1. 1 Neuropathic Pain And Diabetic Neuropathy Dr. Awni Khrais Philadelphia University.

2. 2 Examples Peripheral Postherpetic neuralgia Trigeminal neuralgia Diabetic peripheral neuropathy Postsurgical neuropathy Posttraumatic neuropathy Central Poststroke pain Common descriptors 2 Burning Tingling Hypersensitivity to touch or cold Examples Pain due to inflammation Limb pain after a fracture Joint pain in osteoarthritis Postoperative visceral pain Common descriptors 2 Aching Sharp Throbbing Examples Low back pain with radiculopathy Cervical radiculopathy Cancer pain Carpal tunnel syndrome Mixed Pain Pain with neuropathic and nociceptive components Neuropathic Pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system (either peripheral or central nervous system) 1 Nociceptive Pain Pain caused by injury to body tissues (musculoskeletal, cutaneous or visceral) 2 Presentation Across Pain States Varies 1. International Association for the Study of Pain. IASP Pain Terminology. 2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

3. 3 Nociceptive Pain Nociceptive pain is an appropriate physiologic response to painful stimuli. Tortora G, Grabowski SR. Principles of Anatomy and Physiology. 10th ed.2003. Trauma Ascending inputDescending modulation Dorsal root ganglion Spinothalamic tract Peripheral nociceptors Peripheral nerve Dorsal horn Pain

4. 4 Fiber Types Involved in Neuropathic Pain Aβ fibers —Large diameter, myelinated, fast conduction velocity —Mechanoreceptors normally activated by non-noxious mechanical stimuli (touch) Aδ fibers —Large diameter, myelinated, intermediate conduction velocity —Normally activated by noxious stimuli (transmit sharp pain) C fibers —Small diameter, unmyelinated, slow conduction velocity —Normally activated by noxious stimuli (responsible for secondary pain, normally burning, aching pain) In neuropathic pain abnormal sensations may be transmitted along Aβ, Aδ or C fibers Dworkin Clin J Pain. 2002;18:343-349 Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;11-57

5. 5 Defining Pain What is pain? “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212. International Association for the Study of Pain (IASP) 1994

6. 6 Fiber Types Involved in Neuropathic Pain Aβ fibers —Large diameter, myelinated, fast conduction velocity —Mechanoreceptors normally activated by non-noxious mechanical stimuli (touch) Aδ fibers —Large diameter, myelinated, intermediate conduction velocity —Normally activated by noxious stimuli (transmit sharp pain) C fibers —Small diameter, unmyelinated, slow conduction velocity —Normally activated by noxious stimuli (responsible for secondary pain, normally burning, aching pain) In neuropathic pain abnormal sensations may be transmitted along Aβ, Aδ or C fibers Dworkin Clin J Pain. 2002;18:343-349 Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;11-57

7. 7 IASP Definitions Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212. Pain termDefinition AllodyniaPain due to a stimulus that does not normally provoke pain Analgesia Absence of pain in response to stimulation that would normally be painful HyperalgesiaAn increased response to a stimulus that is normally painful Hyperesthesia Increased sensitivity to stimulation, excluding the special senses Hyperpathia A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold HypoalgesiaDiminished pain in response to a normally painful stimulus Hypoesthesia Decreased sensitivity to stimulation, excluding the special senses

8. 8 Prevalence/Incidence of Neuropathic Pain in Different Conditions 20-24% of diabetics experience painful DPN 1 25-50% of patients >50 years with herpes zoster develop PHN (≥3 months after healing of rash) 1 Up to 20% develop post-mastectomy pain 2 One-third of cancer patients have neuropathic pain (alone or with nociceptive pain) 3 7% of patients with low back pain may have associated neuropathic pain 4 1. Schmader. Clin J Pain. 2002;18:350-4. 2. Stevens et al. Pain. 1995;61:61-8 3. Davis and Walsh. Am J Hosp Palliat Care. 2004;21(2):137-42. 4. Deyo and Weinstein. NEJM 2001;344(5):363 - 370

9. 9 Neuropathic Pain Causes Peripheral causes of neuropathic pain Trauma – e.g. surgery, nerve entrapment, amputation Metabolic disturbances – e.g. diabetes mellitus, uremia Infections – e.g. herpes zoster (shingles), HIV Toxins – e.g. chemotherapeutic agents, alcohol Vascular disorders – e.g. lupus erythematosus, polyarteritis nodosa Nutritional deficiencies – e.g. niacin, thyamine, pyridoxine Direct effects of cancer – e.g. metastasis, infiltrative Central causes of neuropathic pain Stroke Spinal cord lesions Multiple sclerosis Tumors Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical guide to neuropathic pain. 2000: Woolf CJ et al. Lancet. 1999;353:1959-1964.

10. 10 Descriptions of Symptoms Reported by Patients with Neuropathic Pain* How would you describe the pain? (n=1172) *Includes peripheral, central and mixed pain states Data on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey.

11. 11 Signs and Symptoms of Neuropathic Pain Sign/SymptomDescription (example) Spontaneous symptoms Spontaneous pain 1 Persistent burning, intermittent shock-like or lancinating pain Dysesthesias 2 Abnormal unpleasant sensations e.g. shooting, lancinating, burning Parasthesias 2 Abnormal, not unpleasant sensations e.g. tingling Stimulus-evoked symptoms Allodynia 2 Painful response to a non-painful stimulus e.g. warmth, pressure, stroking Hyperalgesia 2 Heightened response to painful stimulus e.g. pinprick, cold, heat Hyperpathia 2 Delayed, explosive response to any painful stimulus 1.Baron. Clin J Pain. 2000;16:S12-S20. 2. Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

12. 12 The Inter-Relationship Between Pain, Sleep, and Anxiety / Depression Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27 Pain Sleep disturbances Anxiety & Depression Functional impairment

13. 13 1.Fishbain DA et al. Pain 1986;26:181-197 2.Krishnan KR et al. Pain 1985;22:279-287 Anxiety and Depression are Prevalent in Chronic Pain Anxiety 283 patients evaluated at pain centers 1 63% significant anxiety symptoms (DSM-III) 56% significant depressive symptoms (DSM-III) Depression 71 patients with chronic low back pain 2 44% major, 11% minor depression (SADS-L)

14. 14 Classifications of Pain Acute Chronic Duration Nociceptive Neuropathic Pathophysiology

15. 15 The Continuum of Pain 1 <1 month Time to resolution  3-6 months Acute Pain Chronic Pain Usually obvious tissue damage Increased nervous system activity Pain resolves upon healing Serves a protective function Pain for 3-6 months or more 2 Pain beyond expected period of healing 2 Usually has no protective function 3 Degrades health and function 3 1. Cole BE. Hosp Physician. 2002;38:23-30. 2.Turk and Okifuji. Bonica’s Management of Pain. 2001. 3. Chapman and Stillman. Pain and Touch. 1996. Insult

16. 16 Development of Neuropathic Pain Woolf and Mannion. Lancet 1999;353:1959-64 Neuropathic pain Spontaneous painStimulus-evoked pain Mechanisms MetabolicTraumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage

17. 17 Neuropathic Pain: Underlying Mechanisms Peripheral Mechanisms Membrane hyperexcitability —Ectopic discharges Peripheral sensitization Central Mechanisms Membrane hyperexcitability —Ectopic discharges Wind up Central sensitization Denervation supersensitvity Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;173:12-24. Woolf CJ et al. Lancet. 1999;353:1959- 1964. Roberts et al. In Casey KL (Ed). Pain and central nervous system disease. 1991

18. 18 “Sciatica”: Mixed Pain State with Several Possible Pathological Mechanisms Baron R, Binder A. 2004 Orthopade. 2004;33(5):568-75 Disc C Fiber A Fiber Nociceptive component: Sprouting from C-fibers into the disc Neuropathic component I: Damage to a branch of the C fiber due to compression and inflammatory mediators Neuropathic component II: Compression of nerve root Neuropathic component III: Damage to nerve root by inflammatory mediators Central sensitization

19. 19 Neuropathic Pain Causes Peripheral causes of neuropathic pain Trauma – e.g. surgery, nerve entrapment, amputation Metabolic disturbances – e.g. diabetes mellitus, uremia Infections – e.g. herpes zoster (shingles), HIV Toxins – e.g. chemotherapeutic agents, alcohol Vascular disorders – e.g. lupus erythematosus, polyarteritis nodosa Nutritional deficiencies – e.g. niacin, thyamine, pyridoxine Direct effects of cancer – e.g. metastasis, infiltrative Central causes of neuropathic pain Stroke Spinal cord lesions Multiple sclerosis Tumors Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical guide to neuropathic pain. 2000: Woolf CJ et al. Lancet. 1999;353:1959-1964.

20. 20 Challenges in Diagnosing Neuropathic Pain Diverse symptomatology 1 Multiple mechanisms 1 Difficulties in communicating and understanding symptoms —Patients may find it difficult to articulate their symptoms clearly —Physicians may find it difficult to interpret some of the terminology patients use to describe their symptoms Variable response to treatment 2 1. Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-64 2. Bonezzi C, Demartini L. Acta Neurol Scand Suppl. 1999;173:25-3

21. 21 Pain Experience in Patients with Neuropathic Pain in EU Survey 88% of patients reported their worst pain as moderate or severe Worst Pain in Last 24 Hours Pain Severity Index Mild Moderate Severe 13% 37% 51% Mild Moderate Severe 21% 54% 25% Mild/no: 0-3; Moderate: 4-6; Severe: 7-10 77% of patients reported a pain severity index of moderate or severe N=602; 93% on Rx medication for pain Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders

22. 22 Current Treatments: Expert Views “A relatively large number of neuropathic pain patients fail to find adequate relief with existing practices because of a ceiling effect of available drugs; these patients often develop significant comorbidity with sizable impact on their quality of life” Smith and Sang. Eur J Pain.2002:6(suppl B):13-18 “We cannot provide adequate treatment to a vast number of patients with established neuropathic pain” Taylor BK. Curr Pain and Headache Rep. 2001;5:151-161

23. 23 Diabetic Neuropathy

24. 24 Diabetic Neuropathies “ The presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes “ Boulton. AJM, Diabetic Md.15:508-514, 1998 Diabetic, American Association

25. 25 Other Definition “ Clinical or subclinical disorders, including somatic and/or autonomic parts of PNS ” Dyck.P, 2005 American Diabetic Association

26. 26 Distribution(%) of Symptoms and Signs of Proximal Neuropathies in Diabetes ------------------------------------------------------------------- Clinical Presentation Vasculitis CIDP MGUS DM ------------------------------------------------------------------- DSPN (motor/sensory) 3 91 100 67 Distal(asymmetric) 27 9 0 0 Multifocal 70 0 0 33

27. 27 Differentiation of Distal Symmetric Polyneuropathy from Mono-/Amyoradiculopathies DSPNMono- /Amyoradiculopathies OnsetInsidiousAcute/sub acute DistributionDistal/length dependent Proximal/Asymmetric Leading signs and symptomsMild to moderate sensory symptoms(- ve or +ve) & mild motor symptoms Sever sensory (+ve pain) motor (weakness and atrophy) symptoms Course of diseaseSlow progressionMonophasic Glycemic controlDependentIndependent Duration of diabetesDependentIndependent Association with retinopathy & nephropathy AssociatedNon Associated

28. 28 Common Mononeuropathies Cranial3 rd, 4 th, 6 th, 7 th ThoracicMononeuritis multiplex PeripheralPeroneal Sural Sciatic Aaron Vinik, and Anahit Mehrabyan,American Diabetes Association (2006)

29. 29 Comparison of features of Mononeuritis & entrapment Aaron Vinik, and Anahit Mehrabyan,American Diabetes Association (2006) MononeuritisEntrapment OnsetSuddenGradual PainAcuteChronic MultiplexOccursRare CourseResolvesPersists without intervention TreatmentPhysical therapyRest/ Splints steroid and local anesthetic injections, surgery

30. 30 Pathogenesis A- Duration and severity of hyperglycemia B- Electrophysiology

31. 31 C- Glucose metabolic and transport dysfunction Polyol pathway, Myoinsitol, Glyation, Oxidative stress, Growth factor, Insulin-like growth, c.peptide, VEGF, Immune Mechansim American Diabetic Association 2005

32. 32 Current Prescription Medication Use Among Patients Treated for Neuropathic Pain Anticonvulsants 13% Antidepressants/ mood stab. 4% Opioids 4% NSAIDs (incl. COX-II) 41% Non-narcotic analgesics 21% Tranquilizers 9% Local anesthetics 6% All other 2% Medications with established efficacy represent a small proportion of Rx IMS global Rx data 4Q 2003 (n=143 million Rx)

33. 33 1)Exclude nondiabetic causes Malignant disease (e.g. bronchogenic carcinoma) Metabolic Toxic (e.g. alcohol) Infective (e.g. HIV infection) Latrogenic (e.g. isoniazid, vinca alkaloids) Medication related (chemotherapy, HIV treatment) Initial management of symptomatic neuropathy

34. 34 2) Explanation, support, and practical measures (e.g. bed cradle to lift bed, clothes off hyperesthetic skin). 3) Assess level of blood glucose control profiles. 4) Aim for optimal stable control. 5) Consider pharmacological therapy. Initial management of symptomatic neuropathy

35. 35 Oral symptomatic therapy of painful neuropathy Drug classDrugDaily dose (mg)Side Effects TricyclicsAmitriptyline Imipramine 25-150 ++++ SSRIsParoxitene Citalopram 40 +++ AnticonvulsantsGabapentin Lamotrigine Carbamazepine 900-1,800 200-400 Up to 800 ++ +++ Antiarrhythmics*MexiliteneUp to 450+++ OpioidsTramadol Oxycodone CR † 50-400 10-60 +++ ++++ All medications in the table have demonstrated efficacy in randomized controlled studies, *Mexilitene should be used with caution & with regular EKG monitoring, † Oxycodone CR may be useful as an add-in therapy in severe symptomatic neuropathy.

36. 36 Thank you

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40. 40 Diabetic Neuropathies “ The presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes “ Boulton. AJM, Diabetic Md.15:508-514, 1998 Diabetic, American Association

41. 41 Current Prescription Medication Use Among Patients Treated for Neuropathic Pain Anticonvulsants 13% Antidepressants/ mood stab. 4% Opioids 4% NSAIDs (incl. COX-II) 41% Non-narcotic analgesics 21% Tranquilizers 9% Local anesthetics 6% All other 2% Medications with established efficacy represent a small proportion of Rx IMS global Rx data 4Q 2003 (n=143 million Rx)

42. 42 Pathogenesis A- Duration and severity of hyperglycemia B- Electrophysiology

43. 43 C- Glucose metabolic and transport dysfunction Polyol pathway, Myoinsitol, Glyation, Oxidative stress, Growth factor, Insulin-like growth, c.peptide, VEGF, Immune Mechansim American Diabetic Association 2005

44. 44 Current Prescription Medication Use Among Patients Treated for Neuropathic Pain Anticonvulsants 13% Antidepressants/ mood stab. 4% Opioids 4% NSAIDs (incl. COX-II) 41% Non-narcotic analgesics 21% Tranquilizers 9% Local anesthetics 6% All other 2% Medications with established efficacy represent a small proportion of Rx IMS global Rx data 4Q 2003 (n=143 million Rx)

45. 45 LANSS Scale Completed by physician in office Differentiates neuropathic from nociceptive pain 5 pain questions and 2 skin sensitivity tests Identifies contribution of neuropathic mechanisms to pain Validated Bennett. Pain. 2001;92:147-57

46. 46 DN4 Diagnostic Questionnaire DN4: Douleur Neuropathique en 4 questions Bouhassira et al. Pain. 2005;114:29-36 Completed by physician in office Differentiates neuropathic from nociceptive pain 2 pain questions (7 items) 2 skin sensitivity tests (3 items) Validated

47. 47 Pain History in Neuropathic Pain Type, distribution and location of pain —Character of complaints e.g. burning, shock-like, pins and needles etc. —Based on anatomic drawing Nerve territory Extraterritorial spread Duration of complaints Average intensity of pain in the last day/week (0-10) Extent of interference with daily activity (0-10) 1. Jensen and Baron. Pain. 2003;102:1-8 Identify the following: 1 Areas of further exploration Previous medical history Exposure to toxins or other drug treatment e.g. taxol, radiation Use of pain medications Associated psychological and mood disturbance

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49. 49 Pathophysiology of Neuropathic Pain: Neuropathic pain is pain initiated or caused by a primary lesion or dysfunction in the nervous system —Peripheral or central in origin Peripheral neuropathic pain may often co-exist with nociceptive pain Peripheral and central mechanisms mediate neuropathic pain independent of aetiology Characterized by positive and negative symptoms —Shared across neuropathic pain states

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51. 51 Sensory Processing and Neuropathic Pain Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182 Nerve function StimulusPrimary afferentSensationMechanism Normal Innocuous mechanical A-betaNormal touch Normal function Noxious, mechanical thermal or chemical A-delta nociceptor C nociceptor Normal sharp pain Normal burning pain Decreased Innocuous mechanical A-beta Tactile hypoanesthesia Decreased transmission of impulses Noxious, mechanical thermal or chemical A-delta nociceptor C nociceptor Mechanical, heal, or cold hypoalgesia Increased Innocuous, mechanical A-beta Dynamic mechanical allodynia Many theories (sensitization, etc.) Noxious, mechanical thermal or chemical A-delta nociceptor C nociceptor Mechanical, heat or cold hyperalgesia Many theories (wind-up, peripheral sensitization etc.)

52. 52 Allodynia*: Simple Tests and Expected Responses Type of allodyniaTestExpected response Mechanical static Manual light pressure on skin Dull pain Mechanical punctate Light manual pinprick with sharp stick Sharp, superficial pain Mechanical dynamic Stroke skin with brush, gauze or cotton Sharp, burning, superficial pain Thermal warm Touch skin with an object at ~40°C Painful, burning sensation Thermal cold Touch skin with object ~ 20 °C Painful, burning sensation Baron R. Clin J Pain. 2000;16:S12-S20. Jensen and Baron. Pain. 2003;102:1-8 *Allodynia: Pain due to a stimulus that does not normally provoke pain

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54. 54 Hyperalgesia*: Simple Tests and Expected Responses Type of hyperalgesia TestExpected response Mechanical pinprick Manual pinprick with a safety pin Sharp, superficial pain Thermal warm Touch skin with an object at ~46°C Painful, burning sensation Thermal cold Touch skin with coolants (acetone) Painful, burning sensation *Hyperalgesia: Increased response to a stimulus which is normally painful Baron R. Clin J Pain. 2000;16:S12-S20. Jensen and Baron. Pain. 2003;102:1-8

55. 55 IASP Definitions: Peripheral Neuropathic and Central Neuropathic Pain Neuropathic pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system Peripheral neuropathic pain Pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system Central neuropathic pain Pain initiated or caused by a primary lesion or dysfunction in the central nervous system Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

56. 56 Most Patients Currently Receive Rx Medications for Neuropathic Pain Almost all patients were receiving Rx meds for their neuropathic pain Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders