1. Pain, Anxiety & Depression:
the aches of the psyche
Dr. Ahmed El Missiry
DPP Msc (neuro-psych) MD MRCPsych MISAM, LLB Law
A Professor of Psychiatry – ASUIP – WHO
Consultant Psychiatrist – Kent & Medway NHS
Researcher, Neuropsychopharmacology Department
Zurich Institute of Technology, Switzerland
Regional Representative – Royal College of Psychiatrists (Addiction – KSS)

2. Disclosure In the past three years I received
Honorariums from ApexPharma, Astra Zeneca, BMS, Delta, Janssen Cilag, Lily, Lundbeck, Pfizer, Wyeth
Research grants from ApexPharma
Advisory ApexPharma, Janssen Cilag, Pharmed International

3. The aches of the psyche …
I do not like my state of mind
I'm bitter, querulous, unkind.
I am always anxious and tense
my thoughts make no sense
I dread the dawn's recurrent light;
I hate to go to bed at night.
I find no peace in paint or type
My world is but a lot of tripe.
I'm disillusioned, empty-breasted
For what I think, I'd be arrested.
I am not sick, I am not well
My quondam dreams are shot to hell.
My soul is crushed, my spirit sore;
I do not like me any more.
I want to stop this pain … before I turn insane
Adapted poems

4. Not knowing where he was, his wife inserted her hands under his clothing and said:
“My brother, no fever in your chest and limbs, but sadness of the heart…”
Ebbs Papyrus

5. Greek Mythology
THE ALGEA were the spirits of pain and suffering of both body and mind and are related to Oizys, the goddess of misery and sadness, and Penthos the god of mourning and lamentation.
Mens Sana en Corpora Sana
Decimus Iuvenalis

6. Why Pain, psychological distress (Anxiety and Depression)?
Anxiety, Depression and Pain Symptoms are highly prevalent conditions
Lifetime prevalence of Pain = 24-37%1
Lifetime prevalence of Depression = 5-10%2
Lifetime prevalence of Anxiety= 20%2
Anxiety, Depression and Pain complicate each other, affect outcomes, cause more morbidity and disability and increase costs.
Regier DA, Myers JK, Kramer M, et al. The NIMH Epidemiologic Catchment Area program: historical context, major objectives, and study population characteristics. Arch Gen Psychiatry.1984;41:
Kessler, R.C., S. Zhao, D.G. Blazer, and M. Swartz, Prevalence, correlates, and course of minor depression and major depression in the National Comorbidity Survey. J Affect Disord, (1-2): p

7. “Comorbidity is the rule, not the exception”
Lifetime comorbidity of mood and anxiety disorders
“Comorbidity is the rule, not the exception”
1 Kessler et al, Arch Gen Psychiatry 1995; 2 DSM-IV-TR™ 2000; 3 Brawman-Mintzer et al, Am J Psychiatry 1993;
4 Rasmussen et al, J Clin Psychiatry 1992 ; 5Dunner, Depression and Anxiety 2001
DEPRESSION
48% of patients with PTSD1
Up to 65% of patients with Panic Disorder2
67% of patients with Obsessive-Compulsive Disorder4
42% of patients with Generalised Anxiety Disorder3
Up to 70% of patients with Social Anxiety Disorder5
Panic Disorder
GAD
Social Anxiety Disorder
Post-Traumatic Stress Disorder
OCD
Pain comorbidity= Av 65%
Pain

8. topics today Strength of association (D/R – Predictive)
Can Pain be distressing? What is the prevalence of Anxiety & depression in painful disorders?
Do depression & anxiety hurt? What is the prevalence of pain symptoms in Anxiety & depression?
Does the presence of pain affect recognition and treatment of anxiety / depression?
What is the common neurobiological basis of pain/anxiety/ depression?
What are the treatments available?

9. Can pain be distressing ?!!
The prevalence of depression in pain disorders [1]
In general population pain = 18% (4.7%-22%)
In Primary Care clinics = 27% (5.9%-46%)
In pain clinics = 52% (1.5%-100%)
In orthopedic clinics = 56% (21%-89%)
In dental/facial pain clinics = 85% (35%-100%)
In gynecology pelvic pain clinics = 13% (12%-17%)
Prevalence of anxiety disorders in patients with chronic pain
In general population= 35 % [2]
back pain clinic = 20% - 57% [3,4]
1- Matthew et al Arch Intern Med. ;163: , 2003
2- Manchikanti et al Pain Physician, Volume 5, Number 2, pp , 2002
3- Sommer 18th European Congress of Psychiatry. February 27, March 2, 2010
4- Moya et al Aten Primaria Sep 15;26(4):

10. The likelihood of anxiety and depression increase with the number of painful symptoms
One thousand adult patients
Any Symptom
Depression
Anxiety N
Pain
16 (7)
5 (2)
2 (1)
215
0-1
50 (22)
27 (12)
17 (7)
225
2-3
67 (35)
44 (23)
25 (13)
191
4-5
140 (61)
100 (44)
68 (30)
230
6-8
113 (81)
84 (80)
68 (48)
130 9+
Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care: predictors of psychiatric disorders and functional impairment. Arch Fam Med.1994;3:

11. Increasing pain predicts increased Anxiety & Depression
<0.001
N=448
Requited from Primary care
<0.001
Blozik et al BMC Musculoskelet Disord Jan 26;10:13.

13. Does Depression Hurt?!
The prevalence of pain in depressed ranged from 15% to 100% (mean prevalence, 65%).
Patients With Pain, %
Study Setting
No. of Patients
Source 69
Primary care
573
Bair et al 51
Psychiatric inpatients 29
Delaplaine et al 85
Neurology clinic
432
Diamond 59
Outpatient clinic
Hollifield et al
Private practice
196
Lindsay and Wyckoff
77 Headache
37 chest pain
Research institution
Mathew et al 56
Psychiatric patients
Merskey and Spear 41 22
Pelz et al 65
Depressed outpatients
150
Singhl 43
General practice 28
Vaeroy and Merskey 60 40
von Knorring 57
161
von Knorring et al
100
Respondents to newspaper advertisement 16
Ward et al 15
Watts

14. Chronic Pain in Depression
Does Depression Hurt?!
Chronic Pain in Depression
subjects representative of the general populations of the United Kingdom, Germany, Italy, Portugal, and Spain.
Pain was 4 times more likely in subjects with major depressive disorder (OR 4.0; 95% CI, )
Ohayon & Schatzberg Arch Gen Psychiatry. 2003;60:39-47

15. Does Depression Hurt?! Results from the FINDER study
FINDER was a 6-month prospective, observational study of 3468 outpatients with depression initiating antidepressant treatment.
56.3% experienced mod/severe pain
53.6% had mod/severe pain-related interference with functioning.
Demyttenaere et al (2010) Journal of Affective Disorders –60

16. 43% of depressed patients experienced chronic painful symptoms1
More Depressive Symptoms … more pain
43% of depressed patients experienced
chronic painful symptoms1
Normal mood (n=18,232) 50
Participants with at least 1 depressive
symptom (n=3140) †† 40
Depression – 5 DSM-IV criteria met (n=748) 30
Patients (%) †† 20 †† †† * 10 * †† * * †
Backache
GI disease
Joint/
articular
Headache
Limb ache
 1 Chronic
painful
symptom
Graph adapted from Ohayon MM, Schatzberg AF. Arch Gen Psychiatry 2003;60: 39–47.

17. Are Pain symptoms a marker for depression?
1,042 consecutive outpatients screened for depression
Gerber et al J Gen Intern Med Mar-Apr;7(2):170-3

18. Does Anxiety Hurt?! *** ***
Brandenburg et al. Poster presented at The 25th Annual Conference of the Anxiety Disorders Association of America (ADAA) , March 2005, Seattle, WA, USA

19. Are Pain symptoms a marker for Anxiety?40 30 20 10
33%
31%
28%
26%
anxiety disorders (%)
Prevalence in
Chest pain Abdominal Headache Fatigue
pain
Kroenke K et al. Arch Fam Med 1994;3:774–779

20. Does Pain affect the recognition of Anxiety & Depressive disorders?
More than 50% of depressed or anxious patients presenting with pain are not recognized
Rates of Recognition of Depression and Anxiety
by Style of Clinical Presentation
Recognised by Clinician (%)
Persistent presented with only somatic & did not believe any psychological cause
presented with only somatic symptoms
Initial presented with only 1 somatic
Initial presented with 1 psychological symptom
Kirmayer LJ et al. Am J Psychiatry 1993; 150:

21. Why we can not see the depression and anxiety in pain?
The Central effect
Stahl, 2008

22. Why we can not see the pain in depression?
The Central effect
Stahl, 2008

23. Difficulty concentrating
Why we can not see the pain?
Diagnostic Criterion Bias
Symptom Overlap
Anxiety*
Depression
Anxiety
Worry
Dry mouth
Palpitations
Sweating
Trembling
Blushing
Stuttering
Depressed mood
Loss of interest or pleasure
Appetite disturbance
Worthlessness
Suicidal ideation
Low self-esteem
Agitation
Irritability
Fatigue
Difficulty concentrating
Sleep disturbance
Muscle tension
GI complaints
Pain
*Symptoms of GAD and SAD.
DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.

24. The Spectrum of Symptoms
Why we can not see the depression?
2- Diagnostic Criterion Bias
The Spectrum of Symptoms
Physical Symptoms
Emotional Symptom
Body Aches and Pains
Sadness & Tearfulness
Headaches
Loss of Interest
Tiredness and Fatigue
Anxiety / Irritability
Sexual dysfunction
Hopelessness
GI Changes
Concentration Difficulties
Vasomotor changes
Negative cognitions & Guilt
Suicidal Ideations
Sleep Disturbances
Appetite \wt changes
Psychomotor problems
Adapted from DSM-IV APA 1994

25. Affective Spectrum Disorders associated with pain
2- Diagnostic Criterion Bias
Affective Spectrum Disorders associated with pain
Mood disorders
Major depressive disorder
Dysthymic disorder
Premenstrual dysphoric disorder
Bipolar disorder (especially bipolar depression or mixed)
Anxiety / neurotic disorders
Generalized anxiety disorder
Panic disorder
Posttraumatic stress disorder
Somatization / somatoform pain disorders
Painful Functional somatic disorders
Fibromyalgia
Irritable bowel syndrome
Migraine

26. Stahl, 2008

27. Somatization Vs Psycholization:
Why we can not see the depression?
3- Presentation Bias
Somatization Vs Psycholization:
Cheung (1987) described 3 explanatory models for illness;
psychological,
somatic, or
mixed
In depression:
45-95% Report Somatic symptoms only
50% Report unexplained symptoms
11% Denies depression

28. Depression and anxiety are Often Missed when The Presentation is Physical
Adapted from Kirmayer et al AJP1993

29. The effect of poor recognition on the patient’s treatment
Mistreatment
Under treatment
Decreased treatment efficacy
Polypharmacy
Increase risk of side effects /drug interactions
Increase risk of substance misuse

30. The effect of poor recognition on the treatment outcomes
Increase depression
Increase Pain
Increase functional disability
Decrease quality of Life
Increased Relapse Rates
Decreased Remission Rates
Increase health care utilization
Increase suicide rates

31. Pain is an independent risk factor for suicide [8]
Chronic pain associated with increased risk of suicide [1, 2, 3]
 Rates of suicidal ideation & attempts [4, 5]
Over 30% of chronic pain patients reported suicidal ideation [6]
37% of patients receiving opioid therapy reported suicidal thoughts & 20% an attempt [7].
Mental pain in is associated with   risk of suicide [9].
[1] Fishbain et al Clin J Pain. 1991;7:29–36
[2] Penttinen et al Am J Public Health. 1995;85:1452–1453.
[3] Tang et al Psychol Med. 2006;36:575–586
[4] Breslau et al Neurology. 1992;42:392–395.
[5] Hinkley et al 1994;9:175–185.
[6] Edwards et al Pain. 2006;126:272–279.
[7] Saffier et al. K Journal of Substance Abuse Treatment. 2007;33:303–311
[8] Ilgen et al Gen Hosp Psychiatry. 2008; 30(6): 521–527.
[9] Van Heeringen et al Psychiatry Res Feb 28;181(2):141-4.

32. “For several years I have been aware of my own mortality, for some strange reason it had been on my mind…Since I have had this deteriorating back problem which causes constant pain and …… a barrier of intimacy … . I had two spinal interventions to cure the pain, I had great disappointment when the first failed, and was devastated when the second failed, ….I was told nothing… I have had one hope and now it is gone …. this feels like the sword of Damocles …. How long it will be another day, month, several months? Before I…..”
Jan 2008

33. The biology of Pain Sensory channels: Pain Modulation
Sensory discriminative component
Motivational affective component
Pain Modulation
Spinal Modulation (Gate Theory) Melzack and Wall 1965
Descending inhibitions
Opioid system
5HT system
NE system
Others
Descending facilitation

34. Ascending pathways Motivational Affective pathway
Sensory- Discriminatory pathway
Stahl, 2008

35. Descending Inhibitory System
Opiate
(endorphins)
Serotonin
Norepenephrine
Sympathetic
Descending Inhibitory System + + 
Sub P (NK1,2,3)
VIP (VIPR)
Somatostatin
Calcitonin
GABA
Glutamate
Glycine
NMDA NO
CCK
Stahl, 2008

36. Descending Tracts

37. Possible Explanation: Descending Pathways
PAIN:
Depletion of monoamines
Increase CRF
IL2 – TNF –IL6
DEPRESSION & ANXIETY:
 Endogenous Opiates
 NE -  5HT
 CCK
 Sub-P

38. Distress and pain disorders share the same anatomical sites
executive functions & perceived control over pain
Process information from sensory to emotional (mood & pain)
Rational cognitive functions & pain processing
Associative and episodic memories
memory of emotional reactions
Reward
increases in negative affects

39. Induction of Negative Mood Disrupts Emotion Regulation Neurocircuitry and Enhances Pain Unpleasantness
Negative or neutral moods were induced in healthy volunteers who underwent heat pain whilst in an fMRI scanner.
Pain was rated more unpleasant after the sad mood induction. Depressed mood was associated with increases in negative pain-related cognitions (catastrophizing)
Background: Depressed mood alters the pain experience. Yet, despite its clear clinical relevance, little is known about the cognitive and neural mechanisms underlying this phenomenon. We tested an experimental manipulation to unravel the interaction between depressed
mood and pain. We hypothesized that dysregulation of the neural circuitry underlying emotion regulation is the mechanism whereby pain
processing is affected during depressed mood.
Methods: Using functional magnetic resonance imaging, we compared the effects of sad and neutral cognitive mood inductions on affective pain ratings, pain-specific cognitions, and central pain processing of a tonic noxious heat stimulus in 20 healthy volunteers.
Results: The increase in negative pain-specific cognitions during depressed mood predicted the perceived increase in pain unpleasantness. Following depressed mood induction, brain responses to noxious thermal stimuli were characterized by increased activity in a broad network including prefrontal areas, subgenual anterior cingulate cortex, and hippocampus, as well as significantly less deactivation when
compared with pain responses in a neutral mood. The participants who reported the largest increase in pain unpleasantness after the sad
mood induction showed greater inferior frontal gyrus and amygdala activation, linking changes in emotion regulation mechanisms with
enhancement of pain affect.
Conclusions: Our results informhowdepressedmoodand chronic pain co-occur clinically and may serve to develop and translate effective
interventions using pharmacological or psychological treatment.
Areas that showed increased activity during pain in the depressed mood state - left insula, thalamus, hippocampus, IFG, dlPFC, OFC, and the sACC. The thalamus and the insular cortex are part of the afferent nociceptive network.
dlPFC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus; OFC, orbitofrontal cortex sACC – subgenual anteria cingulate cortex
Berna C et al. Biol Psychiatry 2010;67:

40. Proposed cognitive models
increased negative mood → increased catastrophizing → increased pain unpleasantness
Pain related cognitions
Increased catastrophizing (rumination)
More activity in IFG and amygdalae
induced Negative mood
explains 34% variability
Strong effect
Mechanisitic hypothesis: Dysfunction of emotion regulation
Increased cognitive load
Pain
Increased Pain Unpleasantness
explains 58% variability
No effect
Increased activity in the left IFG, dlPFC and OFC
Change in neural processing in prefrontal areas
Less activity in IFG and amygdalae
Berna C et al. Biol Psychiatry 2010;67:
dlPFC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus; OFC, orbitofrontal cortex

41. Depressed patients seen in primary care
How we can help ?
Increase Awareness Better identification Proper & early treatment for Neuropathic Pain Proper & early treatment for Depression/anxiety
Depressed patients seen in primary care

42. Treatment for Neuropathic Pain
Treatment / control of cause
Alternative treatments (TENS, Acupuncture)
Pharmacotherapy:
NSAID / Pain Killers
SNRIs / TCA
Anti-epileptics
Alpha 2 Delta agonists
Opiate Based preparation !!
TMS
Epidural blocks
Implantable drug pumps
Neurostimulation
surgical interventions
Psychological: CBT for Pain

43. Risk of iatrogenic addiction in patients treated with opioids
A systematic review 41 studies with conflicting findings Risk can be relatively high (>10%) or low (<0.1%). [1]
A systematic review noted the prevalence of [2]
Lifetime SUD 36% to 56%
Current SUD 43%
Aberrant medication-taking behaviours 5% to 24%
Risk factors for opioid abuse in patients with chronic pain are [3]:
young age,
male gender,
past alcohol or cocaine abuse,
previous drug conviction,
mental health disorders,
pain in multiple regions,
pain after MVA
[1] Wasan et al [2] Martell et al 2007
[3] Højsted & Sjøgren

44. Opioid treatment; may need a revisit
A large population-based study found that opioid usage was significantly associated with:
more severe pain,
poorer self-rated health,
lower quality of life,
less physical activity,
lower employment,
higher levels of health care
utilization, and
more subjects living alone
impaired neuropsychological performance
 reaction times, psychomotor speed, and working memory
Højsted & Sjøgren Curr Opin Anaesthesiol Oct;20(5):451-5.

45. 20-30% partial response (Residual symptom).
Treatment of anxiety and depression
(4)
Psychosocial and
occupational
functioning
restored
Aim at Recovery
(3)
Sustained
absence of
symptoms
(2)
Remission of
symptoms
Quality of Recovery
Symptomatic recovery
Syndromal recovery
Functional recovery.
(1)
Response
To treatment
20-30% partial response (Residual symptom).
Road To Recovery

46. Residual Symptoms Predicts Higher Relapse Rates20 40 60 80
100
120 1 2 4 6 8 10 12
Months of Follow-up
Probability of Remaining Well (% )
Remission (n=41)
Residual Symptoms
(n=19)
Rush AJ, et al Psychiatry Ann. 1995; 25: 704

47. What is the impact of pain on treatment?
The challenge in treatment
What is the impact of pain on treatment?
Painful Somatic symptoms may be less responsive to treatment relative to other symptoms
Depressive symptoms
Positive well being
Non painful
Somatic symptoms
Painful Somatic
symptoms
Greco T et al. J Gen Intern Med 2004; 19:

48. Painful symptoms are associated with worse depression outcome
What is the impact of pain on treatment?
the ARTIST Trial
Depression outcome at 6 month for n=573 Treated in primary care
Painful symptoms are associated with worse depression outcome
458 (80%) have pain
190 (33%) mild pain
165 (29%) moderate pain
103 (18%) severe pain
Depressive symptoms
Around 60% adequate treatment was given
DeVeaugh-Geiss ey al Pain Medicine 2010; 11: 732–741

49. How to achieve recovery?
Proper identification & early treatment for Depression
Pharmacotherapy:
SNRIs / TCA
Mood stabilizers (CBZ)
Alpha 2 Delta agonists (pregabalin / Gabalin)
BZD
Pipe Lines: NMDA Antagonists
Somatic Treatment: TMS
Psychosocial:
CBT for Depression, social inclusion & re-habitation

50. What Antidepressant to Use?
Pooled data from Thase et al & Nemerrof et al

51. What Antidepressant to Use in painful depression?

52. What SNRI to use in Painful Anxiety & Depression?
Duloxetine & Venlafaxine are both effective….
-16
-14
-12
-10 -8 -6 -4 -2 1 2 3 4 6 8 10 12
Least Squares Mean Change
Duloxetine (n=318)
Venlafaxine XL (n=330)
Weeks
Duloxetine 60mg OD
Duloxetine 60 -
120mg
Ven 75mg OD
Ven 150mg OD
Ven 150
225mg
Improvement
No significant difference at 6 or 12 weeks
Perahia D et al. Comparing Duloxetine and Venlafaxine in the Treatment of Major Depressive Disorder
Using a Global Benefit-Risk Approach. New Clinical Drug Evaluation Unit (NCDEU) Florida 2005

53. What Antiepileptic to use?
NNT
Anticonvulsant mechanisms of action
Reduction of excitatory amino acid activity
Modulation of
Ca++
Channels
Increase in CNS GABA activity
Decrease in sodium channel activity
Drug
3.3 (2–9.4) +
Carbamazepine
3.7 (2.4–8.3)
+ (?)
Gabapentin
Lamotrigine
3.0 (2.3–4.5)
Topiramate
3.3 (2.3–5.9)
Pregabalin
Vinik J Clin Endocrinol Metab Aug;90(8):

54. Pregabalin
Sibilia Quilici et al BMC Neurology 2009

55. Pregabalin HAM-A score 20 HAM-D score <15 *** *** *** *** *** * **†
*** †
*** †
*** †
*** † * ** * // D4 EP
*P<0.05, **P<0.01, ***P0.001 vs. placebo
†P<0.05 vs. venlafaxine
Telephone assessment on Day 4. Mean baseline HAM-A ~27.5.
Change over time based on MMRM analysis. Endpoint: 8 weeks (LOCF, ANCOVA)
Herman et al. CINP 2008

56. Ά2δ(pregabalin) TCA - Miratzepine Treatment
SSRI ??
SNRI
Ά2δ(pregabalin)
TCA Miratzepine
CBZ – Lamotrogine – Tiagabine

57. What other interventions to use?
Psychological
Uses
Behavioural
Increase exercise/activity levels; overcome fear–avoidance
Cognitive-behavioural
Reduce depression and anxiety associated with pain; develop effective coping strategies; reduce problematic cognitive styles.
Interpersonal
Address role transitions due to pain; relationship difficulties/conflicts
Adjunctive techniques
Biofeedback
Muscle relaxation; control of physiological parameters contributing to pain (e.g., headache)
Guided imagery
Relaxation; distraction from pain
Hypnosis
Relaxation; pain severity reduction; distraction
Progressive muscle relaxation
Muscle relaxation; distraction from pain

58. Conclusion:
Despite the frequent coexistence of depression , anxiety and pain the magnitude and implications of that relationship are still unclear.
Neglecting the treatment of fatigue, low energy , and painful physical symptoms in depressed patients can lead to unsatisfactory outcomes, characterized by a failure of depressed patients to return to normal social and occupational functioning.
Keller MB et al 1992 , Judd LL et all 1998, Angst J 1992and Kupfer DJ 1991; Sheline YI et al 1996; Blier P et al. 2001

60. THANKS Dr. Ahmed El Missiry A Professor of Psychiatry – ASUIP – WHO
DPP Msc (neuro-psych) MD MRCPsych MISAM, LLB Law
A Professor of Psychiatry – ASUIP – WHO
Consultant Psychiatrist – Kent & Medway NHS
Researcher, Neuropsychopharmacology Department
Zurich Institute of Technology, Switzerland
Royal College of Psychiatrists Regional Representative KSS – Addiction
Office:
Pagoda CMHC Hermitage Lane, Barming Maidstone.
Kent ME16 9PD
Tel:
Mobile: