Dr.Mahesh Desai- renouned Psychiatrist of Gujarat shares his view on TCA in triad of Depression, anxiety and chronic pain

1. By
Dr. Mahesh R. Desai

2.  How many of you feel that psychiatrists can be of help
in treating patients of various chronic pain disorders?
 How many of you feel that patients are not ready to go
to psychiatrist and you fear losing them?
 How many of you feel that psychiatric patients are
demanding and time consuming and you don't want to
see them again?

3.  NSAIDS and other newer pain killers.
 Opioids group of drugs.
 Benzodizepines and other muscle relaxants.
 Various antidepressants drugs.

4.  Tricyclic compound
E.g: amitryptyline, amoxapine, clomipramine, doxepine, dotheipine,
desipramine, imipramine, nortryptyline,protryptyline,trimipramine.
 SNRI:- duloxetine, venlafexine, desvenlafexine,levo- melanacipram.
 SSRI:- citalopram, escitalopram, paroxetine, fluoxetine,
fluoxamine, sertralline.
 Tetracyclic group:- meprotyline.
 Dopamine reuptake blocker:- bupropion.
 5HT1A receptor antagonists:- vilazodone.
 5HT2 receptor antagonists:- nafazodone,trazadone.
 5HT3 receptor antagonists:- vortioxetine.
 Noradrenergic antagonists:- mirtazapine.

5. Which of the following Tricyclic Antidepressants may
be used to break the triad of depression, anxiety and
chronic pain?
A. Amitriptyline
B. Nortriptyline
C. Doxepin
D. Dothiepin (Dosulepin)
E. All of the above

6.  The IASP currently defines chronic pain variously
as
 “pain without apparent biological value,” pain “that
has persisted beyond the normal tissue healing time . . .
as determined by common medical experience,”
 and (or) as
 “a persistent pain that is not amenable, as a rule, to
treatments based upon specific remedies.”

7.  International association for study of pain has defined
pain as " unpleasant sensory and emotional experience
associated with actual or potential tissue damage or
described in terms of such damage".

9. CHRONIC PAIN Commonly associated with
presence of inflammation
due to inflammatory
mediators, immunoactive
substances at the site of
injury
Local actions
and can result
in a more
generalized
response that
leads to a
chronic pain
condition.
Mediators Inflamm. 2013; 2013: 340473.
Opening of
voltage-gated
sodium channels
(VGSCs) that are
crucial for
central and
peripheral
sensitization and
the excitability of
neurons in the
CNS and PNS
A complex
neurobiological
phenomenon

10.  NE and 5-HT have been implicated in the underlying patho-
physiology of chronic pain
 Pain originates in the primary sensory neurons and terminates
in the dorsal horn of the spinal cord.
 In the dorsal horn, pain signals activate many brain structures
through the ascending pain pathway
 The final result is pain manifesting clinically.
 A dysfunctional 5-HT or NE system in the spinal cord is likely
to have a dysfunctional descending 5-HT or NE pathway, which
explains co morbid pain symptoms in patients with depression
 TCA also works on serotonin release and uptake in mast cells
in periphery.

11.  Chronic pain is a large and growing public health problem and is
generally associated with physical, psychological, social and
cultural risk factors. (Raghuram Janki Raman)
 Chronic pain reported in 17% of males and 20% of females.
 Costly medical phenomenon
 According to Jackson and st.onge management of pain disorders
in U.S. exceeds 100 billions $, which includes medical care ,
workers compensation, lost work productivity.
 15%U.S. population affected with neuropathic pain- Wolfe and
Trivedi, Barrett et, al (2007) found that the average annual cost of
pain medications per diabetic pt with peripheral neuropathy is
1000 dollars or so.
 Co- morbid depression 57% patient with pain have substantially
increased risk of depression anywhere from 2-5 times that of
general population.

12.  Prevalence of depression among pain patients in psychiatry
clinics 35%
 In pain clinics 38%
 Rheumatology clinic 52%
 Dental clinic 78%
 Unfortunately both remain under recognized and under
treated in general population.
 Most common hypothesis-
a) Depression precedes pain,
b) Pain precedes depression,
c) Prior depression heightens the risk of subsequent
depression in new onset of pain,
d) Few phenomenon occur independently.

13.  Following different types of pain can be distinguished:
 Nociceptive pain- caused by any lesion or potential tissue
damage.
 Inflammatory pain due to inflammatory processes.
 Neuropathic pain induced by a lesion or disease affecting the
somato-sensory system.
 In the absence of a neurological disorder or peripheral tissue
abnormality, the concept of fourth pain category ( functional/
dysfunctional) has been introduced supported by the existence
of any abnormal central operation of inputs leading to pain
hypersensitivity e.g.:- IBS, fibromyalgia , tension headache.

14.  In chronic pain syndromes the activation of multiple
path I physiological mechanisms lead to a shift
towards hyperexcitability of the somatosensory
system.
 Chronic pain is not a pure nociceptive physical
experience but involves different dimensions of
humans as- affect, cognition, behavior as social
relations, convergence of multiple activated system
with reciprocal influences.

15.  Chronic pain = Pain which has persisted beyond normal healing time taken
in the absence of other criteria to be 3 months
 Major depression and dysthymia occur in 50% and 75% patients with chronic
pain
 Anxiety, depression and cognitive states such as catastrophisation are also
associated with a heightened experience of pain through inhibition of
modulatory pathways
 Patients with neuropathic pain do not always respond to standard analgesics such
as NSAIDs, or at times even opioids
 The best studied and in longest use drugs are antidepressants and
anticonvulsants.

16.  Shared clinical features : fatigue, cognitive complaints,
functional limitations, sleep disturbance, anxiety.
 They share common neuro- biological pathways.
 Associated multiple somatic complaints e.g.,
forgetfulness, difficulty in concentration. Patient
complaining about other areas of life impacted by
pain.
 Changing pain, patient coming with thick files, all
investigation done, doctor shopping, this should give
you a hint about co-morbid depression.
Current psychiatry, Chronic pain and depression volume .15 no. 3141

17.  OA, RA
 Low Back Pain
 Chronic regional pain syndrome
 Headache
 Myofascial pain syndrome
 Chronic Neurological pain syndrome
 Neuropathic pain , neuralgia
 Diabetic neuropathy
 Chronic visceral pain syndrome

18. The STOP-PAIN Project
o Evaluated the burden of chronic pain in 728 people
o 82% endorsed symptoms of depression (as measured by the
Beck Depression Inventory), with :
 about 56% reporting moderate to extremely severe levels
and
 34.6% reporting suicidal ideation.
o All of the anxiety disorders in both surveys were significantly
more likely to occur in people with neck and (or) back pain than
in people without.
Can J Psychiatry. 2015 Apr; 60(4): 160–167.

19. Psychology Today: 2014

21.  Due to the role of serotonin and norepinephrine in pain
transmission, TCAs are commonly used to treat several
types of pain 1
 Several organizations suggest that TCAs are effective in the
treatment of :-
 Neuropathic pain
 Pain accompanied by insomnia, depression, or anxiety
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e. New
York, NY: McGraw-Hill; 2016

22. ACOEM: American College of Occupational & Environmental Medicine Guideline 2014
ASA/ASRA: AmericanScoiety of Anaesthelogist/ American Society of Regional Anaesthesia &Pain Medicine
ACOEM 2014 Norepinephrine adrenergic reuptake blocking antidepressants are
listed as examples of first line medications for pain therapy.
Does not specify which TCA(s) to use
ASA/ASRA 2010 TCAs should be used as part of a multimodal approach for a
variety of patients with chronic pain.
Does not specify which TCA(s) to use, but lists the following as
examples: amitriptyline, nortriptyline, desipramine, imipramine.

23. ASIPP 2012 In patients with neuropathic pain resistant to opioids, TCAs in combination with higher
opioid doses may be needed.
Does not specify which TCA(s) to use.
CDC 2016 TCAs are first-line agents for neuropathic pain.
Newer formulations (e.g., nortriptyline and desipramine) have better side effect profiles
compared to older formulations (e.g., amitriptyline and imipramine). Dosing varies by
agent, but low dosages (e.g.,
ICSI 2013 TCAs are recommended for treatment of neuropathic pain, especially in patients with
coexisting insomnia, anxiety, or depression.
Tertiary and secondary amines are effective, but tertiary amines are associated with more
anticholinergic side effects and should be avoided in elderly patients.
Nortriptyline and desipramine are listed as examples of secondary amines; amitriptyline
and imipramine are listed as examples of tertiary amines.
Analgesia may be seen at lower doses than those recommended for treatment of
depression; TCAs should be initiated at low doses; doses should be gradually increased over
several weeks to months.
ASIPP: Association Society of Interventional Pain Physician
CDC: Center for Disease Control & Prevention

24. NICE: National Institute for Health & Clinical Excellence
AAN 2011 Amitriptyline should be considered for treatment of painful
diabetic neuropathy. There is insufficient evidence to support
or refute the use of desipramine, imipramine, or the
combination of nortriptyline and fluphenazine in the
treatment of painful diabetic neuropathy
Canadian Pain
Society 2014
TCAs are first-line agents for chronic neuropathic pain. If
patients fail TCA monotherapy, combination or mono-therapy
with a gabapentinoid or SNRI (e.g., duloxetine) may be
considered
NICE 2013 NICE recognizes TCAs as examples of commonly used
pharmacological treatments for neuropathic pain.

25.  Prior to the initiation of antidepressant treatment for
chronic pain, the potential for adverse effects caused
by antidepressants should be carefully considered
 The benefits should outweigh the risks.
 All antidepressants carry a black box warning detailing
the increased risk of suicidal ideation in children and
adolescents.
 The antidepressant dose should be started low and
slowly titrated up while monitoring for adverse effects

26. LOW+ Moderate ++ High +++
Antidepress
ants
Efficacy Evidence
based
support
Dose Side effect
loading
Amitryptylin
e, doxepine,
imipramine.
Yes +++ Low to
standard
+++
Venlafexine Yes ++ Standard +
Duloxetine Yes ++ Standard +
Bupropion Yes + Standard +
Desipramine,
nortryptyline
.
Yes ++ Low to
standard
+++
Paroxetine,ci
talopram
Modest + Standard +
Fluoxetine No - Standard +

27. Drug
therapy
Diabetic
polyneuropat
hy
Posttherpeti
c neuralgia
Trigeminal
neuralgia
Chronic
regional
pain
syndrome
First line Duloxetine,ga
bapentin,preg
abalin,TCA,
venlafexine.
TCA,gabapen
tin,pregabalin
,5%lignocaine
patch,emla
patch
Carbamazepi
ne
Gabapentin,
pregabalin,
TCA,duloxeti
ne
Second line or
thirdline
Tramadol,tap
entadol SR.
Tramadol,tap
entadol SR
Baclofen,lamo
trigine.
NSAIDS,oral
prednisone,
bisophosphon
ates
Others( bz of
the associated
dependence
in long term
therapy)
Opioids Opioids Topical
capsaicin, iv
lignocaine
,opioids

28. Gabapentin 300-1200 mg thrice a day
Pregabalin 50-300 twice a day
Carbamazepine 100--600 mg twice daily
Amitryptyline 10-75 mg at night
Duloxetine 30-90 mg a day
Venlafexine 150-225 mg a day
Tramadol 50-400 mg a day
Tapentadol SR 50-250 mg twice a day
Morphine,oxycodone Start 5 mg a day and titrate gradually.
5% lignocaine patch/EMLA patch Apply to affected area for 12hours per
day ( trigeminal neuralgia)

29. Recent evidence based
guidelines.
 TCA first choice of treatment along with
gabapentine and pregabalin.
 SNRI duloxetine and venlafexine second choice.

30. Type of
pain
TCA SSRI Carbama
zepine
Casaocin Gabapen
tine
Tramado
l
Diabetic
neuropathy
1.4 6.7 3.3 5.9 3.7 3.4
Peripheral
nerve
injury
2.5 - - 3.5 - -
Post-
herpetic
neuralgia
2.3 _ 3.4 5.3 3.2 _
Central
pain
2.5 - 3.4 - - -

31. Medications Pain NNT NNH
Group 1(non-
addictive)
Acute pain
‘nociceptive'
Paracetamol
4g/day
Arthritis pain
Post surgical pain
4-5
1.7
12(GI SEs)
NSAIDS
-ibuprofen
-meloxicam
- celecoxib
- diclofenac
-ketoprofen
- piroxicam
Acute pain
Topical
Migraine
1.6-4.2
4.5
6-9
(GI SEs)
Low in small dose
Less than oral
NSAIDS
Short- term use

32. Group
2(addictive)
Acute pain '
nociceptive'
Inflammatory
pain
Neuropathic
pain
NNT NNH
-tramadol
(100mg,150mg)
Post surgical 2.4-4.8 8.3
-paracetamol
500mg + codeine
60 mg
Post surgical 2.2
Aspirin 650 mg +
codeine 60mg
Post-surgical 3.6
Paracetamol 650 mg
+ propoxyphene
100 mg
Post surgical 4

33. Group 3( non-
addictive)
Neuropathic
pain
NNT NNH
Amitriptyline Neuropathic
pain
3.6 6
Pregabalin Diabetic
neuropathy
2.9 3.7
Gabapentin Post herpetic
neuralgia
Central
neuropathic
pain
Fibromyalgia
3.9
5
13-22
Venlafexine Neuropathic
pain
3.1 16.2
Duloxetine Neuropathic
pain
6-8 9.6

34. Group-
4(addictive)
Acute pain'
nociceptive'
Inflammatory
pain
Neuropathic
pain
NNT NNH
Opioids(
morphine),oxyco
ntin,buprenorph
ine,fentanyl)
Acute pain
Neuropathic
pain
2.5-4.3 4.2(nausea,const
ipation)
7.1(dizziness,
vomiting)

35. • On a dichotomous outcome fluoxetine was less effective than
dothiepin (Peto OR: 2.09, 95% CI 1.08 to 4.05),
• In head-to-head comparisons, only dothiepin was found to be
significantly more effective than fluoxetine (Peto OR: 2.09, 95% CI 1.08
to 4.05).
• No statistically significant differences between
 Fluoxetine and TCAs, and
 Between fluoxetine and individual comparator ADs were found on
continuous outcome (overall SMD random effects: 0.07, 95% CI - 0.06 to
0.20).
 Dothiepin was better tolerated than fluoxetine (Peto OR: 1.44, 95% CI
0.98 to 2.12).

36.  Take a good history , real like it was taught in
undergraduate days .
 Minimum basic medical work up and good
explanation about illness in layman's word.
 Master one or two drugs from psychotropic drug
basket and learn to use them judiciously.
 Encourage them to continue their life with lifestyle
changes ( exercise, yoga, meditation).
 Explain about time lag of 1-3 weeks in all
antidepressants and explain common side effects
which starts first.

37.  Below 45 with no co- morbid medical or cardiac
problem- TCA
 Which TCA:
 Between all TCA 's for your purpose dotheipine -- because of better
tolerance and we can push it to optimum dose of 150 mg.
 If there is no depression you can give it up to 75-100 mg
 Common side effects include dryness of mouth, constipation,
difficulty in urination, tachycardia, giddiness, sedation, etc.

38.  Those above 45 or with co- morbid cardiac or medical
problem use duloxetine, dose 40-60mg.
 40mg for pain and 60mg for co- morbid depression.
 Common side effects include nausea,vomiting,
headache, perspiration.
 You can also use long acting benzodizepines( like
dizepam,chlordizepoxide) ,clonazepam etc for not
more than 4-6 weeks.

39.  moderate to severe depression with co morbid issues
like drug dependence, stressful life events, suicidal
ideas or even gestures.
 All those who attempt suicide must be screened by
psychiatrist.
 Resistant to pharmacological intervention- 6 to 12
weeks trial on adequate dose of one or two different
antidepressants.
 Patients in need of psycho- therapeutic intervention.

40.  Pain is pain ,whether real or imaginary - don't label it as
malingering.
 Don't go for extensive, expensive investigations for some rare
disorder.
‘You will lose the patient to other pathies.’
 Don't tell it is all in mind, remove it or we will send you to
mental hospital.
 Don't give benzodizepines for more than 4-6weeks. If at all
you use than please avoid using alprazolam, lorazepam.

41.  Avoid morphine group of drugs in all disorders of
functions.
 Don't change antidepressants every few days and as far
as possible don't change the brand.
 Avoid frequent follow ups.
 Writing reference to psychiatrist in small letters in one
corner of prescription.

42. Which of the following Tricyclic Antidepressants may be
used to break the triad of depression, anxiety and
chronic pain?
A. Amitriptyline
B. Nortriptyline
C. Doxepin
D. Dothiepin (Dosulepin)
E. All of the above

43. Enjoy your day