The document discusses neuropathic pain and its treatment. It defines neuropathic pain as pain initiated or caused by primary lesions or dysfunction in the nervous system. Some examples of neuropathic pain given are postherpetic neuralgia, diabetic peripheral neuropathy, and post-surgical neuropathy. The document outlines approaches to diagnosing neuropathic pain, including listening to the patient's description of their pain, looking for sensory abnormalities, and locating the region of pain to a neuroanatomical area. It discusses treating neuropathic pain with topical medications, systemic medications like anticonvulsants, antidepressants and opioids.

1. Neuropathic Pain and Its Treatment

3. IASP Definition of Pain “ Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”

4. Nociceptive vs Neuropathic Pain Mixed Type Caused by a combination of both primary injury and secondary effects Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system Postoperative pain Mechanical low back pain Sickle cell crisis Arthritis Postherpetic neuralgia Neuropathic low back pain CRPS* Sports/exercise injuries Central post- stroke pain Trigeminal neuralgia Distal polyneuropathy (eg, diabetic, HIV) . Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9 .

5. Nociceptive pain Pain caused by an inflammatory or non-inflammatory response to a noxious stimulus Neuropathic pain " Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system"1 Pain with nociceptive and neuropathic components 1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, Wash: IASP Press; 1994:209-214. Understanding Key Types of Pain

6. Recognition of Nociceptive Pain Examples Pain due to inflammation Limb pain after a fracture Joint pain in osteoarthritis Common descriptors Aching Throbbing Nociceptive pain Pain caused by an inflammatory or non-inflammatory response to a noxious stimulus Other characteristics Pain typically localised at site of injury Usually time limited, resolving when damaged tissue heals Responds to conventional analgesics McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

7. Example of Chronic Nociceptive Pain Osteoarthritis of the knee Normal joint Osteoarthritis1 Synovial fluid Joint capsule Synovial membrane Cartilage Inflammation as bones rub together Thinned cartilage Scott DL. Osteoarthritis and rheumatoid arthritis. In: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

8. Recognition of Neuropathic Pain Examples2 Postherpetic neuralgia Diabetic peripheral neuropathy Postsurgical neuropathy Post-stroke pain Spinal cord injury Common descriptors2 Burning Stabbing (lancinating) Tingling Electric lightening Hypersensitivity to touch or cold (allodynia) Neuropathic pain " Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system"1 Other characteristics2 Pain not necessarily at site of lesion Usually a chronic condition Responds poorly to conventional analgesics 1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, Wash: IASP Press; 1994:209-214. 2. Clinical States: Neuropathic Pain. In: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

9. COMMON TYPES OF NEUROPATHIC PAIN PERIPHERAL Polyradioculopathy Alcoholic polyneuropathy Entrapment neuropathies (carpal tunnel) Nerve compression by tumor Diabetic neuropathy Phantom limb pain Postherpetic neuralgia Trigeminal neuralgia CENTRAL Compressive myelopathy from spinal stenosis HIV myelopathy MS Parkinson disease Post ischemic myelopathy Poststroke pain Posttraumatic spinalcord injury

10. Physiology of Pain Perception Transduction Transmission Modulation Perception Interpretation Behavior Injury Descending Pathway Peripheral Nerve Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Ascending Pathways Dorsal Horn Brain Spinal Cord Adapted with permission from WebMD Scientific American ® Medicine .

11. Pathophysiologies Involved in Neuropathic Pain Disorders that develop after trauma affecting limbs with or without obvious peripheral nerve injury Incedents include: Crush injuries Lacerations Fractures Occasionally after a MI or CVA Burning accompanied by diffuse tenderness and pain on light touch Autonomic Nervous System dysfunction Early changes: Warm skin temperature Erythema Edema Late changes: Cool and pale or cyanotic appearance Dystrophic changes such as smooth, glossy skin and bone demineralization Stiff, painful joints Thermography used to document differences in regional blood flow www.aware-rsd.org/ id58.html Source: Stoelting and Miller

12. NERVE INJURY Ectopic Nociceptor Fiber discharges sensitization Interactions Tonic Activation of C Fibers Fixation of SP Release of EAA on NK1 Receptor ACTIVATION OF NMDA RECEPTORS CENTRAL SENSITIZATION

13. Multiple Pathophysiologies May Be Involved in Neuropathic Pain More than one mechanism of action likely involved Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy

14. Example of Neuropathic Pain: Ulnar Nerve Lesion Following Bone Fracture Ascending input Descending modulation Trauma leading to nerve lesion Perceived pain Impulses generated within ulnar nerve Spinal cord Peripheral nociceptors McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. Lesion

15. Example of Neuropathic Pain Diabetic Peripheral Neuropathy In diabetic neuropathy, sensorimotor impairment may occur in a“sock- and-glove” pattern Hyperaesthesia Decreased sensation Absence of superficial pain Boulton AJ, et al. Diabetes Care 2004;27:1458–86. Boulton AJ, et al. Diabetes Care. 2005;28:956-62. Kumar S, et al. Diabet Med 1994;11:480-484.

16. Co-presentation of Nociceptive and Neuropathic Pain Nociceptive pain Examples - low back pain with associated lumbar radiculopathy cancer pain carpal tunnel syndrome Neuropathic pain Both types of pain co-exist in many conditions McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

17. Example of Co-existing Pain Herniated disc causing low back pain and lumbar radiculopathy McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

18. Example of Co-existing Pain Herniated disc causing low back pain and lumbar radiculopathy Lumbar vertebra McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. Disc herniation Activation of peripheral nociceptors – cause of nociceptive pain component Compression and inflammation of nerve root – cause of neuropathic pain component

19. Example of Co-existing Pain Patient presents with both types of pain Herniated disc causing low back pain and lumbar radiculopathy McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. Constant ache, throbbing pain in the low back Lesion Shooting, burning pain in the foot Activation of local nociceptors Ectopic discharges from nerve root lesion

20. Prevalence of Neuropathic Pain Painful Diabetic Neuropathy (PDN) Painful diabetic neuropathy occurs in up to 26% of all people with diabetes 1 Diabetes is a significant healthcare problem in Africa and the Eastern Mediterranean / Middle East regions, affecting: An estimated 35 million people (5% of the adult population) in 2007 2 A predicted 63 million people (6% of the adult population) by 2025 2 Low back pain In patients with chronic low back pain, 35% may have predominantly neuropathic pain 3 Postherpetic Neuralgia (PHN) Neuropathic pain affects 25-50% of people over 50 who have had herpes zoster 4 1. Davies M, et al. Diabetes Care. 2006;29:1518-22. 2. International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels (Belgium); 2006. 3. Freynhagen R, et al. Curr Med Res Opin. 2006;22:1911-20. 4. Schmader KE. Clin J Pain 2002; 18(6):350-54.

21. Prevalence of Neuropathic Pain

23. Percentages of Herpes Zoster Patients With Persistent Pain Central Hospital Tripoli 0 10 20 30 40 50 60 70 80 0 19 29 39 49 59 69  70 Age (y)  1 month  1 year % of patients

24. Quiz Question Give three examples of neuropathic pain Answer Diabetic peripheral neuropathy Postherpetic neuralgia Post-surgical neuropathy Post-stroke pain Spinal cord injury Low back pain with a neuropathic component

26. Assessing the Patient With Pain Onset and duration Location/distribution Quality Intensity Aggravating/relieving factors Associated features or secondary signs/symptoms Associated factors mood/emotional distress functional activities Treatment response

27. Positive Sensory Symptoms Merskey H, Bogduk N, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994. International Association for the Study of Pain (IASP) pain terminology. Positive symptom Definition Spontaneous pain Painful sensations felt with no evident stimulus Allodynia Pain due to a stimulus which does not normally provoke pain (e.g. touching, movement, cold, heat) Hyperalgesia An increased response to a stimulus which is normally painful ( e.g. cold, heat, pinprick) Dysaesthesia An unpleasant abnormal sensation, whether spontaneous or evoked ( e.g. shooting sensation) Paraesthesia An abnormal sensation that is not unpleasant, whether spontaneous or evoked (e.g. tingling, buzzing, vibrating sensations)

28. Negative Sensory Symptoms Merskey H, Bogduk N, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994. International Association for the Study of Pain (IASP) pain terminology. Negative symptom Definition Hypoaesthesia Diminished sensitivity to stimulation, excluding the special senses (e.g. touch, pain) Anaesthesia A total loss of sensation (especially tactile sensitivity) Hypoalgesia Diminished pain in response to a normally painful stimulus Analgesia Absence of pain in response to stimulation that would normally be painful

29. Diabetic Peripheral Neuropathy Numbness or insensitivity to pain or temperature Tingling, burning, or prickling sensation Sharp pains or cramps Extreme sensitivity to touch, even light touch Loss of balance and coordination Muscle weakness and loss of reflexes Symptoms are often worse at night National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic neuropathies: the nerve damage of diabetes. Available from: http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/neuropathies.pdf. Accessed 15 Jul 2009.

30. Consider a Neuropathic Component in Low Back Pain Neuropathic symptoms in low back pain may include4: Positive sensory symptoms, e.g. tingling or burning pain Negative sensory symptoms, e.g. numbness 1. Kavoussi R. Eur Neuropsychopharmacol. 2006 Jul;16 Suppl 2:S128-33. 2. Devor M. In: McMahon SB, Koltzenburg M, editors. Textbook of Pain. London: Elsevier; 2006. pp.905-28. 3. Baron R. Nat Clin Pract Neurol. 2006;2(2):95-106. 4. Audette JF, et al. Curr Pain Headache Rep 2005;9(3):168-77. 5. Freynhagen R, et al. Curr Med Res Opin. 2006;22:1911-20. Excessive release of neurotransmitters2,3 Neuropathic back pain may have many clinical causes, including radiculopathy, spinal stenosis and trauma Chronic low back pain may have a neuropathic component in more than one-third (55%) of patients5

31. Post-herpetic Neuropathy Extreme sensitivity to touch (interferes with dressing, bathing, grooming, eating and mobility) Hyperalgesia and allodynia Intermittent itching Numbness Ongoing, spontaneous, burning pain Intermittent, sharp, l ancinating pain McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.

32. Quiz Question Give three examples of positive sensory symptoms Answer Spontaneous pain Allodynia Hyperalgesia Dysaesthesia Paraesthesia

33. Diagnostic Approach

34. The 3 L Approach to Diagnosis Patient verbal descriptors of pain, Q & A Nervous System lesion or abnormality Sensory abnormalities (skin and joints) Listen Look Locate

35. Listen to the Patient Description of Pain Question patients about their pain Duration Frequency Quality Intensity Be alert and ask for common verbal descriptors of neuropathic pain (e.g. tingling, electric shock-like, numbness, burning, shooting) Use analogue or numerical scales to quantify the pain Location Pattern Provokers Relievers

36. Locate the Region of Pain to a Neuroanatomical Area Lumbar radiculopathy Carpal tunnel sequelae Diabetic peripheral neuropathy

37. Applying the 3L Approach Differentiates Neuropathic from Nociceptive Pain Pain Listen Locate Look Neuropathic "shooting" "electric shock“ "burning" "tingling" "itching" "numbness" The painful region may not necessarily be the same as the site of injury Pain occurs in the neurological territory of the affected structure (nerve, root, spinal cord, brain) Bedside tests demonstrate sensory abnormalities Nociceptive "aching" "throbbing" Painful region is typically localised at the site of injury Physical manipulation causes pain in site of injury Sensory abnormalities not indicated

38. Applying the 3L Approach Differentiates Neuropathic from Nociceptive Pain Can you detect sensory abnormalities using simple bedside tests? Consider specialist referral if neuropathic pain is still suspected consider also pain treatment in the interim period No Yes Look Probable nociceptive pain No Listen Are verbal descriptors suggestive of neuropathic pain? Yes Confirmed neuropathic pain diagnosis Initiate treatment No Yes Locate Can you identify the responsible nervous system lesion or disease?

39. Pain Treatment Continuum Least invasive Most invasive Psychological/physical approaches Topical medications *Consider referral if previous treatments were unsuccessful. Interventional techniques* Continuum not related to efficacy Sys tem ic medications*

40. Treatment Approach Hx / PE Emergency Non-emergent Pain crisis Chronic Adjuvant analgesics Ketamine etc Optimize opiods Consider regional anesthesia Opioid rotation

41. PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN

42. PAIN EXCESS NOCICEPTION +++ INFLAMMATION NEUROPATHIC PAIN PSYCHOLOGICAL PARACETAMOL NSAIDS Weak opioids MORPHINIC Antidepressants Antiepileptics Neurostimulation Anti NMDA etc. Psychotherapies Relaxation Psychotropics Psycho-social treatment

43. Neuropathic pain - Therapy Local therapy Antidepressants Anticonvulsants Opioids In the case of inadequate effect: consultation with a pain specialist Causal therapy

44. Pharmacologic Treatment Options Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain topical analgesics (capsaicin, lidocaine patch 5%) anticonvulsants (gabapentin, lamotrigine, pregabalin) antidepressants (nortriptyline, desipramine) opioids (oxycodone, tramadol) Consider safety and tolerability when initiating treatment

45. FDA-Approved Treatments for Neuropathic Pain Carbamazepine trigeminal neuralgia Duloxetine peripheral diabetic neuropathy Gabapentin postherpetic neuralgia Lidocaine Patch 5% postherpetic neuralgia Pregabalin* peripheral diabetic neuropathy postherpetic neuralgia *Availability pending based upon controlled substance scheduling by the DEA.

46. Pharmacologic Agents Affect Pain Differently BRAIN Descending Modulation Central Sensitization PNS Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Anticonvulsants Opioids Tricyclic/SNRI Antidepressants CNS Spinal Cord Peripheral Sensitization Dorsal Horn

47. Topical vs Transdermal Drug Delivery Systems Systemic activity Applied away from painful site Serum levels necessary Systemic side effects Peripheral tissue activity Applied directly over painful site Insignificant serum levels Systemic side effects unlikely Topical (lidocaine patch 5%) Transdermal (fentanyl patch)

48. Anticonvulsant Drugs for Neuropathic Pain Disorders Postherpetic neuralgia gabapentin* pregabalin * Diabetic neuropathy carbamazepine phenytoin gabapentin lamotrigine pregabalin * HIV-associated neuropathy lamotrigine Trigeminal neuralgia carbamazepine* lamotrigine oxcarbazepine Central poststroke pain lamotrigine *Approved by FDA for this use. HIV = human immunodeficiency virus.

49. Pregabalin in Neuropathic Pain Disorders FDA approved for postherpetic neuralgia and diabetic neuropathy Anticonvulsant: uncertain mechanism Determined intestinal absorption Usually well tolerated; serious adverse effects rare dizziness and sedation can occur No significant drug interactions Peak time: 2 to 3 h; elimination half-life: 5 to 7 h Usual dosage range for neuropathic pain up to (75 mg –600mg )daily dose

50. Efficacy of Pregabalin in mechanical allodynia Static Dynamic Pregabalin +++ +++ Gabapentin +++ +++ Morphine +++ - Amitriptyline +++ - static=pressure (von Frey) dynamic=stroking (cotton wool)

51. Pregabalin binding site Pregabalin and Gabapentin binds specifically on    subunit of Ca ++ channel Function needs to be verified ( Viedeo from pfizer )

52. Guidelines for the Treatment of Neuropathic Pain

53. International Association for the Study of Pain (IASP) Recommendations First line Calcium channel α 2- δ (alpha-2- delta) ligands (pregabalin, gabapentin), tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors ( SNRIs), and topical lidocaine Second line Opioid analgesics or tramadol alone or in combination with one of the first-line medications. Third line Medications including carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, bupropion, citalopram, mexiletine, Nmethyl-D-aspartate (NMDA) receptor antagonists, and topical capsaicin. Dworkin RH, et al. Pain. 2007 Dec 5;132(3):237-51.

54. Canadian Pain Society Guidelines *5% gel or cream - useful for focal neuropathy such as postherpetic neuralgia. SNRI: serotonin/noradrenaline reuptake inhibitor; TCA: tricyclic antidepressant; CR: controlled-release Moulin DE, et al. Pain Res Manag. 2007 Spring;12(1):13-21. 1st line pregabalin or gabapentin TCA Add additional agents sequentially if partial but inadequate pain relief (do not add SNRI to TCA) 2nd line SNRI topical lidocaine * 3rd line tramadol or CR opioid analgesic 4th line cannabinoids, lamotrigine, methadone, topiramate, valproic acid

55. Efficacy in Patients with Diabetic Peripheral Neuropathy Pregabalin significantly reduces pain associated with diabetic peripheral neuropathy1 Pain reductions are positively correlated with dosage1 Pain-related sleep interference is also significantly improved1 Freeman R, et al. Diabetes Care. 2008;31(7):1448-54. -3 0 -1.5 -2.5 -1 Placebo (n=550) Pregabalin 150 mg/day (n=175) Pregabalin 300 mg/day (n=265) Pregabalin 600 mg/day (n=507) Endpoint least-squares mean pain scores -2 -0.5 -1.49 -2.05* -2.36 † -2.75 † *p=0.007 vs placebo †p<0.0001 vs placebo

56. Safety/Tolerability in Low Back Pain Physician (%) Patients (%) Overall assessment by physicians and patients of the tolerability of pregabalin treatment 56.2 38.4 3.7 1.6 50.5 44.7 3.4 1.5 Patients with adverse events: 7% Most frequently reported adverse events: Dizziness 1% Fatigue 1% Somnolence 1% Nausea 0.6% Treatment terminated due to adverse events: 4% Patients ‘very satisfied’ or ‘satisfied’ with the tolerability of pregabalin: 95% Physicians coring tolerability of Pregabalin as ‘very good’ or ‘good’: 95% 1. Mallison RB, et al. MMW Fortschr Med 2007;(149 Jg.):S13-20. 2. Mallison RB, et al. Eur J Neur 2006;13 (Suppl 2):224. Very good Good Moderate Unsatisfactory Very satisfied Satisfied Moderately satisfied Not satisfied

57. 60%Very satisfied Satisfied 35% Moderately satisfied 3% Un satisfied 2% Safety/Tolerability in Low Back Pain Pain Clinic Central hospital Tripoli

58. Antidepressants in Neuropathic Pain Disorders* Multiple mechanisms of action Randomized controlled trials and meta-analyses demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy Onset of analgesia variable analgesic effects independent of antidepressant activity Improvements in insomnia, anxiety, depression Desipramine and nortriptyline have fewer adverse effects *Not approved by FDA for this use.

59. Tricyclic Antidepressants: Adverse Effects Commonly reported AEs (generally anticholinergic): blurred vision cognitive changes constipation dry mouth orthostatic hypotension sedation sexual dysfunction tachycardia urinary retention Desipramine Nortriptyline Imipramine Doxepin Amitriptyline Fewest AEs Most AEs AEs = adverse effects .

60. Principles of Opioid Therapy for Neuropathic Pain Opioids should be titrated for therapeutic efficacy versus effect Fixed-dose regimens generally preferred Document treatment plan and outcomes Consider use of opioid written care agreement Opioids can be effective in neuropathic pain Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants) Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction

61. Interventional Treatments for Neuropathic Pain Neural blockade sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) Neurolytic techniques alcohol or phenol neurolysis pulse radio frequency neural ablative procedures. Stimulatory techniques spinal cord stimulation peripheral nerve stimulation Medication pumps CRPS = complex regional pain syndrome.

62. Summary of Advances in Treatments for Neuropathic Pain* Botulinum toxin: low back pain Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related neuropathy, with gabapentin CR oxycodone: diabetic neuropathy Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others Levetiracetam: neuropathic pain and migraine Oxcarbazepine: neuropathic pain; diabetic neuropathy Bupropion: neuropathic pain Transdermal fentanyl: low back pain *Applications not approved by FDA.

63. Take Home Message Chronic neuropathic pain is a disease, not a symptom “ Rational” polypharmacy is often necessary combining peripheral and central nervous system agents enhances pain relief Treatment goals include: balancing efficacy, safety, and tolerability reducing baseline pain and pain exacerbations improving function and QOL New agents and new uses for existing agents offer additional treatment options

64. Conclusion Several peripheral and central mechanisms underly the various neuropathic pain symptoms. Therapeutic options should be more symptom oriented and (ideally) mechanism oriented. The multiplicity of mechanisms in the same patient may explain why response to a single intervention is often partial.

66. http://www.thermogramcenter.com/Images_files/RSD%20arms.jpg

67. PAF injury In addition to changes in the expression levels of Na + - channels, their activity (passage of current and inactivation kinetics) may also be rapidly modified by processes of phosphorylation elicited by inflammatory agents.

68. Current Pharmocological Agents for Neuropathic Pain Sodium channel blockers Antidepressant Drugs that enhance GABAergic function NMDA receptor antagonists Others

69. Na + Channels Na + Channels present in the dorsal root ganglia (DRG) of peripheral afferent fibre (PAF) can be classified into 2 types :- 1. Tetrodotoxin (TTX) - sensitive Low threshold channels which rapidly activate and inactivate; 2. Tetrodotoxin (TTX) - resistant High threshold channels with slower kinetics of activation an inactivation.

70. Na + Channels modulators Phenytoin Carbamazepine Sodium valproate Lamotrigine Topiramate Mexiletine Lidocaine blockade of peripheral TTX sensitive Na + channels in damaged PAFs Antiallodynic actions

71. Descending inhibitory pathways and monoamine receptors Receptors Transduction systems Effect 5-HT 1A Open K + channel - hyperpolarize DH - antinociception 5-HT 2A Activate PLC - depolarize DH - nociception 5-HT 3 Open Ca ++ channel - depolarize DH - nociception  1 Positively couple with - nociception adenylate cyclase  2A Negatively couple - inhibit nociception with adenylate cyclase Monoamines exert inhibitory or excitatory actions via distinct receptor subtypes differentially coupled to intracellular transduction systems.

72. Tricyclic antidepressants Inhibit 5-HT and NE reuptake  1 antagonist muscarinic antagonist histamine antagonist Amitriptyline is also potent 5-HT 2A antagonist.

73. Inhibitory interneurons in the dorsal horn (DH) Gamma - amino - butyric acid (GABA) is a major inhibitor neurotransmitter in the brain. A widespread inhibitory influence of GABA ergic interneurons on nociceptive transmission in the DH and supraspinal structures. Drugs which enhance GABA ergic function such as sodium valproate, clonazepam and gabapentin can partially inhibit pain transmission.

74. Gabapentin pharmacokinetics Rapidly absorbed orally, no effect of foods no protein binding is not metabolized no enzyme induction / inhibition effect excreted unchanged via urine dose titration in patient with renal insufficiency t 1/2 ~ 5-7 h bid or tid dosing

75. Gabapentin dosage and side effects 600 - 3,600 mg/day somnolence, dizziness, ataxia, fatigue, nystagmus and weight gain

76. Gabapentin binding site Gabapentin binds specifically on    subunit of Ca ++ channel Function needs to be verified

77. PAF injury and Excitatory amino acids (EAA) PAF injury glutamate content in DH dorsal horn excitability mediated via NMDA receptors / AMPA receptor [Ca ++ ] i levels antinociceptive efficacy of opioid NMDA receptor antagonists e.g. dextromethorphan, ketamine and dizolcipine potentiates the analgesic properties of opioids in neuropathic pain

78. Pain and neural plasticity at spinal level Chronic pain / inflammation CCK Neurokinins c-GRP Neuropathic pain CCK antinociceptive potency of morphine Neurokinins Galanin No

79. Cholecystokinin (CCK) CCK act as an endogenous antiopioid. CCK reduces the release of Leuenkephalin acting at the  -opioid receptors. CCK B antagonist e.g. L365260 and CI-988 enhance the antinociceptive effects of morphine in rats.