pain depression

2. Prof. Hani Hamed Dessoki,
M.D.Psychiatry
Acting Dean, Faculty of Nursing
Prof. Psychiatry
Founder of Psychiatry Depart., Beni Suef University
Supervisor of Psychiatry Depart., El-Fayoum University
Treasurer of Egyptian Psychiatric Association
2020
Pain & Depression

3. Agenda
 Introduction
 Pain and depression
 Neurobiology of depression and pain
 Different management
 Take home Message

4. Psychiatric Disorders in the Community
Out of every 100 citizens
30% are suffering from a mental problem that
needs attention.
20% will seek traditional healers or general
practitioner’s (GPs) help.
10% will be recognized by the GP to be
psychiatric cases.
2.3% will be referred to the psychiatrist.
0.5% will need inpatient treatment.

5. Major Depressive Disorder (MDD)
 MDD can be a chronic, recurrent, and
progressive condition1
 MDD is associated with alterations in functional
and structural changes in the brain2
 MDD, stress, and pain are all associated with
similar suppression of neurotrophic factors and
compromised neuroplasticity2
 Remission, not response, is the ultimate goal
of treatment3,4
1. Kendler et al. Am J Psychiatry 2000;157(8):1243-51.
2. Maletic et al. Int J Clin Pract 2007;61(12):2030-40.
3. Keller et al. Arch Gen Psychiatry 1992;49(10):809-16.
4. APA. Am J Psychiatry 2000;157(4 suppl):1-45.

6. Depressed Patients Usually
Present with Physical Symptoms
69%
Presented
ONLY With
Physical
Symptoms
Other
N = 1146 patients with major depression
1. Simon GE, et al. N. Engl J Med. 1999;341(18):1329-1335.

7. 69% of depressive patients complain of physical symptoms
Trivedi Madhukar H. The link between depression and physical symptoms. Primary care companion to the Journal of clinical psychiatry.
Physicians Postgraduate Press; 2004;6(Suppl 1):12-6.
Adapted from DSM-IV-TR, APA 2000

8.  Depression and pain commonly occur
together and both can have detrimental
effects on patient health, personal and
social function, and overall quality of life.

9.  Numerous studies indicate that
patients with pain are at increased
risk for a lifetime history of
depression, as compared to the
normal population.

10.  According to the World Health
Organisation study in primary care
settings across the world, approximately
one-fifth of all primary care patients suffer
from persistent debilitating pain, and they
are four times more likely to have co-
morbid anxiety or depression than pain-
free primary care patients.

11.  Similarly, depressed patients are also
associated with more pain complaints
and greater impairment in functional
capacity.
 In addition, the risk of depression is
greater when the pain is more diffuse,
as indicated by the number of painful
sites, and has a greater effect on the
quality of life

14. Pain Depression
RECIPROCAL RELATIONSHIP

15.  Many factors can interfere with the
successful treatment of chronic pain
including undiagnosed diseases, mental
disorders, emotional distress,
personality traits, and personal beliefs.
Depression is not simply a comorbid
condition but interacts with chronic pain
to increase morbidity and mortality.
Chronic pain & depression

16.  In addition, serotonin
and norepinephrine
were principally
investigated since these
neurotransmitters are
located in the main pain
pathway as well as
preclinical and clinical
evidence have
suggested a significant
role of such
neurotransmitters
regarding the
development and
treatment of pain.

17. There are at least two sides to the
neurotransmitter story
Sex
Appetite
Aggression
Concentration
Interest
Motivation
Depressed
Mood
Anxiety
Irritability
Thought
process
References:
1. Adapted from: Stahl SM. In: Essential Psychopharmacology:
Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge
University Press 2000.
2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.
3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35.
4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.
Norepinephrine (NE)
• Both serotonin and norepinephrine mediate a broad
spectrum of depressive symptoms
Serotonin (5-HT)
Vague Aches
and pain

18.  In fact, a number of psychotropic agents such as
selective serotonin reuptake inhibitors (SSRIs),
noradrenergic and specific serotonin receptor
antagonist (NaSSa), serotonin-norepinephrine
reuptake inhibitors (SNRIs) have been actively
tried for the treatment of pain disorders or
painful somatic symptoms regardless of patients'
diagnosis, all of which are involved in serotonin
and norepinephrine neurotransmission.

19. COMMON UNDERSTANDING ON ETIO-
PATHOLOGIC MECHANISM
Several clinical and biological factors have been demonstrated
to be involved in the development of pain. For instance,
1. altered neuromodulation,
2. abnormalities of the immune-genetic system (i.e.,
alterations in pro-inflammatory cytokines and their gene
expression),
3. alteration in melatonin,
4. aberration in 3H-imipramine binding sites on platelets,
5. the oxidative stress reaction,
6. a disturbance of neurotransmitters,
7. stress susceptibility
8. alterations of hypothalamus-pituitary-adrenal axis function
9. and cognitive vulnerability are known to at least partly play
a role in the manifestation of pain.

20.  In addition, a number of psychosocial factors
(i.e., self esteem, self-efficacy, anger,
sexual abuse, personality profile, early
childhood abuse) are also crucially involved
in the development of pain.
 Interactions of all of which clinical and
biological factors aforementioned are also
common in the development of depression.

21. Genetic factors
 Patients with chronic pain have more first degree
relatives with depression compared with the
general population.
 Significantly higher rates of depression have
been found in family members even for patients
with chronic pain without a personal history of
depression.

22.  According to a previous human genetic
study, the galanin-2 and mu opioid receptors are
plausible candidates for mediating the effects of
pain on mood.

23.  In addition, a recent study found that
serotonin 1A receptor (5HTR1A) and
serotonin 2A receptor gene promoter
variations have gender-dependent
modulatory effects on depression and
physical function in patients with pain.
 Furthermore, that study demonstrated that
pain after lumbar surgery modulates the
association between 5HT gene
polymorphisms and depression.

25.  The physiological pathway of pain. FC: frontal
cortex, PSC: primary sensory cortex, HT:
hypothalamus,CC: cingulated cortex, AMD:
amygdala, MTN: medial thalamic nuclei, LTN:
lateral thalamic nuclei, FNE: free nerve ending.
The whole process of perception of pain is
following: Transduction → Transmission (central
sensitization) → Modulation → Perception.

28. Pain pathways and biochemical
findings
 The CNS pathway responsible for inhibition of pain
sensation includes projections from brainstem nuclei
to the spinal cord dorsal horn via the dorsolateral
funiculus (DLF).
 More specifically, DLF fibers are comprised of
serotonergic projections from the raphe nuclei,
dopaminergic projections from the ventral
tegmental area (VTA), and noradrenergic
projections from the locus coeruleus.

29. The neurotransmitter pathway
story
Adapted from References:
1. Stahl SM. J. Clin Psych. 2002;63:203-220.
2. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.
3. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.
Dysregulation of Serotonin (5HT)
and Norepinephrine (NE) in the
brain are strongly associated
with depression
Dysregulation of 5HT and NE in
the spinal cord may explain an
increased pain perception
among depressed patients1-3
Imbalances of 5HT and NE may
explain the presence of both
emotional and physical
symptoms of depression.
Descending Pathway
Ascending
Pathway
Ascending
Pathway
Descending
Pathway

30. The Link Between
Depression and Chronic Pain
 Serotonin (5-HT) and
norepinephrine (NE)
are key mediators of
mood in the brain
 5-HT and NE are
key modulatory
neurotransmitters in
the descending pain
pathway and are part of
the body’s endogenous
analgesic system
Opiates
–
Cortex
Lateral Hypothalamus
Thalamus
Amygdala
Medulla
NE
5-HT –
GLU
Substance P +
GABA
Interneuron – Nociceptor
A
A, c

31. What is more important,
serotonin or NE?
Depression
• TCA’s, SSRI’s, and
mixed reuptake inhibitors
are equally effective.
• Choice of medication
depends on side-effects,
patient preference, cost.
Nelson et al. Biol Psych 1999; Williams
et al. Ann Int Med 2000; Hansen et al.
Ann Int Med 2005.
Pain
• NE is more important
• Mixed reuptake
inhibitors are more
effective than SSRI’s
≠
Sindrup et al. Pain 1999;
Fishbain et al. Pain Med 2000;
Yokogawa et al. Anesth Anal 2002.

32. Noradrenergic system
 Dysfunction of the central noradrenergic system has
been hypothesized to play a role in the
pathophysiology of MDD, based upon evidence of
decreased norepinephrine metabolism, increased
activity of tyrosine hydroxylase, and decreased
density of norepinephrine transporter in the locus
coeruleus in depressed patients.
 In addition, decreased neuronal counts in the locus
coeruleus, increased alpha-2 adrenergic receptor
density, and decreased alpha-1 adrenergic receptor
density have been found in the brains of depressed
suicide victims post-mortem.

33. Biogenic amines have been important in
hypotheses of mood disorders
 The catecholamine hypothesis of depression
was an important organizing step that helped to
define modern biological research in psychiatry.
 It states that depression is caused by a
functional deficiency of catecholamines,
particularly norepinephrine (NE), whereas
mania is caused by a functional excess of
catecholamines at critical synapses in the brain.

34. SNRIs
 Some people love SNRIs because they experience
more relief from depression when norepinephrine
levels are increased.
 There is evidence to support the idea that low
norepinephrine could play a role in contributing to a
person’s depression.
 Some people respond very well to the SNRI class,
while others experience a backlash of unwanted
side effects.

35. a crucial role of dopamine
neurotransmission
 That study found a crucial role of dopamine
neurotransmission in terms of pain-related
depression of behaviour, pain-related
depression of mesolimbic dopamine release and
role of endogenous dynorphin/κ-opioid receptor
systems.

36.  Dopamine release was blocked by both
NSAID and opioid analgesics, indicating the
potential relationship of opioid with affective
dimensions of pain.
 Alteration of mesocorticolimbic prodynorphin
expression by noxious stimulus.

37.  In a study with pramipexole, a dopamine
receptor agonist, for the treatment of
fibromyalgia.

38. Brain-derived Neurotrophic Factor (BDNF),
Stress, and Neurogenesis in the Adult Brain
 Neurogenesis (the birth of new neurons) continues postnatally and
into adulthood
• BDNF is associated with production of new neurons and their growth
and development1
 The hippocampi appear to have important functions related to both
mood and memory
• Data suggest that neurogenesis occurs in the hippocampus2
• Data from depressed patients have shown reduced hippocampal
volume3
 BDNF influences regulation of mood4 and perception of pain5
 BDNF is downregulated in MDD and increased with successful
antidepressant treatment4
 Both 5-HT and NE are believed to play roles in the modulation of
BDNF1
1. Duman et al. Arch Gen Psychiatry 1997;54(7):597-606.
2. Gould E. Neuropsychopharmacology 1999;21(2 suppl):46S-51S.
3. Sheline et al. Proc Natl Acad Sci USA 1996;93(9):3908-13.
4. Shimizu et al. Biol Psychiatry 2003;54(1):70-5.
5. Duric and McCarson. Neuroscience 2005;133(4):999-1006.

39. The Monoamine Hypothesis of Gene Action:
The Impact of Stress on BDNF
Stahl. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:187.
Preprinted with permissions from Cambridge University Press.

40. Pain and Stress Lower BDNF Gene
Expression in Animal Models
*p<.05 compared to control
Duric and McCarson. Neuroscience 2005;133(4):999-1006.
0
2
4
6
8
PgBDNFmRNA/ng-actin
mRNA
Control Acute
Stress
Chronic
Stress
* *
Formalin
Acute and Chronic Stress
0
2
4
6
8
PgBDNFmRNA/ng-actin
mRNA
Control 2:45h 24h
*
*
6h
*
10-Day
CFA
*
Acute and Chronic Pain
Changes in Hippocampal BDNF Synthesis

43.  These descending fibers suppress pain
transmission at the nociceptive spinal cord
neurons presumably by hyperpolarizing
afferent sensory neurons using endogenous
opioids, or serotonin and norepinephrine as
principal inhibitory mediators.

44.  The pathophysiology of acute pain is fairly clear,
but chronic pain is still a great enigma, and
includes a number of neurotransmitters (GABA,
glutamate, norepinephrine, serotonin, neurokinin
1, nitric oxide, substance P, glycine and opioids).

45.  Current theories assume that continuous
stimulation of the pain pathways (C-fibres)
leads to overactivation of N-methyl-D-
aspartate receptors in the dorsal horn of the
spinal cord.

46.  For example, patients with pain show reduced
blood flow in the caudate and thalamic areas
involved in the central processing of noxious
signals and elevated concentrations of
cerebrospinal fluid substance P and brain-
derived neurotrophic factor.

47. The potential similarities in biological markers between
pain disorders and depression.

48. Overlapping clinical symptoms
 Patients with pain and depression have
important similarities, as reflected in elevated
levels of depressed mood, alexithymia,
anger, decreased energy and fatigue, cognitive
defect, increased vulnerability to stress, heart
rate variability and sleep disturbance (decreased
REM latency).

49.  Furthermore, the severity of pain is highly
associated with some depression-related
symptoms and impairments such as depressed
mood, fatigue, functional disability, suicidal
ideation, poor daily health status and more
somatic symptoms.

50. The association of pain and depression in
pathophysiology and symptomatology.

52. Depression and Pain
Patients with pain have 2-5 times
increased depression
incidence
Greater risk of depression with:
Multiple pain complaints
Multiple episodes
Severe pain
Patients with pain and depression
have greater:
Pain complaints
Pain intensity
Chronicity
Directionality?

53. Similarities and Differences Between Pain
and Depression in Older Adults

54. Neuroimaging Studies
Many, but not all, of the same brain areas that are
stimulated by physical pain are also stimulated
by:
-Induced sadness
-Social exclusion
-Grief

55. Psychological and Physical Pain
 “I have suffered from severe, recurrent depression for 40
years. The psychological pain that I felt during my
depressed periods was horrible and more severe than
my current physical pain associated with metastases in
my bones from cancer.”
 “I woke up in the middle of the night to use the bathroom
and forgot that my furniture had been re-arranged. I
accidentally tripped over my cocktail table, breaking both
of my legs. The pain that I experience from depression is
so much worse than the pain associated with my
breaking both of my legs.”
 Psychic pain.
Mee et al, J Psychiatric Res2006

56. Physical
Pain
During
Depression

57. Sleep, Pain, and Depression
 50-80% of patients with chronic pain have a
significant sleep disturbance
 Sleep disturbance is one of the cardinal
symptoms of depression
 Insomnia predicts depression onset
 Experimental disruption of slow-wave sleep
increases pain sensitivity
 Sleep deprivation can temporarily relieve
depressive symptoms

58. DepressionPain
Treatment Overlap for Pain and
Depression
“Opium cure” for depression never worked
ECT not effective for chronic pain
Antidepressant response:
-Depression response usually 6-8 weeks
-Pain response usually 3-4 weeks
Noradrenergic drugs have direct analgesic properties
Pure serotonergic drugs have no direct effect on pain
 Doses for pain are roughly ½ of those for
depression

59. Key Similarities and Differences
Human suffering
Sleep disturbance
High placebo response
Brain areas
Human suffering
Prevalence
Neurotransmitters
Medication effects

60. TREATMENT RECOMMENDATIONS
 Ask about pain and about depression
 Ask about pain and depression treatments
 Work to understand effects of mental health on
use of pain treatments
 Do not assume that one problem is causing the
other
 Consider antidepressants for pain and for
depression.

61. Effects of antidepressants and
cognitive therapy
 Despite no evidence for the superiority of one
class of antidepressants in the treatment of pain,
contemporary antidepressants involving
serotonin and norepinephrine activities such
as venlafaxine, duloxetine and milnacipran have
consistently shown the promising effect for
controlling pain among variable psychotropic
agents.

62. Antidepressants:
The Importance of Serotonin and
Norepinephrine in the Treatment
of Depression

63. Beyond Synapse: 5-HT and NE Aid BDNF
Synthesis (Preclinical Evidence)
1. Manji et al. Biol Psychiatry 2003;53(8):707-42.
2. Tsankova et al. Nat Neurosci 2006;9(4):519-25.
= inhibitory┴

64.  In this context, it appears reasonable that all three
major neurotransmitters are related to the
pathophysiology of depression/pain and, as such,
are relevant targets for pharmacological
intervention.
 Triple reuptake inhibitors under development,
which enhance neurotransmission of all three
systems, should be a potential next-generation
therapeutic agent to provide more reliable efficacy
and a quicker therapeutic effect.

65. Ratios of Serotonin to
Norepinephrine Reuptake Inhibition
 Below are different ratios of serotonin to norepinephrine reuptake inhibition. As you can
see, Effexor has the most lop-sided ratio. Newer drugs like Cymbalta and Pristiq slightly
bridged the gap, but still focus more on serotonin than norepinephrine. The latest SNRI
approved for depression called Fetzima favors the norepinephrine, but has almost an
equally balanced ratio.
Venlafaxine – (30:1)
Duloxetine – (10:1)
Desvenlafvaxine – (10:1)
Fetzima – (1:2)
Fetzima (Levomilnacipran)
 Approved in 2013, this is an antidepressant that works as a serotonin-norepinephrine
reuptake inhibitor (SNRI). It contains the “levo” enantiomer of the drug milnacipran and has
similar effects. In comparison to other drugs, this drug provides a more balanced reuptake
of both serotonin and norepinephrine. What makes this drug different from other SNRIs is
that its ratio of reuptake inhibition is almost even (1:2).

66. Non-Antidepressant SNRIs
Sibutramine
 Approved 1998, is an appetite suppressant drug that was initially prescribed
to help treat obesity. Due to the fact that it’s been associated with increased
risk of strokes and cardiovascular problems, it was pulled from the
market in 2010. This drug acted centrally as an SNRI with a distinct
mechanism of action, closely resembling amphetamines.
 It differs from other appetite suppressants (e.g. amphetamines) because it
doesn’t force the release of neurotransmitters, it only prevents their
reuptake.
Savella (Milnacipran)
 Approved 2009, this drug is utilized for the treatment of fibromyalgia. It has
also been approved to treat major depression in countries outside the
United States. This drug inhibits the reuptake of serotonin and
norepinephrine at a ratio of 1:3. The drug Fetzima (Levomilnacipran) which
was approved in 2013 in the United States is very similar to this drug and it
inhibits reuptake at a 1:2 ratio – which is slightly more balanced.

67. Duloxetine and Remission
 MDD: Placebo-controlled studies with 60 mg
duloxetine
 Remission rates of duloxetine vs. other
antidepressants
 Remission rates of duloxetine in special
populations

68. Remission Rates: SSRIs vs. SNRIs
 There is controversy whether the SNRIs
(venlafaxine, duloxetine) are more efficacious
than SSRIs
 The advantage of duloxetine vs. selected SSRIs
has been shown in patients with moderate and
severe depression
Thase. Psychopharmacol Bull 2008;41(2):58-85.

69. Duloxetine Showed Higher Remission Rate than
SSRIs in More Severely Depressed Patients
*p<.05 vs. placebo, ‡p = .034 vs. SSRIs
Remission: HAMD17≤7 at endpoint
Mallinckrodt et al. Neuropsychobiology 2007;56(2-3):73-85.
*
* *
‡
HAMD17 ≤19 HAMD17 = 20-24 HAMD17 ≥25
PatientsAchievingRemission,%
*

70. Duloxetine-treated Patients Achieved Higher
Remission Rate than Those Treated with SSRIs
*p = .034, MMRM-CAT
The secondary endpoint, HAMD17 showed a significant remission; however, the primary endpoint, remission at week
12 by QIDS-SR did not show significant difference
Remission: HAMD17 total score ≤7 at 12 weeks (MMRM-CAT)
Martinez et al. Int clin Psychopharmacol 2012;27(1):17-26.
Estimated probability of remission: Duloxetine vs. Generic SSRIs
*
PatientsAchieving
Remission,%
N = 378 N = 372

71. Be Careful with Opioid Analgesics
 Accidental deaths in US from prescription
opioids exceed deaths from heroin & cocaine
 More deaths in Washington State last year from
prescription opioids than from traffic fatalities!

72. Cognitive Behavioral Therapy (CBT)
 Cognitive behavioural therapy (CBT) with a
focus on cognitive coping strategies and
behavioural rehearsal has demonstrated the
strongest evidence.
 However, currently available most evidence is
for treatments of adult pain but few for
adolescent and older patients with chronic pain.

73. Take Home Message