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MANEGEMENT OF CHRONIC(NEUROGENIC) PAIN   Dr. A.V. Srinivasan   MD.,DM.,Ph.D .,   D.Sc (HON).F.I.A.N.,F.A.AN.   Emeritus pr...
Chronic Pain                             Understanding, Impact and                                    AwarenessProthiaden ...
“Pain May be Inevitable, but Misery is Optional”                                                                    Dee Ma...
Pain is undertreated  •       In 2001, Barry Furrow wrote “Pain is undertreated” in the American health-          care sys...
Indian Scenario  • Despite an essentially stoic and less demanding Indian patient; the    obligation to manage pain comes ...
Decade of Pain Control and Research  • In late 2000, US Congress passed into law a provision,    which the president signe...
What is Pain?   •      Pain is always a subjective experience   •      Everyone learns the meaning of “pain” through exper...
Qualities of Pain  •       Organic vs. psychogenic  •       Acute vs. chronic  •       Malignant or benign  •       Contin...
Acute vs. Chronic Pain                                      ACUTE                           CHRONIC    Function           ...
Categorization of Chronic pain                                                                         Types of Pain      ...
Different types of pain            Nociceptive descriptors                                      Neuropathic descriptors   ...
Current Understanding of Pain   •        Chronic pain is NOT a normal part of aging.   •        Emotions play a key role i...
Understanding Pain PathophysiologyProthiaden in Chronic Pain   Company Confidential © 2010 Abbott
What causes pain?                                                             •    Trauma/ injury initiates immediate     ...
Peripheral and Central Pathways for Pain                                 Ascending Tracts                          Descend...
Pain PathwayProthiaden in Chronic Pain   Company Confidential © 2010 Abbott
Pathophysiology of Chronic Pain  • In chronic pain, the nervous system remodels    continuously in response to repeated pa...
Pain-Sensing System in the Malfunction in Chronic Pain                                                                    ...
Pathophysiology of Pain       • Inferred from characteristics, etiology or         pathophysiology       • Types          ...
Nociceptive Pain  Presumably results from ongoing activation of primary  afferent neurons responding to noxious stimuli  •...
Neuropathic Pain• Initiated by a primary lesion in the nervous system; believed to be  sustained by aberrant somatosensory...
Idiopathic and Psychogenic Pain    Idiopathic Pain    • Usually exists in the absence of an identifiable physical or      ...
Recent Developments In Pain Management  • Greater understanding of the pathophysiology underlying    chronic pain syndrome...
Progress in Chronic Pain Management:                             Therapeutic Modalities for                             Ch...
“Describing pain only in terms of its              intensity is like describing music only in              terms of its lo...
Pain Assessment       • Characterize the pain       • Characterize the disease, relationship between         pain and dise...
Pain Assessment  Components  • History: temporal features, intensity, topography, quality,    exacerbating/alleviating fac...
Pain Intensity Rating Scales   • Visual Analogue Scale (VAS)                                         No pain       -------...
Progress in Chronic Pain Management                             Therapeutic Modalities for                             Chr...
Therapeutic Options for Chronic Pain Management  •       Pharmacotherapy (Analgesics)           – Non-opioids           – ...
Status of antidepressants in chronic pain management  • Best evidence: TCAs            – Inhibit both NA and 5-HT reuptake...
Prothiaden in Chronic Pain   Company Confidential © 2010 Abbott
Which TCA? • TCAs differ little in terms of their analgesic efficacy   (Dworkin et. al 2007). • Amitriptyline is the most ...
Prothiaden in Chronic Pain   Company Confidential © 2010 Abbott
Prothiaden: Pharmacokinetics            – Rapidly absorbed from GIT on oral              administration            – Tmax:...
Safety      Adverse events:      – Atropine-like side effects including dry mouth, disturbance of        accommodation, ta...
Tolerability  • Extensive clinical studies as well as over two decades of clinical    experience indicate that it is a wel...
Mode of action: Dosulepin in chronic pain                                                                                 ...
Mode of action    Ascending Tracts             Descending Tracts                                                          ...
Dothiepin in management of chronic pain  • Dothiepin was used in a titrating dose in patients of    atypical facial pain (...
Proven efficacy in managing chronic pain         – In Prothiaden group pain           score measured on VAS           redu...
Recommendations of Treatment GuidelinesProthiaden in Chronic Pain   Company Confidential © 2010 Abbott
Practice Guidelines for Chronic Pain Management  • Developed by American Society of Anesthesiologists Task Force on    Chr...
Prothiaden in Chronic Pain   Company Confidential © 2010 Abbott
Take                                                         Homes !  Pain needs to be treated                            ...
Thank youProthiaden in Chronic Pain   Company Confidential © 2010 Abbott
Dedicated to my family for      making everything worthwhileProthiaden in Chronic Pain   Company Confidential © 2010 Abbott
READ NOT TO CONTRADICT OR CONFUTE                  NOR TO BELIEVE AND TAKE FOR GRANTED                  BUT TO WEIGH AND C...
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Manegement of chronic neurogenic pain

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Manegement of chronic neurogenic pain

  1. 1. MANEGEMENT OF CHRONIC(NEUROGENIC) PAIN Dr. A.V. Srinivasan MD.,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, Chennai Former Head, Institute of Neurology- Madras medical college. South Africa -26-07-2011
  2. 2. Chronic Pain Understanding, Impact and AwarenessProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  3. 3. “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.Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  4. 4. 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.Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  5. 5. 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 costsProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  6. 6. 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.Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  7. 7. 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 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. (American Society of Anesthesiologists, 2002; Loeser et al, 2001; Merskey H et al, 1994; Portenoy et al, 1996)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  8. 8. 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 bodyProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  9. 9. 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/QOLProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  10. 10. Categorization of Chronic pain Types of Pain Types of Pain (Psychogenic) (Psychogenic) Pain arising from Pain arising from Pain arising from Pain arising from pain receptors pain receptors Pain with NO apparent cause Pain with NO apparent cause Nervous system Nervous system [Nociceptive Pain] [Nociceptive Pain] (e.g. Low back pain or some (e.g. Low back pain or some [Neuropathic Pain] [Neuropathic Pain] pelvic pain in women) pelvic pain in women) Peripheral Peripheral Central CentralSuperficical / /SomaticSuperficical Somatic Deep / /Visceral Deep Visceral (Brain and Spinal cord) (Peripheral nervous (Peripheral nervous (Brain and Spinal cord) system) system)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. 304Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  11. 11. Different types of pain Nociceptive descriptors Neuropathic descriptors Cramping, tender Shooting Gnawing, heavy Hot-burning Aching Sharp Splitting StabbingProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  12. 12. 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. 98) 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 1993Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  13. 13. Understanding Pain PathophysiologyProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  14. 14. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  15. 15. Peripheral and Central Pathways for Pain Ascending Tracts Descending Tracts Cortex Thalamus Midbrain Pons Medulla(Brookoff, 2000) Spinal Cord Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  16. 16. Pain PathwayProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  17. 17. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  18. 18. Pain-Sensing System in the Malfunction in Chronic Pain Acute pain: Pain Pain-sensing signals are initiated in response to a Sensing stimulus • They elicit a pain-In chronic pain, relieving responsepain signals aregeneratedwithout Chronic pain:physiologicsignificance Pain signals are generated for no reason and may be intensified • Pain-relieving mechanisms may be defective or deactivated (Illustration: Seward Hung, 2000)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  19. 19. Pathophysiology of Pain • Inferred from characteristics, etiology or pathophysiology • Types – Nociceptive – Neuropathic – Idiopathic • Therapeutic implicationsProthiaden in Chronic Pain et (Portenoy al, 1996) Company Confidential © 2010 Abbott
  20. 20. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  21. 21. 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 (Portenoy et al, 1996)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  22. 22. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  23. 23. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  24. 24. Progress in Chronic Pain Management: Therapeutic Modalities for Chronic Pain Management AssessmentProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  25. 25. “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.157-162Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  26. 26. 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 (Portenoy et al, 1997)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  27. 27. Pain Assessment 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 (Portenoy et al, 1997)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  28. 28. Pain Intensity Rating Scales • Visual Analogue Scale (VAS) No pain ----------------------------------- Worst pain • Numerical Rating Scale 0 ------------------------------------- 10 Worst pain No pain imaginable • Categorical Scale None (0) Mild (1 – 4) Moderate (5 – 6) Severe (7 – 10) • Pain Faces Scale 0 2 4 6 8 10 No Hurts just a Hurts a little Hurts even Hurts a whole Hurts as much hurt little bit bit more more lot as you can imagine • Brief Pain Inventory Shade areas of worst pain. Put an X on area that hurts most (Cleeland, 1991; Jacox et al, 1994)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  29. 29. Progress in Chronic Pain Management Therapeutic Modalities for Chronic Pain Management: TreatmentProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  30. 30. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  31. 31. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  32. 32. Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  33. 33. 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. Amitriptyline ProthaidenProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  34. 34. Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  35. 35. 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 metabolitesProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  36. 36. 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 studiedProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  37. 37. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  38. 38. Mode of action: Dosulepin in chronic pain Dosulepin potentiate serotonin and norepinephrine in descending pain-suppression pathways 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 Daniel a. Monti M.D. et. al. Management of chronic pain in elderly patients. Practical geriatrics; December 1996 Vol 49, No. 12 Brookoff, 2000Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  39. 39. Mode of action Ascending Tracts Descending Tracts TCAs potentiate serotonin and norepinephrine in descending pain- suppression pathways 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. Prothiaden in Chronic Pain Company Confidential © 2010 Abbott(Brookoff, 2000)
  40. 40. 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)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  41. 41. 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: 959-967Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  42. 42. Recommendations of Treatment GuidelinesProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  43. 43. 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 –33Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  44. 44. Prothiaden in Chronic Pain Company Confidential © 2010 Abbott
  45. 45. Take Homes ! Pain needs to be treated TCAs are the aggressively to recommended first-line prevent sensitization therapy in chronic pain Dothiepin is better Chronic pain even more tolerated in relation so as to combat to its side effects Neuroplasticity than amitriptylineProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  46. 46. Thank youProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  47. 47. Dedicated to my family for making everything worthwhileProthiaden in Chronic Pain Company Confidential © 2010 Abbott
  48. 48. READ NOT TO CONTRADICT OR CONFUTE NOR TO BELIEVE AND TAKE FOR GRANTED BUT TO WEIGH AND CONSIDER THANKYOU My sincere thanks to ABBOTT and SAMPATH(CRO)Prothiaden in Chronic Pain Company Confidential © 2010 Abbott

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