Chronic pain is common. Depression often co-exist with chronic pain. This article looks at the pathophysiology, prevalence of chronic pain and depression. The role of TCA, especially dosulepin and amitriptyline has been discussed.

1. Chronic pain: Core
concepts and TCAs
DR SUDHIR KUMAR MD (Med) DM (Neuro)
CONSULTANT NEUROLOGIST
APOLLO HOSPITALS, KUKATPALLY/JUBILEE HILLS
(HYDERABAD)

2. Consensus statement on Role of tricyclic
Antidepressants in chronic neuropathic pain In India
Endorsed by
Indian society for the study of pain (Indian chapter for the study of chronic
pain)

3. Existing Guidelines in Neuropathic Pain
Mechanism and Pharmacokinetics of
Tricyclic Antidepressants: The
Number Needed to Treat and
Number Needed to Harm
Current Status of Tricyclic Antidepressants
in Tension-type Headache.
Adverse Effects of Tricyclic
Antidepressants
Tricyclic Antidepressants in Cancer Pain
and Chemotherapy-induced
Neuropathic Pain
Tricyclic Antidepressants in Painful
Polyneuropathy
Persistent Idiopathic Facial Pain and
Trigeminal Neuralgia
Central Neuropathic Pain Syndromes
Current Status of Tricyclic Antidepressants in
Post-surgical, Post-traumatic and
Phantom Limb Pain
Drug Interactions of Tricyclic Antidepressants
with Various Other Analgesics used in
Chronic Pain and Cancer Pain
1
2
3
4
5
6
7
8
9
10
Salient Features Mentioned in the
Guidelines

4. Objectives
To effectively and responsibly prescribe TCAs and enhance the quality of
life, in patients of chronic neuropathic pain in India
Tricyclic antidepressants is one of the foremost and first-line Therapies being
prescribed for management of chronic neuropathic pain across the globe
But there are no current best practice drug status Guidelines on TCA drug
class in India, and hence this is an initiative To put a consensus-based
review on the same, with regard to pain practices in India

5. Introduction
Kodiath MF. A Comparative Study of Patients with Chronic Pain in India and the United States. Clin Nurs Res August 1992 vol. 1 no. 3 278-291
Pain is the most frequently reported symptom in the health care
industry today
Chronic pain in the US costs millions of dollars annually, and its
financial impact is mounting
Affects nearly all normal activities and often leaves the person
feeling helpless and hopeless

6. Pain: Good or bad ?
 Not all pain is a disease
 Protector to us most of the time.
 Acute pain constitutes a signal to a conscious brain about the
presence of noxious stimuli and/or ongoing tissue damage.
 This acute pain signal is useful and adaptive, warning the
individual of danger and the need to escape or seek help.
JL Henry. The need for knowledge translation in chronic pain. Pain Res Manage 2008;13(6):465-476.

7. Chronic pain as a disease !
Pain is a major healthcare problem worldwide.
Although acute pain may reasonably be considered a
symptom of disease or injury, chronic and recurrent
pain is a specific healthcare problem, a disease in its
own right
- The European Federation of International
Association for the Study of Pain Chapters

8. Chronic pain - Definition
Smith BH. Chronic pain in primary care. Fam Pract. 1999 Oct;16(5):475-82.
The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant
sensory and emotional experience with actual or potential tissue damage or described by
patients in terms of such damage’
The IASP defines chronic pain as ‘pain which has persisted beyond normal tissue healing
time’, taken in the absence of other criteria, to be 3 months

9. Chronic pain - Prevalence
 In a random survey of 2012 Canadians, chronic pain was
reported by 29% of respondents, with increased frequency in
women and older age groups.
 The average duration of pain was 10.7 years
 The average intensity was 6.3 on a 10-point scale
 Almost 70% of those reporting pain were worried about
addiction
Moulin DE, Clark AJ, Speechley M, Morley-Forster PK. Chronic pain in Canada – prevalence, treatment, impact and the role of opioid analgesia.
Pain Res Manage 2002;7:179-84.

10. Chronic pain - Causes
 Chronic pain can arise from sundry causes.
 Some of the more common types of chronic pain include
those of
 Osteoarthritis, rheumatoid arthritis
 Low back
 Shoulder and neck
 Headache (including migraine)
 Myofascial pain syndromes
 Chronic regional pain syndromes
 Stump and phantom limb pain
 Neuropathic pain, herpes zoster (shingles) and postherpetic
neuralgia, trigeminal neuralgia
 Diabetic neuropathy
 Chronic visceral pain syndromes, and others.
JL Henry. The need for knowledge translation in chronic pain. Pain Res Manage 2008;13(6):465-476.

11. Chronic Pain - Pathophysiology
The mediators of pain
 H+
 K+
 Substance P
 Bradykinin
 5HT
 Phospholipids &
Prostaglandins
Harrison's Principles of Internal Medicine (17th Edition).New York, NY, USA: McGraw-Hill Professional Publishing, 2008.

12. Pain transmission and
modulatory pathways
Harrison's Principles of Internal Medicine (17th Edition).New York, NY, USA: McGraw-Hill Professional Publishing, 2008.
A. Transmission system
for nociceptive messages.
B. Pain-modulation network

13. Ascending pain pathways

14. Circuit of pain modulatory
pathway.
Marks DM. Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise. Current Neuropharmacology, 2009, 7, 331-336

15. Chronic pain processes
 Neurogenic inflammation
 Damaged nerve
 Sensitization
 Loss of nociceptive control
 Mental overload
Whitten, Christine, MD, Donovan, Marilee, RN, PhD, Cristobal, Kristene, MS.
Treating Chronic Pain: New Knowledge, More Choices. Clinical Contributions.
The Permanente Journal. Fall 2005. Vol. 9. No. 4. Retrieved: January 15,
2006 from: http://xnet.kp.org/permanentejournal/fall05/pain3.html.

16. Chronic pain mechanisms
Whitten, Christine, MD, Donovan, Marilee, RN, PhD, Cristobal, Kristene, MS. Treating Chronic Pain: New Knowledge, More Choices. Clinical
Contributions. The Permanente Journal. Fall 2005. Vol. 9. No. 4. Retrieved: January 15, 2006 from: http://xnet.kp.org/permanentejournal/fall05/pain3.html.

17. Factors that increase pain
 Physical
 Chemical
 Behavioural
 Thoughts and emotions
 Structural
Whitten, Christine, MD, Donovan, Marilee, RN, PhD, Cristobal, Kristene, MS. Treating Chronic Pain: New Knowledge, More Choices. Clinical
Contributions. The Permanente Journal. Fall 2005. Vol. 9. No. 4. Retrieved: January 15, 2006 from: http://xnet.kp.org/permanentejournal/fall05/pain3.html.

18. Viscous cycle of pain
Whitten, Christine, MD, Donovan, Marilee, RN, PhD, Cristobal, Kristene, MS.
Treating Chronic Pain: New Knowledge, More Choices. Clinical Contributions.
The Permanente Journal. Fall 2005. Vol. 9. No. 4. Retrieved: January 15,
2006 from: http://xnet.kp.org/permanentejournal/fall05/pain3.html.

19. Chronic pain: Consequences
 Immobility and consequent wasting
of muscle, joints, etc
 Depression of the immune system
and increased susceptibility to
disease,
 Fatigue, disturbed sleep,
 Poor appetite and nutrition
 Dependence on medication
 Overdependence on family and
other caregivers JL Henry. The need for knowledge translation in chronic pain. Pain Res Manage 2008;13(6):465-476.
– Overuse and often inappropriate
use of professional health care
systems
– Poor performance on the job or
inability to work
– Disability
– Isolation from society and family;
and turning inwards
– Anxiety, fear, bitterness, frustration,
depression and suicide
Often sets the stage for the emergence of a complex set of
physical and psychosocial changes

20. Chronic Pain: Mx
 Patient evaluation
 Multimodal or multidisciplinary pain management programs
 Single Modality Interventions
Practice Guidelines for Chronic Pain Management. Anesthesiology 2010; 112:810 –33

21. Patient evaluation
1. Medical records review or patient condition
2. Physical examination
3. Psychological and behavioral evaluation
4. Interventional diagnostic procedures
 Diagnostic facet joint block
 Diagnostic sacroiliac joint block
 Diagnostic nerve block (e.g., peripheral or sympathetic, medial
branch, celiac plexus, and hypogastric).
 Provocative discography
Practice Guidelines for Chronic Pain Management. Anesthesiology 2010; 112:810 –33

22. Multimodal pain management
programs
 Multimodal interventions - use of more than one type of
therapy for the care of patients with chronic pain.
 Multidisciplinary interventions - multimodality approaches in
the context of a treatment program that includes more than
one discipline.
 Effective in reducing the intensity of pain reported by patients
for periods of time ranging from 4 months to 1 yr
Practice Guidelines for Chronic Pain Management. Anesthesiology 2010; 112:810 –33

23. Single Modality Interventions
 Ablative techniques
 Acupuncture
 Blocks
 Botulinum toxin
 Electrical nerve stimulation
 Epidural steroids with or without local anesthetics
 Intrathecal drug therapies
 Minimally invasive spinal procedures
 Pharmacologic management
 Physical or restorative therapy
 Psychological treatment
Practice Guidelines for Chronic Pain Management. Anesthesiology 2010; 112:810 –33

24. Pain and Depression
Cause or effect?
 A growing body of literature has focused on the
interaction between depression and pain symptoms.
 Labeled by some authors as the depression-pain
syndrome or depression- pain dyad, implying that
 The conditions often coexist
 Respond to similar treatments,
 Exacerbate one another, and
 Share biological pathways and neurotransmitters.
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

25. Pain and Depression
Some questions to be answered……
 What is the prevalence of pain symptoms in patients
with depression and, conversely, what is the prevalence
of depression in patients with pain complaints?
 Does the presence of pain affect provider recognition
and treatment of depression?
 Does the presence of pain affect depression outcomes
such as functional limitations, quality of life, health care
costs and utilization, and treatment efficacy?
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

26. Pain and Depression
Some questions to be answered……
 Does the presence of depression affect these same
clinical outcomes in patients treated for pain?
 Is antidepressant treatment for painful symptoms and
comorbid depression effective?
 What are the common biological pathways and
implications for treatment choice when depression and
pain coexist?
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

27. What is the prevalence of pain symptoms in
patients with depression?
 The prevalence of pain ranged from 15% to 100% (mean
prevalence, 65%).
Pain symptoms in patients with depression
69
51
85
59 59 56
41
65
43
0
10
20
30
40
50
60
70
80
90
1
Patientswithpain%
Primary care Psychiatric inpatients Neurology clinic
Outpatient clinic Private practice Psychiatric patients
Psychiatric patients Depressed outpatients General practice
Bair MJ. Depression and pain comorbidity.
Arch Intern Med. 2003;163:2433-2445

28. What is the prevalence of pain
symptoms in patients with
depression?
 Depressive symptoms predict future episodes of low
back pain, neck-shoulder pain, and musculoskeletal
symptoms
 Low back pain is more than 2 times as likely to be
reported by individuals with depressive symptoms
 Specific complaints of headache, abdominal pain, joint
pain, and chest pain are frequently reported by patients
with depression in primary care settings and by elderly
nursing home residents.
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

29. What is the prevalence of depression in
patients with pain complaints?
 Several reviews have examined the prevalence of major depression in
patients with pain.
Prevalence rates for concurrent depression in patients with pain
52
38
56
85
13
18
27
0
10
20
30
40
50
60
70
80
90
1
Patientswithdepression%
Pain clinics Psychiatric clinics Orthopedic clinics
Dental clinics Gynecology clinics Population based settings
Primary care clinics
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

30. What is the prevalence of depression
in patients with pain complaints?
 Patients with multiple pain symptoms are 3 to 5 times
more likely to be depressed than patients without pain
 Subjects with chronic pain are 3 times as likely to meet
depression criteria as those without chronic pain.
 An international study - patients with pain lasting longer
than 6 months were more than 4 times as likely to have
a depressive disorder as those without chronic pain.
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

31. Does the presence of pain affect
provider recognition and treatment of
depression?
 More than 50% of patients with depression report somatic complaints
only.
 At least 60% of these somatic complaints are pain related.
 Patients with depression in primary care settings are more likely to
report various pain symptoms
 The patient’s presentation of physical complaints (and the prominence
of pain symptoms) interferes with the recognition of depression for
patients in primary care settings.
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

32. Does the presence of pain affect
depression outcomes?
 Presence of up to 5 different pain complaints is associated with
increased symptoms of depression.
 Progressive pain severity at baseline is associated with
 Poor depression outcomes, including more severe depression
 More pain related functional limitations
 Worse self-rated health
 Higher unemployment rate
 More frequent use of opioid analgesics, and
 More frequent pain-related doctor visits
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

33. Does the presence of depression affect
clinical outcomes in patients treated for
pain?
 Depression is associated with an array of poor pain
outcomes and worse prognosis.
 Patients with pain and comorbid depression experience
 More pain complaints
 More intense pain,
 More amplification of pain symptoms, and
 Longer duration of pain.
 Unfortunately patients with both conditions were more
likely to have persistent pain and nonrecovery.
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

34. Is antidepressant treatment for painful symptoms
and comorbid depression effective?
Source No. of
patients
Sample Medication Outcome
Pain Depression
Blumer et al 104 Chronic pain TCA 57%
improved
Improved
Hill and
Blendis
27 Non-organic
abdominal pain
TCA 100%
improved
100%
improved
Singh and
Verma
60 Pain, no
etiology
TCA 80%
improved
Improved
Ward et al 36 Chronic back
pain
TCA 50%
improved
70%
improved
Bair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

35. Common biological pathways when
depression and pain coexist?
 Common link between pain and depression could be
associated with two neurotransmitters, 5-HT and NE.
 Both serotonergic and norepinergic pathways from the
brainstem ascend into the brain and mediate numerous
emotional and physical functions.
 They also descend down the spinal cord where they
suppress nociceptive inputs
Williams LJ. Depression and pain: an overview. Acta Neuropsychiatrica 2006: 18:79–87.

36. Antidepressants for chronic
pain !
 Have a genuine analgesic action
 The analgesic efficacy is without any effect on mood in
depressed chronic-pain patients
 The dose required to achieve an optimum analgesic response
is usually lower than that required to achieve an
antidepressant effect
 Variation exists in analgesic efficacy among chemical classes
Mico JA. Antidepressants and pain. Trends Pharmacol Sci. 2006 Jul;27(7):348-54.

37. Analgesic MOA of
antidepressants
Verdu et al. Antidepressants for the Treatment of Chronic Pain. Drugs 2008; 68 (18): 2611-2632

38. Tricyclic antidepressants, produce spinally and supraspinally mediated
analgesia in chronic pain states by mechanisms distinct from those
that enhance mood

39. Analgesic MOA of TCAs
 The various mechanisms of TCAs identified and reported for
their analgesic activity are as follows:
 Potentiation of the suppressant effect of adenosine on central
neurons.
 Blockade of alpha-2 adrenoceptors leading to increased
accumulation of catecholamines (Nor-epinephrine).
 Inhibition of reuptake of monoamines (noradrenaline, serotonin) in
the neurons of the central nervous system.
 Potentiation of the actions of biogenic amines in the central
nervous system by blockade of their major means of physiological
inactivation-reuptake at nerve terminals.
Panda P. Antinociceptive Property of Tricyclic Antidepressants – A Review. International Journal
of Research in Pharmaceutical and Biomedical Sciences. 2011. 2(2); 345-50

40. TCAs Vs SSRIs
 The well known TCAs have the greatest analgesic efficacy
 When TCAs are used as analgesic drugs, their undesirable
effects occur less commonly and are less severe
 SSRIs provide less consistent analgesia as compared to TCAs
Mico JA. Antidepressants and pain. Trends Pharmacol Sci. 2006 Jul;27(7):348-54.

41. Comparative analgesic efficacy
Antidepressants No. of human studies NNT
TCA 23 3.1
SSRI 3 6.8
SNRI 3 5.5
Mico JA. Antidepressants and pain. Trends Pharmacol Sci. 2006 Jul;27(7):348-54.

42. TCAs in treatment of chronic pain
 The TCAs are extremely useful for the management of patients
with chronic pain.
 Analgesic effect of TCAs has a more rapid onset and occurs at
a lower dose than is typically required for the treatment of
depression.
 Furthermore, patients with chronic pain who are not depressed
obtain pain relief with antidepressants.
 There is evidence that tricyclic drugs potentiate opioid
analgesia.
Harrison's Principles of Internal Medicine (17th Edition).New York, NY, USA: McGraw-Hill Professional Publishing, 2008.

43. Painful conditions that respond
to TCAs
 Post herpetic neuralgia
 Diabetic neuropathy
 Tension headache
 Migraine headache
 Rheumatoid arthritis
 Chronic low back pain
Harrison's Principles of Internal Medicine (17th Edition).New York, NY, USA: McGraw-Hill Professional Publishing, 2008.c

44. American Pain Society and American
College of Physicians
 In low back pain (LBP), TCAs have been the most frequently-
tested antidepressants
 TCAs are effective for pain relief in LBP.
 Their analgesic effect has been reported to be similar to that
of NSAIDs.
Dharmshaktu. Efficacy of Antidepressants as Analgesics: A Review. J Clin Pharmacol published online 17 March 2011

45. Pearls for practice
 Pain has traditionally been seen as secondary to something
else –the result is
 undertreated or untreated pain, unnecessary suffering,
 heavier reliance on the health care system,
 loss of productivity in the work force, absenteeism,
 increased comorbidity, and
 a cycle of illness
 Total pain alleviation is the prime goal of pain
management
 Management of any form of persistent pain requires not
only a reduction in pain intensity but also improvement of
quality of life

46. Pearls for practice
 TCAs are extremely useful for the management of patients with
chronic pain
 American Pain Society and American College of Physicians
guidelines state that TCAs are effective for pain relief in low
back pain

47. Dosulepin/Dotheipin
Chemical structure of DothepinChemical structure of Amitriptylline
Dosulepin is a Thio-analouge of amitriptyline.

48. Superiority of Dosulepin over
Amitriptylline
 Better tolerated than Amitriptyline
 Well tolerated in geriatric patients with no cardiac toxicity
 No changes in electrocardiophysiology
Khan A.A study of dothiepin hydrochloride in elderly patients with special reference to cardio
vascular system. Modern geriatrics august 1975

49. Efficacy Of Prothiaden In Depression In Rheumatoid
Arthritis
A phase IV, open, single arm, prospective study was initiated with
dothiepin hydrochloride
Dothiepin 75 mg/day for 6 weeks
Results: 25 Rheumatoid arthritis patients suffering from co-morbid MDD
completed the 6-week dothiepin hydrochoride treatment and were
considered for final analysis
49

50. Efficacy Of Prothiaden In Depression In
Rheumatoid Arthritis
0
10
20
30
40
50
60
70
80
Marked
Improvement
Moderate
Improvement
0
10
20
30
40
50
60
70
80
Good Fair
Percentage
Percentage
Global impression of efficacy at 6 weeks
ASSESSMENTIMPROVEMENT
Overall Assessment of Tolerability
50

51. CONCLUSIONS
 Chronic pain is common in our practice.
 Depression and chronic pain often co-exist
 Tricyclic antidepressant especially Dothiepin is very effective in
chronic pain reduction
 Dothiepin is well tolerated and there are no serious adverse
effects
 Dothiepin treatment is cost-effective too.

52. Knowing is not enough; we must apply.
Willing is not enough; we must do.
– Goethe
Thank You 
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