chronic pain: role of tricyclic antidepressants, dolsulepin

Chronic pain: Core concepts and TCAs

DR SUDHIR KUMAR MD (Med) DM (Neuro)CONSULTANT NEUROLOGISTAPOLLO HOSPITALS, KUKATPALLY/JUBILEE HILLS (HYDERABAD)

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)

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

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Salient Features Mentioned in the Guidelines

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

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 todayChronic pain in the US costs millions of dollars annually, and its financial impact is mountingAffects nearly all normal activities and often leaves the person feeling helpless and hopeless

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.

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

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

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.

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.


Chronic Pain - PathophysiologyThe 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.

Pain transmission and modulatory pathways


A. Transmission system for nociceptive messages.

B. Pain-modulation network

Ascending pain pathways

Circuit of pain modulatory pathway.

Marks DM. Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise. Current Neuropharmacology, 2009, 7, 331-336

Chronic pain processes

Neurogenic inflammation

Damaged nerve

Sensitization

Loss of nociceptive control

Mental overloadWhitten, 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.

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.

Factors that increase pain

Physical

Chemical

Behavioural

Thoughts and emotions

Structural


Viscous cycle of pain


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


– 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

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

Patient evaluation

1. Medical records review or patient condition2. Physical examination3. Psychological and behavioral evaluation4. 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


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


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


Pain and DepressionCause 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

Pain and DepressionSome 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?


Pain and DepressionSome 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?


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

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Primary care Psychiatric inpatients Neurology clinic

Outpatient clinic Private practice Psychiatric patients

Psychiatric patients Depressed outpatients General practiceBair MJ. Depression and pain comorbidity. Arch Intern Med. 2003;163:2433-2445

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.


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

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Pain clinics Psychiatric clinics Orthopedic clinics

Dental clinics Gynecology clinics Population based settings

Primary care clinics


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.


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.


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


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.


Is antidepressant treatment for painful symptoms and comorbid depression effective?

Source No. of patients

Sample Medication OutcomePain 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


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.

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.

Analgesic MOA of antidepressants

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

Tricyclic antidepressants, produce spinally and supraspinally mediated analgesia in chronic pain states by

mechanisms distinct from those that enhance mood

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

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


Comparative analgesic efficacy

Antidepressants No. of human studies NNT

TCA 23 3.1

SSRI 3 6.8

SNRI 3 5.5


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.


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

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

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

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

Dosulepin/Dotheipin

Chemical structure of Dothepin Chemical structure of Amitriptylline

Dosulepin is a Thio-analouge of amitriptyline.

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

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

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Efficacy Of Prothiaden In Depression In Rheumatoid Arthritis

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ASSESSMENTIMPROVEMENT

Overall Assessment of Tolerability

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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.

Knowing is not enough; we must apply.Willing is not enough; we must do.

– Goethe

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chronic pain: role of tricyclic antidepressants, dolsulepin

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