbirth.

Source: Hu Li,Wang Chenyang,Feng Xiaojing,Wu Jing.
Perinatal pain-comorbid research and progress of postpartum depression[J].
Journal of Huazhong University of Science and Technology (Medical Edition), 2022,51(02):262-266.