Manegement of chronic neurogenic pain

MANEGEMENT OF CHRONIC(NEUROGENIC) PAIN

Dr. A.V. SrinivasanMD.,DM.,Ph.D .,D.Sc (HON).F.I.A.N.,F.A.AN.Emeritus professor of Tamilnadu Dr. M.G.R Medical University. Adjunct Professor –IIT, ChennaiFormer Head, Institute of Neurology- Madras medical college.South Africa -26-07-2011

Prothiaden in Chronic PainProthiaden in Chronic Pain Company Confidential © 2010 AbbottCompany Confidential © 2010 Abbott

Understanding, Impact and Understanding, Impact and AwarenessAwareness

Chronic PainChronic Pain


“Pain May be Inevitable, but Misery is Optional”

Dee Malchow

Pain constitutes nearly 40% of the total of patient visits to doctors.1

1 Mäntyselkä et al. Pain as a reason to visit the doctor: a study in Finnish primary health care. Pain. 2001 Jan;89(2-3):175-80.


Pain is undertreated

• In 2001, Barry Furrow wrote “Pain is undertreated” in the American health-

care system at all levels.2

• The term "opiophobia" has been coined to describe this remarkable clinical

aversion to the proper use of opioids to control pain.

• The possible reasons for health-care providers' failures to properly manage

pain are many;

– Occasional lack of knowledge about appropriate treatment choices for

pain management

– A reflection of a Culture hostile to drug use

– Threats of legal action.

– Worry about tolerance and addiction and other adverse drug effects

– Something as trivial as the lack of insurance cover, can lead to patients

suffering unnecessary pain as a result.

2. R.M. Marks and E.J. Sachar, "Undertreatment of Medical Inpatients with Narcotic Analgesics,"Annals of Internal Medicine, 78 (1973): 173.


Indian Scenario

• Despite an essentially stoic and less demanding Indian patient; the

obligation to manage pain comes to the fore not only to complete the

perfection of a clinicians management.

• But also, it is an independent entity with physical and psychological

components that in adherence to best practices can neither be

ignored nor treated such that adverse effects eclipse the malady.

• This importance of pain management is further increased when

benefits for the patient are realized,

– Early mobilization which tends to prevent the more dangerous

complication of a deep vein thrombosis;

– Shortening hospital stay

– Reducing costs


Decade of Pain Control and Research

• In late 2000, US Congress passed into law a provision, which the president signed , that declared the 10 year period beginning Jan 1st 2001, as the Decade of Pain Control and Research.

• The American Pain Society has actively supported the Decade of Pain Control Research, and it has been a focal point for the development of numerous programs to advance awareness and treatment of pain and funding for research.


What is Pain?

• Pain is always a subjective experience

• Everyone learns the meaning of “pain” through experiences

usually related to injuries in early life

• As an unpleasant sensation it becomes an emotional experience

• Pain is a significant stress physically, emotionally

(American Society of Anesthesiologists, 2002; Loeser et al, 2001; Merskey H et al, 1994; Portenoy et al, 1996)

The International Association for the Safety of Pain (IASP) defines pain an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage, or both.


Qualities of Pain• Organic vs. psychogenic• Acute vs. chronic• Malignant or benign• Continuous or episodic

Perceiving Pain• Algogenic substances – chemicals released at the site of the

injury• Nociceptors – afferent neurons that carry pain messages• Referred pain – pain that is perceived as if it were coming from

somewhere else in the body


Acute vs. Chronic Pain

ACUTE CHRONIC

Function To warn None (destructive)

Etiology Usually Clear Complex/obscure

Pt. Mood Anxiety/fear Depression/anger

MD impact Comforting Frustrating/draining

Role of Rx Control/cure Improve function/QOL


Categorization of Chronic pain

Types of PainTypes of Pain

Pain arising from pain receptors

[Nociceptive Pain]

Pain arising from pain receptors

[Nociceptive Pain]

(Psychogenic)

Pain with NO apparent cause(e.g. Low back pain or some

pelvic pain in women)

(Psychogenic)

Pain with NO apparent cause(e.g. Low back pain or some

pelvic pain in women)

Pain arising from Nervous system[Neuropathic Pain]

Pain arising from Nervous system[Neuropathic Pain]

Central(Brain and Spinal cord)

Central(Brain and Spinal cord)

Peripheral (Peripheral nervous

system)

Peripheral (Peripheral nervous

system)

Superficical / SomaticSuperficical / Somatic Deep / VisceralDeep / Visceral

Keay, KA; Clement, CI; Bandler, R (2000). "The neuroanatomy of cardiac nociceptive pathways". in Horst, GJT. The nervous system and the heart. Totowa, New Jersey: Humana Press. p. 304


Different types of pain

Nociceptive descriptors Neuropathic descriptors

Cramping, tender Shooting

Gnawing, heavy Hot-burning

Aching Sharp

Splitting Stabbing


Current Understanding of Pain• Chronic pain is NOT a normal part of aging.

• Emotions play a key role in painful experience

• Pain sounds a warning, signaling damage to tissues, and has survival value so pain receptors do not adapt to prolonged stimulation and pain sensation may intensify as pain thresholds are lowered by continued stimulation.

• The 19th Century viewed pain as a solely physiological entity with two theories dominating – the “specificity” & the “summation” theories. 8

• Paradigm Shift:

– Pain perception impulses are modified by ascending and by descending pain-suppressing systems activated by various environmental and psychological factors.

– 1965 Melzack & Wall: Gate Theory of Pain marked a turning point in understanding transmission and modulation of nociceptive signals, and recognition of pain as a psychophysiological phenomenon.

• The concept of Neuroplasticity was recognized and accepted adding dynamism to neuronal & brain structure with neuroimaging of the central nervous system in three domains; anatomical, functional, and chemical imaging helping measure changes in chronic pain.

• Taken together these three domains have changed our thinking on pain; now considered an altered brain state in which there may be altered functional connections or systems and components of degenerative aspects of the CNS. 9

8) 11. J.A. Paice, C. Toy, and S. Short, "Barriers to Cancer Pain Relief: Fear of Tolerance and Addiction," Journal of Pain and Symptom Management, 16 July 1998): 1-9.9) Quick Reference Guide for Clinicians No. 1a. AHCPR Publication No. 92-0019: February 1993


Understanding Pain Pathophysiology


What causes pain?

• Trauma/ injury initiates immediate nerve impulses to brain

• Injury to cells result in chemical release

• H+

• K+

• Substance P• Bradykinin• 5HT• Phospholipids Prostaglandins

• Blood vessels leak resulting in inflammation

• Stimulate C-fibres (slow response)


Peripheral and Central Pathways for Pain

Ascending TractsAscending Tracts Descending TractsDescending Tracts

Cortex

Midbrain

Medulla

Spinal Cord

Thalamus

Pons

(Brookoff, 2000)


Pain Pathway


Pathophysiology of Chronic Pain

• In chronic pain, the nervous system remodels continuously in response to repeated pain signals

– nerves become hypersensitive to pain

– nerves become resistant to anti-nociceptive system

• If untreated, pain signals will continue even after injury resolves

• Chronic pain signals become embedded in the central nervous system

(Marcus, 2000)


Pain-Sensing System in the Malfunction in Chronic Pain

(Illustration: Seward Hung, 2000)

Acute pain:Pain-sensing signals are initiated in response to a stimulus

• They elicit a pain-relieving response

Chronic pain:Pain signals are generated for no reason and may be intensified

• Pain-relieving mechanisms may be defective or deactivated

Pain Sensing

In chronic pain, pain signals are generated without physiologic significance


Pathophysiology of Pain

• Inferred from characteristics, etiology or pathophysiology

• Types

– Nociceptive

– Neuropathic

– Idiopathic

• Therapeutic implications

(Portenoy et al, 1996)


Nociceptive Pain

Presumably results from ongoing activation of primary afferent neurons responding to noxious stimuli

• Pain consistent with degree of tissue injury

• Described as aching, squeezing, stabbing, throbbing

• Subtypes:

– Somatic: related to activation of somatic afferent neurons

– Visceral: related to activation of visceral afferent neurons

(Loeser et al, 2001; Portenoy et al, 1996)


Neuropathic Pain

• Initiated by a primary lesion in the nervous system; believed to be sustained by aberrant somatosensory processing in the peripheral or central nervous system

• Independent of obvious ongoing nociceptive activation

• Burning, shooting, electrical quality; may be aching, throbbing, sharp

• Subtypes:

– Presumed “central generator”

deafferentation pain (central pain, phantom pain)

Sympathetically-maintained pain

– Presumed “peripheral generator”

Polyneuropathies and mononeuropathies



Idiopathic and Psychogenic Pain

Idiopathic Pain

• Usually exists in the absence of an identifiable physical or psychologic pathology that could account for pain

• Uncommon in patients with progressive illness

Psychogenic Pain

• Presents positive evidence of a predominant psychologic contribution and may be labeled with a specific psychiatric diagnosis

(Loeser et al, 2001; Merskey et al, 1994; Portenoy et al, 1996)


Recent Developments In Pain Management

• Greater understanding of the pathophysiology underlying chronic pain syndromes

• Scientific breakthroughs in molecular biology; insight into pain at the molecular level

• Advances in drug therapy (drug delivery technologies)

• Multimodal therapy

• Multidisciplinary teams, shared decision-making that includes patients

• Patients’ rights movement

(JCAHO, 1999; Loeser et al, 2001)


Therapeutic Modalities for

Chronic Pain Management

Assessment

Progress in Chronic Pain Management:Progress in Chronic Pain Management:


“Describing pain only in terms of its

intensity is like describing music only in

terms of its loudness”

von Baeyer CL; Pain Research and Management 11(3) 2006; p.157-162


Pain Assessment

• Characterize the pain

• Characterize the disease, relationship between pain and disease and potentially treatable etiologies

• Clarify syndromes and infer pathophysiology

• Determine need for urgent therapy

• Identify other needs

• Develop a therapeutic strategy



Components• History: temporal features, intensity, topography, quality,

exacerbating/alleviating factors• Physical Exam: determine existence of underlying pathology

• Lab and Radiographic Tests: appropriate to pain syndrome

Assessment Tools• Pain Intensity Scales: VAS, NAS, “faces” scale

• Multidimensional Pain Measures: Brief Pain Inventory, McGill Pain Questionnaire


Pain Assessment


Pain Intensity Rating Scales• Visual Analogue Scale (VAS)

No painNo pain ----------------------------------- ----------------------------------- Worst painWorst pain

• Categorical Scale None (0) Mild (1 None (0) Mild (1 – 4) Moderate – 4) Moderate (5 (5 – 6) Severe – 6) Severe (7 – 10(7 – 10) )

• Numerical Rating Scale0 -------------------------------------0 ------------------------------------- 10 10

No painNo painWorst pain Worst pain imaginableimaginable

(Cleeland, 1991; Jacox et al, 1994)

00

No No hurthurt

22

Hurts just a Hurts just a little bitlittle bit

44

Hurts a little Hurts a little bit morebit more

66

Hurts even Hurts even moremore

88

Hurts a whole Hurts a whole lotlot

1010

Hurts as much Hurts as much as you can as you can

imagineimagine

• Pain Faces Scale

• Brief Pain Inventory Shade areas of worst pain. Put an X on area that hurts mostShade areas of worst pain. Put an X on area that hurts most


Progress in Chronic Pain Management

Therapeutic Modalities for Therapeutic Modalities for

Chronic Pain Management:Chronic Pain Management:

TreatmentTreatment


Therapeutic Options for Chronic Pain Management

• Pharmacotherapy (Analgesics)– Non-opioids – Adjuvant Analgesics

• Antidepressants• Anticonvulsants

– Opioids• Rehabilitative Approaches• Psychologic Interventions• Anesthesiological Approaches• Neurostimulatory Techniques• Surgery• Complementary/Alternative Approaches• Lifestyle Changes

(Cashman, 1996; Portenoy et al, 1997; Hanks et al, 1998; Galer, 1998; Stein, 1995)


Status of antidepressants in chronic pain management

• Best evidence: TCAs – Inhibit both NA and 5-HT reuptake

• TCAs are superior to SSRIs in pain management

• TCAs are superior to the anticonvulsant

• There is no consensus regarding which of the many TCA

derivatives is most effective.

• The choice of TCA is therefore dictated largely by adverse

effects

Neurologic Complications of Cancer Therapy Current Treatment Options in Neurology 1999, 1.428-437

Litsedge, A Double-Blind Comparison of Dothiepin and Amitriptyline for the Treatment of Depression with Anxiety, Psychopharmacologia (Berl.) 19, 153--162 (1971)



Which TCA?

• TCAs differ little in terms of their analgesic efficacy (Dworkin et. al 2007).

• Amitriptyline is the most widely studied TCA and is commonly used in neuropathic pain.

• Prothiaden being similar to amitriptyline is a good choice for the management of pain especially as it enjoys a relatively safer adverse event profile.

Prothiaden is a derivative of amitriptyline namely its thio-analogue.Prothiaden is a derivative of amitriptyline namely its thio-analogue.

Amitriptyline Prothaiden



Prothiaden: Pharmacokinetics

– Rapidly absorbed from GIT on oral administration

– Tmax: 3 - 4 hours– Metabolized in liver to active metabolites -

northiaden, northiaden S-oxide and dothiepin S-oxide

– Excreted mainly in urine and also in faeces– A half-life of about 50 hours has been reported

for dosulepin and its metabolites


Safety

Adverse events:

– Atropine-like side effects including dry mouth, disturbance of accommodation, tachycardia, constipation and hesitancy of micturition, are common early in treatment, but usually lessen as treatment continues

– Initially, dosulepin may impair alertness; patients likely to drive vehicles or operate machinery should be warned of this possibility.

Contra-indications : Recent MI, heart block, arrhythmias, mania, liver disease & during breast feeding

Dose:Adults: 50 mg to 150 mg daily.

Children: Not studied

Pregnancy and lactation: Not adequately studied


Tolerability

• Extensive clinical studies as well as over two decades of clinical experience indicate that it is a well tolerated drug.

• The nature of side-effects reported are typical of a tricyclic antidepressant, it is better tolerated than other tricyclic antidepressants.

• “The general trend appeared to show better patient tolerance of Dothiepin than to any other active controls”.

• Goldstein and Claghorn (1980)

Dothiepin is better tolerated in relation to its side effects than amitriptyline.

Litsedge, A Double-Blind Comparison of Dothiepin and Amitriptyline for the Treatment of Depression with Anxiety, Psychopharmacologia (Berl.) 19, 153--162 (1971)


Mode of action: Dosulepin in chronic pain

Daniel a. Monti M.D. et. al. Management of chronic pain in elderly patients. Practical geriatrics; December 1996 Vol 49, No. 12 Brookoff, 2000

Dosulepin potentiate serotonin and norepinephrine in descending pain-suppressionpathways in the spinal cord.

Descending fibers that pass down from brainstem to spinal cord, inhibiting incoming sensations (ascending pathways) of pain.

A lot of these descending fibers originate in the locus ceruleus, others in the raphe nuclei.

Jann et. al. Antidepressant Agents for the Treatment of Chronic Pain and Depression. Pharmacotherapy 2007;27(11):1571–1587


Mode of action

Ascending TractsAscending Tracts Descending TractsDescending Tracts

(Brookoff, 2000)

TCAs potentiate serotonin andnorepinephrine in descending pain-suppressionpathways in the spinal cord.

Descending fibres that pass down from brainstem to spinal cord, inhibiting incoming sensations (ascending pathways) of pain. A lot of these descending fibres originate in the locus coeruleus, others in the raphe nuclei.


Dothiepin in management of chronic pain

• Dothiepin was used in a titrating dose in patients of atypical facial pain (Starting dose 12.5 mg, dose range 25-137.5 mglday) for 9weeks

– 34/48 dothiepin were pain free (score 0/1 mild, occasional) at week 9. vs 21/45 placebo

– Reduction in analgesic use; 83% dothiepin, 42% placebo

(Feinmannet al.,1984)


Proven efficacy in managing chronic pain

– In Prothiaden group pain

score measured on VAS

reduced from 56.7 to 42.2

– In placebo group, pain score

increased from 59.7 to 64.1

– Dothiepin is effective in

relieving pain, disability and

reducing the duration of early

morning stiffness in out-

patients with RA

– The analgesic effect of

dosulepin is INDEPENDENT

of its antidepressant effect

G. Ash et. al. The effect of dothiepin on subjects with rheumatoid arthritis and depression. Rheumatology 1999; 38: 959-967


Recommendations of Treatment Guidelines


Practice Guidelines for Chronic Pain Management

• Developed by American Society of Anesthesiologists Task Force on

Chronic Pain Management and the American Society of Regional

Anesthesia and Pain Medicine

• Meta-analyses of randomized controlled trials indicate that tricyclic

antidepressants provide effective pain relief for a variety of chronic

pain etiologies for assessment periods ranging from 2 to 8 weeks,

with dry mouth and somnolence or sedation as reported side effects

(Category A1 evidence).

• Strongly agree to use of TCAs in chronic pain management.

Anesthesiology 2010; 112:810 –33



Take Homes !

Pain needs to be treated aggressively to

prevent sensitization

Chronic pain even more so as to combat Neuroplasticity

TCAs are the recommended first-line therapy in chronic pain

Dothiepin is better tolerated in relation

to its side effects than amitriptyline


Thank you


Dedicated to my family for making everything worthwhile


THANKYOU

My sincere thanks to ABBOTT and SAMPATH(CRO)

My sincere thanks to ABBOTT and SAMPATH(CRO)

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Manegement of chronic neurogenic pain