Chronic pain and depression are both common conditions, and in many patients, they co-exist. This presentation looks at the link between chronic pain and depression. Various drugs that can be used to treat chronic pain/depression have been discussed, with a special emphasis on tricyclic antidepressants.

1. Chronic Pain & Depression
Management: The Hen & Egg
Conundrum
Dr Sudhir Kumar MD DM
Senior Consultant Neurologist
Apollo Hospitals, Hyderabad

2. Chronic Pain
• Pain- a subjective sensory and emotional experience.
• Chronic pain is any persistent or intermittent pain that lasts
more than 3 months.
• Major types
– Neuropathic: a lesion or disease involving the nervous system
– Nociceptive: a consequence of actual or threatened damage to
nonneural tissues
Neural Plasticity, vol. 2016, Article ID 6402942, 9 pages, 2016
Pain, vol. 156, no. 6, pp. 1003–1007, 2015.

3. Pain Pathways
• Ascending pathways
– Fast (red)
– Slow (green)
• Descending (blue)

4. Pathogenesis of
Acute Pain
Marcus D.A. (2009) Physiology of Chronic Pain. In: Chronic Pain. Current Clinical Practice. Humana Press

5. Pathogenesis of
Chronic Pain
Marcus D.A. (2009) Physiology of Chronic Pain. In: Chronic Pain. Current Clinical Practice. Humana Press

6. Depression Pathways

8. Relation between Pain and Depression
• Both brain regions and the neurological function system, whereby chronic pain
may lead to depression
• Depression can cause pain — and pain can cause depression
• 85% of patients with chronic pain are affected by severe depression
• The biological basis for depression has focused on dysregulation of the
neurotransmitters serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine (NE),
and dopamine.
• NE and 5-HT have been implicated in the underlying pathophysiology of chronic
pain
Archives of Internal Medicine, vol. 163, no. 20, pp. 2433– 2445, 2003.
Journal of Neurology, Neurosurgery, and Psychiatry, vol. 74, no. 11, pp. 1587–1589, 2003.

9. Pain and depression
Pain
• One fifth of the general population are affected
• Opioid receptor to relieve patients’ pain
• Opioids have been widely applied to treat various
chronic pains, such as cancer pain, nociceptive pain,
and neuropathic pain.
Depression
• Third leading contributor to the global disease
burden.
• Research suggest that there are three classical
types: μ, δ, and κ receptors, all of which involve in
regulating mood, and some potential mechanisms
have been studied.
• The combined effect of the μ receptor agonist and κ
receptor antagonist was found to have the potential
to reduce the occurrence of dysphoria like
behaviours
• Moreover, the κ receptor antagonist has been
indicated to have a possibly antidepressant effect

10. The neurotransmitters
• Serotonin (5-HT)
• Dopamine (DA)
• Norepinephrine (NE)
• Decreased availability: results in depression
• Vital to the occurrence and development of pain
Pharmacol Ther. 2015 Mar;147:1-11.

11. The neurotransmitters
• Chronic pain significantly damage DA activity in the limbic midbrain
area
• DA found reduced in chronic pain
• Inflammatory response has been shown to cause pain and
depression
• Inflammatory response-mediated pain may be more strongly
associated with depression
Journal of Neuroscience, vol. 35, no. 27, pp. 9957–9965, 2015.
Schizophrenia Research, vol. 118, no. 1–3, pp. 292–299, 2010.

12. The neurotransmitters
• Glutamate functions as one of the main excitatory neurotransmitters in
the CNS and exists in synapses throughout the brain
• Glutamate and its receptor subtypes, n-methyl d-aspartic acid (NMDA)
receptor and α-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid
(AMPA) receptor, have been found to be involved in the occurrence and
development of chronic pain and depression
Neural plasticity. 2017;2017.

13. The neurotransmitters
• Chronic pain and depression and may involve the same brain structures,
neurotransmitters, and signalling pathways
• Benzodiazepines used in treating chronic pains, including neuropathic pain
or inflammatory pain by antihyperalgesic effect of the GABAA
• GABAA receptors, including the α1, α2, α3, or α5 subunit, have also been
found to be involved in mood regulation.
• Benzodiazepines have a potential as antidepressant therapy.
• Benzodiazepines can potentially treat chronic pain-induced depression.
Neural plasticity. 2017;2017.

14. Which came first?
Chronic Pain Depression

15. They may be connected…….
• Chronic Pain
• Patients with chronic pain are prone
to depression because of the
continuous disease burden imposed
by the pain.
• Because of the reciprocal nature of
depression and pain, the presence of
both conditions in a patient may lead
to an increased number of medical
visits as well as to higher health care
costs
• Depression
• Major depressive disorder (MDD) is a
multifaceted disease that presents
with both emotional symptoms (e.g.,
depression, guilt, suicidal ideation)
and physical symptoms (e.g., sleep
disruption, gastrointestinal
disturbance, unexplained aches and
pains).
• Headache, neck and back pain,
abdominal pain, and musculoskeletal
pain are common in patients with
depression
Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433-2445.

16. TCA as “Double Duty” drugs
• TCAs are the Drugs used for depression, found
effective also for chronic pain as reported in
many studies. Hence commonly used in both.
Micó J, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain". Trends Pharmacol Sci. 27 (7): 348–54

17. Mechanism
• Their main mechanism of action involves
– reinforcement of the descending inhibitory pathways by increasing
the amount of norepinephrine and serotonin in the synaptic cleft at
both supraspinal and spinal levels.
• The analgesic effect occurs
– In the absence of depression or where there was no antidepressant
effect
– At doses lower than those used for depression
– With an earlier onset of effect (i.e., within 1 week) than that required
for an antidepressant effect.
J Psychiatry Neurosci 2001;26(i):30-6. 17

18. MECHANISM OF ACTION OF ANTIDEPRESSANTS AS ANALGESICS
Mechanism of action Site of action TCA SNRI SSRI
1.Reuptake inhibition of monoamine Serotonin, Noradrenaline +
+
+
+
+
-
2.Receptor antagonism Adrenaline(alpha 1) NMDA +
+
-
+milnacipran
-
-
3.Blocker or Activation of ion channel Sodium channel blocker + +venlafaxine +fluoxetine
Calcium channel blocker + -duloxetine
Potassium channel blocker + ?
4.Adenosine Increase adenosine availability and
local release, activation of adenosine
A1 receptors
+amitriptyline ? ?
5.GABA b receptors Increase GABA b receptor function +amitriptyline
desipramine
? +fluoxetine
6.Opiod receptor binding/opioid mediated
effect
Activation of ƍ and ũ opioid receptors + +venlafaxine +paroxetine
7.Inflammation Decrease PGE2 production + ? +fluoxetine
Decrease TNF α production + ? ?
J clinical pharmacol 2012:52,6,17-
18

19. TCAs FOR PAIN
• TCAs should be initiated at low dosages—10 to 25 mg in a single dose at
bedtime—and then titrated every 3 to 7 days by 10 to 25 mg/d as
tolerated
• TCAs should be titrated to maximum dosages of 75 to 150 mg/d as
tolerated
• TCA treatment should last 6 to 8 weeks, with at least 1 to 2 weeks being at
the maximum tolerated dosage.
19

20. NEUROPATHIC PAIN
• Neuropathic pain is defined by the International Association for the Study
of Pain (IASP) as ‘pain caused by a lesion or disease of the somatosensory
nervous system.
• Around 7–8% of adults have pain with neuropathic characteristics.
• Most common cause of neuropathic pain are
• Diabetic neuropathy(25%)
• HIV associated sensory peripheral neuropathy(35%)
• Chemotherapy induced peripheral neuropathy
• Postherpetic neuralgia(19%)
• Trigeminal neuralgia
• Postsurgical pain(10%)
20

21. NEUROPATHIC PAIN
• Tricyclic antidepressants (TCAs) are the “gold standard”
antidepressants for the treatment of persistent
neuropathic pain.
• TCAs along with SNRIs and gabapentinoids are first line
therapy. 3
• TCAs are one of the most studied antidepressants for the
treatment of neuropathic pain.
• Their use as a first-line therapy is supported across
multiple guidelines 3
1. Drugs Aging. 1996; 8: 459
2. Neurology. 1995; 45( Suppl 9): 17– 25.
3.Pain Med2019 Jun ; 20(Suppl 1): S2–S12.
21

22. FIBROMYALGIA
• Efficacy of TCAs is well-established in fibromyalgia.
• Amitriptyline has long been used in pharmacological treatment.1
• TCAs are effective at doses lower than those needed for the
treatment of depression.2
• A meta-analysis by Arnold et al included 9 RCTs with TCAs
(amitriptyline, dosulepin) in fibromyalgia patients observed.3
– 30% patients showed improvement in all outcomes (fatigue, sleep,
pain,stiffness, tenderness)
– A greater effect was seen on sleep disorders and fatigue than on pain,
indicating that TCAs had a moderate analgesic effect in fibromyalgia.
1 .Biomedicines 2017 Jun; 5(2): 20.
2. J Musculoskel Pain. 1996;4:37-47.
3.Psychosomatics. 2000;41:104-113 22

23. OTHER CHRONIC PAIN CONDITIONS
Low back pain
• According to American Pain Society and
American College of Physicians
guidelines, TCAs are effective for pain
relief in LBP.1
• Their analgesic effect has been reported
to be similar to that of NSAIDs.2
• A meta analysis revealed that
antidepressants had a statistically
significant effect in reducing LBP when
compared with placebo. Patients treated
with antidepressants experienced a small
but significant improvement of 0.41 (95%
CI 0.22–0.61) in the standardized mean
difference for pain severity.3
Chronic headache
• Meta-analyses have demonstrated that
patients receiving antidepressants were
twice as likely to report headache
improvement (rate ratio [RR]: 2.0; 95%
CI: 1.6 to 2.4.94–96 The beneficial effect
of TCAs was the largest of all
antidepressants.
1. Ann Intern Med. 2007;147:505-514.
2. Pain Symptom Manage. 2004;28:72-95.
3. Arch Intern Med. 2002;162:19-24.
Am J Med. 2001;111:54-63.
23

24. RHEUMATOID ARTHRITIS
• TCAs have only weak analgesic effects in patients with RA, with or without depressive
symptoms.1
• In a study of 123 RA patients with anxiety/depression, patients treated with
DMARDs+antidepressants achieved remission significantly more often (p=0.024) than
ones receiving DMARDs only. Thus, successful treatment of depression/anxiety with
antidepressants provided more significant positive influence on treatment response to
DMARDs and biologics on a five-year follow-up.2
• A Cochrane review(2011) concluded that3
– There is currently insufficient evidence to support the routine prescription of
antidepressants as analgesics in patients with RA as no reliable conclusions about
their efficacy can be drawn from eight placebo RCTs.
1.Rheumatology 2008;47:1117–1123
2.Annals of rheumatic disease ,vol 77,supp 2
3.Cocrane database syst rev 2011 Nov 9;(11 24

25. Benefits of TCA in Pain and Depression
Pain Depression
TCAs are the most studied
antidepressants for the treatment of
neuropathic pain
People with severe depression that fail to
respond to other treatments. TCAs are
effective
Reduce pain in lowered doses as compare
to depression
108 studies of newer antidepressants that
found TCAs to be effective in treating
depression.
Br Med Bull. 2001;57:161–178

26. Less Number Needed to treat (NNT) of TCAs
• In a Cochrane review of 61 RCTs, it was found that TCAs had 4
– A number needed to treat (NNT) of 3.6 for the achievement of
moderate pain relief
– A number needed to harm (NNH) for adverse effects, defined as
an event leading to withdrawal from a study, of 28.
– For minor adverse effects, the NNH was 9.
Cochrane Database Syst Rev 2007;4: CD005454

27. Dosulepin a Safe TCA
• Dosulepin, also known as dothiepin is a tricyclic antidepressant.
• It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has
other actions including anti-histaminic, anti-adrenergic, anti-serotonergic, anti-
cholinergic, and sodium channel blocking effects.
• Indication
– Dosulepin is licensed for the treatment of depressive illness in adults along with
chronic pain or anxiety
Contraindication
– Recent myocardial infarction
– Heart block of any degree or other cardiac arrhythmias
– Mania
– Severe liver disease
27
PrescQIPP DROP-List. Bulletin available at www.prescqipp.info

28. Dothiepin Vs Amitriptyline
• 23 independent studies performed in 8 countries over an 18-year period
between 1971 and 1988 in over 1000 evaluable patients indicates that
dothiepin is as effective as amitriptyline but is better tolerated
Donovan, S., Vlottes, P.W. & Min, J.M. Drug Invest. (1991) 3: 178. https://doi.org/10.1007/BF03259561
D=Dothiepin
A=Amitriptyline

29. • Dothiepin Versus Amitriptyline for Depression An Analysis of Comparative Studies1
– Dothiepin is equally effective as amitriptyline and better tolerated
– Consistent pattern of findings in these studies suggests - dothiepin is better than amitriptyline in the
treatment of depression
• A Double-Blind Study of Dothiepin Hydrochloride and Amitriptyline in Out-Patients with Masked
Depression2
– Frequency and severity of side-effects like hypotension, tiredness/sleepiness and dry mouth -
significantly less with dothiepin than with amitriptyline at Week 1 (p <0·05)
– The overall incidence and severity of side-effects was also less with dothiepin at all assessments during
the trial
• Single-blind comparative study of once daily dothiepin and divided daily doses of amitriptyline3
– Dothiepin caused a greater improvement than amitriptyline after 4 weeks of treatment - judged
by depression scores, total scores and global assessments
– The incidence of side-effects was less in number and severity with dothiepin than with
amitriptyline
1.Donovan et al. Dothiepin Versus Amitriptyline for Depression An Analysis of Comparative Studies. Drug Invest. 3 (3): 178-182, 1991 01 14-2402/91/0003-01 78.
2.Dahl et al. A Double-Blind Study of Dothiepin Hydrochloride (Prothiaden) and Amitriptyline in Out-Patients with Masked Depression. Int Med Res (1981) 9,103
3. Rees et al. A single-blind comparative study of once daily dothiepin (‘Prothiaden’) and divided daily doses of amitriptyline. Cum. Med. Res. Opin., (1976),4,416.
Dosulepin or Amitriptyline – Which is a better choice?
Dosulepin (Dothiepin) is a safer and equally effective alternative to Amitriptyline

30. Proprietary and confidential — do not distribute 30
SSRI vs Dosulepin – which has got better tolerability?
SSRI treatment results in more side-effect related drop outs compared to Dosulepin

31. Conclusion
• Chronic pain and depression are probably linked to each other as they share the
common pathways on neurotransmission
• Depressed patients may have both neuropathic and nociceptive pain
• Alternatively, patients in chronic pain may have some level of depression
• TCA are safe, cost-effective agents that are useful in both conditions
• In depression with pain – TCAs should be preferred
• Dosulepin may prove to be a useful treatment option for patients of Chronic pain
with Depression or anxiety

32. THANK YOU