A Review of the Emotional Aspects of Neuropathic Pain: From Comorbidity to Co-Pathogenesis
A Review of the Emotional Aspects of Neuropathic Pain: From Comorbidity to Co-Pathogenesis
0 R. Torta V. Ieraci (&) F. Zizzi Department of Neuroscience ''Rita Levi Montalcini'', University of Turin , Turin , Italy
Neuropathic pain is characterized by both sensory and affective disturbances, supporting the notion that pain and mood disorders share common pathogenetic mechanisms. Moreover, biological and neuroimaging data show that common brain areas are involved in the modulation of painful and emotional experiences. Improved understanding of the molecular mechanisms underlying the role of neuroinflammation in regulation of affective behavior in neuropathic pain states is important for the development of novel therapeutic strategies. Psychological issues must be considered a factor influencing treatment and outcome in patients with neuropathic pain. Funding: Pfizer, Italy.
Mood disorders; Molecular mechanisms; Neuroinflammation; Neuropathic pain; Therapeutic strategies
Neuropathic pain is associated with a
substantial economic burden for both individuals and
society . There is strong evidence available to
suggest that patients with neuropathic pain
experience worse health-related quality of life
(QOL) than the general population [2–4], and a
negative effect of neuropathic pain has also
been reported in other health conditions [5, 6].
Chronic pain with a neuropathic component
has been shown to be associated with worse
QOL, greater psychological distress, increased
interference with sleep, and loss of more
workdays than chronic pain without a neuropathic
Neuropathic pain is characterized by sensory
symptoms such as gain or loss of somatosensory
function, burning and evoked pain, as well as
abnormal temporal summation . Nerve
injury models have shown sensory disturbances
to arise from interactions between neurons,
immune and immune-like glial cells, and other
immune cell-derived inflammatory mediators,
including cytokines and chemokines, ATP,
histamine, bradykinin and prostaglandins; in this
sense, neuropathic pain is a neuro-immune
disorder . This report discusses the
relationships between mood disorders and neuropathic
pain, with a focus on the pathogenetic
mechanisms linking these two disorders, and reviews
available treatment strategies.
Compliance with Ethics Guidelines
This article is based on previously conducted
studies and does not involve any new studies of
human or animal subjects performed by any of
MOOD DISORDERS IN PATIENTS
WITH NEUROPATHIC PAIN
Clinically, neuropathic pain is characterized by
both sensory and affective disturbances, and
this frequent comorbidity supports the notion
that pain and mood disorders share some
common pathogenetic mechanisms [
]. It is
important, therefore, to treat an affective
disorder that coexists with pain. The affective
disturbances associated with pain include working
memory dysfunction, impaired cognition,
decreased appetite, depression, anhedonia,
disruptions to sleep cycles, and impaired familial
and social interactions [
]. The most common
regions of the brain involved with pain in
affective disturbances are the nucleus
accumbens, the medial prefrontal cortex and the
periaqueductal gray [
]. However, while
available research highlights that there are some
psychological variables common across
different disorders, every pathology is characterized
by some specific psychological aspects [
Neurological disorders associated with
neuropathic pain are characterized by important
associations between psychosocial factors and
The importance of emotional aspects of pain
is particularly evident for depression and
]. Depression is predictive for pain in
many conditions, including chronic
musculoskeletal pain, multiple sclerosis, post-stroke
pain and Parkinson’s disease [
the presence of a neuropathic component
correlates with higher values for depression and
]. Depression can also be
associated with alexithymia, with evidence suggesting
that if these two factors are present together,
they have a combined influence on the affective
component of pain . Anxiety is frequently
present in patients with chronic pain
conditions, and appears to be correlated with pain
]. Neuropathic pain is
associated with specific psychological factors: fear
linked to the painful sensation and perceived
danger associated with different activities may
cause irritability and social withdrawal .
Importantly, an inadequate response of
neuropathic pain to various drug therapies constitutes
a substantial unmet need .
OF PAIN AND AFFECTIVE
Supraspinal neuroinflammation has a potential
role in the development of affective disorders in
patients with neuropathic pain conditions.
Evidence suggests sickness behavior, cognitive
impairment, depression and other
neuropsychiatric disorders all have immune mechanisms
associated with pro-inflammatory cytokines
and chemokines [
]. There is growing
evidence, particularly from preclinical models,
that nerve injury leads to specific
neuroinflammation in affective forebrain regions, with such
injury responsible for these affective
disturbances; nerve injury-evoked supraspinal
neuroinflammation has been shown to underlie the
development of affective disturbances by
disrupting critical physiological processes [
Peripheral Inflammation and Affective
Peripheral inflammation, or an immune
challenge, is known to trigger a constellation of
symptoms, including fatigue, pain, an altered
sleep pattern, anorexia and affective
disturbances, many of which represent adaptive
responses considered to promote survival, and
are collectively termed sickness behavior [
Clinically, major depressive disorder has a
marked inflammatory component, with
elevated blood levels of the pro-inflammatory
cytokines (TNF and IL-6) [
depressed patients with painful neuropathy
have higher TNF levels than patients with
painful neuropathy who do not have
depression; this observation supports the existence of
a common inflammatory mechanism for
neuropathic pain and mood disorders [
Immune-to-Brain Signaling and Inflammatory Cytokines as Neuromodulators
Current understanding of immune-to-brain
signaling comprises three non-exclusive signaling
pathways: neural transmission, humoral
transmission and molecular transmission [
Supraspinal cytokines and chemokines are
thought to act as neuromodulators within a
cytokine network of neurons, microglia and
astrocytes, acting to regulate cytokine
production and cytokine receptor expression, and both
amplifying and attenuating cytokine signals.
Nerve injury-evoked supraspinal
neuroinflammation appears to disturb physiological cytokine
concentrations, causing a ‘sub-inflammatory’
]. Critical regions for affective state
regulation, such as the hippocampus,
hypothalamus, amygdala, nucleus accumbens and
frontal cortical regions, show particularly strong
expression patterns for cytokine and chemokine
Inflammatory Cytokines and Affective
Disturbances in the Neuropathic Brain
Specific anatomical regions of the
hippocampus, medial prefrontal cortex (mPFC), and
interconnected regions such as the striatum/
NAcc, ventral tegmental area (VTA),
hypothalamus, amygdala and periaqueductal gray (PAG)
are critical for the regulation of affective
]. Peripheral neuropathy leads to
increased expression of pro-inflammatory
cytokines as well as increased glial activation
within these brain structures, and emerging
evidence suggests that neuroinflammation in
these brain regions leads to affective
]. In the mPFC, hippocampus and the
ventral postero-lateral thalamus and brainstem
structures, neuroinflammation induced by
nerve injury has been linked with both
allodynia and hyperalgesia [
]. Emerging evidence
has led to the proposal of a model in which it is
postulated that, after nerve injury, the
transmission of peripheral inflammation to the
brain via immune-to-brain signaling pathways
in the interconnected hippocampal-mPFC
circuitry leads to supraspinal neuroinflammation,
and is critical to the development of depression,
anhedonia, cognitive impairment and sleep
]. It is thought that there is a
glutamatergic modulation system involved,
either directly via elevated glutamate levels,
altered expression of NMDA and AMPA
receptors and glutamate transporters, or indirectly
through metabolites of the indoleamine
2,3-dioxygenase pathway [
]. Suppression of
critical brain neurotrophic factors by cytokines
may lead to reduced neurogenesis and
neuroplasticity. TNF modulation of the dopaminergic
systems has been shown to be associated with
blunted reward, and midbrain glial activation
may play a role in midbrain cell death as well as
altered glucocorticoid expression associated
with affective disturbances [
detailed anatomical examination along with
improved understanding of the precise
molecular mechanisms underlying the role of
neuroinflammation in regulation of affective
behavior in neuropathic pain states is likely to
be important for the development of novel
FOR NEUROPATHIC PAIN
The common biological background in many
emotional and pain states may, at least in part,
explain the frequent association between pain
and a depressed mood, and biological and
neuroimaging data show that common brain
areas are involved in the modulation of both
painful and emotional experiences [
Increased levels of pro-inflammatory cytokines
have been found to be associated with both
depressive disorders and pain, suggesting that
activation of the neuroimmune system may be
a factor underlying the high co-occurrence of
depression, pain and other medical disorders
Neuropathic pain is widely recognized as one
of the most intractable pain conditions to
manage, with clinical outcomes often
]. When treating chronic pain, the
ultimate goal is to reduce, but not necessarily
eliminate pain, but to achieve better QOL, by
restoring normal function and reducing
comorbidities such as depression, anxiety and
sleep disorders [
The activity of antidepressants on pain
shows two phases: the first is fast and acts on
pain directly, and the second becomes
apparent later, through mood normalization [
the psychoactive agents, tricyclic
antidepressants and serotonin-norepinephrine reuptake
inhibitors are the only classes shown in
randomized controlled trials to be effective for
pain, and are currently indicated as
guideline-recommended first-line treatment for
neuropathic pain therapy [
antidepressants have been shown to have both
anxiolytic and analgesic effects at low doses,
without antidepressant activity [
contrast, even at low doses, the selective serotonin
reuptake inhibitors and dual-acting
serotonergic and noradrenergic antidepressants have
antidepressant, anxiolytic and analgesic effects
]. While conventional antipsychotic agents
have been used regularly to treat pain in recent
decades, the occurrence of adverse effects,
combined with the lack of specificity of their
analgesic action, are important limitations; the
atypical antipsychotics have better tolerability
]. Antidepressants have been shown to
reduce chronic pain in both depressed and
non-depressed patients, suggesting that they
have independent analgesic mechanisms,
which combined with their ability to treat
comorbid depression and pain-related sleep
issues, suggest these agents may be of
particular utility [
The role of adult hippocampal neurogenesis
in emotions remains to be fully elucidated,
although several studies have suggested that
this process may be involved in both cognitive
and emotional function and that it is
deregulated in neuropsychiatric disorders such as
major depression. Several psychoactive drugs,
including antidepressants and anticonvulsants,
can modulate neurogenesis in adults [
Growing evidence suggests that gabapentin and
pregabalin are able to produce
concentration-dependent increases in the numbers of
newborn mature and immature neurons, along
with a parallel decrease in the number of
undifferentiated precursor cells [
]. In stressed
adult mice, anticonvulsant administration has
been shown to prevent the appearance of
depression-like behaviors induced by chronic
restraint stress and to promote hippocampal
neurogenesis, although the clinical relevance of
this finding, if any, remains to be clarified [
It is likely that several disorders, including
anxiety, epilepsy, pain, fibromyalgia and sleep
interference, may share neuronal hyperactivity
in various brain circuits, and available data
suggest the existence of novel molecular
pathways that may be potential targets for new
The combination of antidepressants and
anticonvulsants (i.e. gabapentin and
duloxetine, pregabalin and duloxetine) may
provide increased efficacy over monotherapy, but
further studies of combination therapies are
28, 30, 31
]. The combination of
duloxetine and gabapentinoids was generally
well tolerated, with an adverse event profile
and rate similar to those of duloxetine
monotherapy, with the exception of
significantly less insomnia occurring in the
combination treatment group [
combination of pregabalin and duloxetine
was also generally well tolerated; however,
moderate to severe drowsiness was more
frequent during combination therapy [
Patients with neuropathic pain often fail to
respond adequately to pharmacologic
treatments and their pain is therefore termed
]. An integrated
psychopharmacological and psychological approach is
necessary for treatment in some patients [
Psychoeducational interventions can improve
treatment adherence, while cognitive
behavioral intervention may be more useful in
modifying distorted beliefs on pain. When
focusing on the patient’s life experiences,
brief psychodynamic psychotherapy
interventions can also be useful.
AS PREDICTORS OF PAIN
Perceived pain intensity is not proportional to
the type or extent of tissue damage, but depends
on the interaction between cognitive,
emotional, socio-cultural and physical factors
], and can be strongly influenced by
stress, anxiety and depression . Conversely,
it is important that the role of pain on
emotional and cognitive performance is established.
Early assessment for coexisting psychiatric
comorbidity using appropriate methods may
help achieve early referral to a psychologist or a
It is also important to highlight that in
several neurological conditions, catastrophism is a
factor that is associated with or predicts pain.
Neurological conditions where catastrophism
has affected pain include multiple sclerosis,
lumbar or musculoskeletal pain, migraine,
postherpetic neuralgia, cerebral palsy, the sequelae
of severe traumatic brain injuries, as well as
neuropathic pain following surgical procedures,
neuropathic pain due to HIV and phantom limb
Neuropathic pain is widely recognized as one of
the most intractable pain conditions to manage,
with clinical outcomes often unsatisfactory.
Psychological factors such as depression and
anxiety must be taken into consideration as
factors that may influence treatment and
outcome. Moreover, when treating chronic pain, it
must be remembered that the ultimate goal is
not simply to reduce pain, but to achieve better
QOL, by restoring normal function and
reducing comorbidities such as depression, anxiety
and sleep disorders.
This supplement has been sponsored by Pfizer,
Italy. The article processing charges for this
publication were also funded by Pfizer, Italy.
The authors thank Marie Cheeseman who
provided English editing of the manuscript on
behalf of Springer Healthcare Communications.
This medical writing assistance was funded by
Pfizer, Italy. All named authors meet the
International Committee of Medical Journal Editors
(ICMJE) criteria for authorship for this
manuscript, take responsibility for the integrity of the
work as a whole and have given final approval
to the version to be published.
The authors equally contributed to the
preparation of the manuscript.
Disclosures. Riccardo Torta reports receiving
honorarium from Pfizer. Valentina Ieraci and
Francesca Zizzi have nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by any of the
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
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