unmet needs in peripheral neuropathy

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  3. 3. PDN: Painful Diabetic neuropathy DAG :Di-AcylGlycerol LDL :Low-Density Lipoprotein PKC: Protein Kinase C. Rayaz .AM et al, Pathophysiology and Treatment of Painful Diabetic Neuropathy ,Current Pain and Headache Reports 2008, 12:192197 3 Pathophysiology of PDN
  4. 4. 4 1 Peripheral neuropathies are frequent, although their clinical relevance tends to be underestimated in comparison with CNS diseases considered to be more severe and epidemiologically more relevant: both these assumptions should be carefully weighed against the available data. 2 The frequency of peripheral neuropathies increases with age, thus having a negative impact on a part of the population potentially already affected by other neurological or systemic diseases. This might produce a sum of negative effects, worsening the quality of life of the patients. 3 Several peripheral neuropathies occur in the context of systemic diseases or medical conditions requiring drug administration. Unmet Needs & Issues Expert Opin Pharmacother. 2016;17(3):381-94.
  5. 5. 5 4 Many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Time from symptom onset to actual diagnosis is very high making it difficult to reverse the actual nerve damage 5 Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% of all neuropathy patients and 50% or more of patients with small fibre neuropathy. 6 Treatment of the underlying disease may improve disease- related neuropathies. However, severe peripheral neuropathies requiring intense and sometimes urgent treatment are isolated diseases of the peripheral nervous system and need specific treatment. Unmet Needs & Issues Expert Opin Pharmacother. 2016;17(3):381-94.
  6. 6. 6 7 No effective preventive/causal treatment is available for several peripheral neuropathies with high incidence, while symptomatic treatment of neuropathic pain related to peripheral neuropathies is more effective. 8 Preclinical studies are based on animal models that only partially recapitulate the full clinical features of the human disease. Refinement of these models will be a critical step in the future investigation of more effective treatments of peripheral neuropathies. 9 An effective multidisciplinary, coordinated approach including not only neurologists but also specialists of the related medical conditions is needed in order to design more relevant clinical trials on the treatment of peripheral neuropathies Unmet Needs & Issues Expert Opin Pharmacother. 2016;17(3):381-94.
  7. 7. 7 Indian Scenario Prevalence of DPN in India Indian J Med Res. 2011;133:369-380 Author Year Study City Prevalence (%) High prevalence of DPN ranging from 9- 64% 1 High Prevalence
  8. 8. 8 The cases had a mean age of 47.6 10.2 years (59% males) duration of symptoms of 5.9 8.2 months prior to presentation. Overall prevalence of DPN was 29.2% [95% CI 22.8-35.7]. PN among matched control was 10.7% (95% CI 3.5-17.8). Prevalence of DPN showed an increasing trend with age. J Postgrad Med. 2014 Jul-Sep;60(3):270-5. 1 High Prevalence Indian Scenario Prevalence of DPN in India
  9. 9. 9 The interrelationship between neuropathic pain, sleep, and anxiety/depression Pain Functional impairment Anxiety and depression Sleep disturbance Nicholson B et al. Comorbidities in chronic neuropathic pain, Pain Med 2004;5(Suppl 1):S9-27. 2 Negative Symptoms Indian Scenario Prevalence of DPN in India
  10. 10. 10 Most experimental studies in humans and animals show that sleep deprivation produces hyperalgesic changes1 Concurrent management of disturbed sleep and pain in patients with chronic pain is advisable:1 Pain enhances arousal and disrupts sleep Sleep deprivation and sleep disruption increase pain sensitivity and vulnerability to pain A vicious circle with sleep disorder and chronic pain maintaining and augmenting each other may result Sleep disruption contributes to pain 1. Lautenbacher S et al. Sleep deprivation and pain perception ,Sleep Med Rev 2006;10:357-69. 2 Negative Symptoms
  11. 11. 11 Pain intensity increases with increasing sleep disturbance in patients with neuropathic pain Presentpainintensity p=0.0001 603 patients with neuropathic pain of multiple etiologies MOS = Medical Outcomes Study Rejas J et al. Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain Euro J Pain 2007;11:329-40. Worse sleep 0 10 20 30 40 50 60 No pain Mild Discomforting Distressing Horrible Excruciating Mean MOS Sleep Scale 9-item index score 53.7 51.8 47.1 40.5 38.8 34.1 2 Negative Symptoms
  12. 12. 12 Neuropathic Pain is Prevalent Across a Range of Different Conditions HIV = human immunodeficiency virus 1. Sadosky A et al. Pain Pract 2008; 8(1):45-56; 2. Davis MP, Walsh D. Am J Hosp Palliat Care 2004; 21(2):137-42; 3. So YT et al. Arch Neurol 1988; 45(9):945-8; 4. Schifitto G et al. Neurology 2002; 58(12):1764-8; 5. Morgello S et al. Arch Neurol 2004; 61(4):546-51; 6. Stevens PE et al. Pain 1995; 61(1):61-8; 7. Smith WC et al. Pain 1999; 83(1):91-5; 8. Freynhagen R et al. Curr Med Res Opin 2006; 22(10):1911-20; 9. Andersen G et al. Pain 1995; 61(2):187-93; 10. Siddall PJ et al. Pain. 2003; 103(3):249-57; 11. Rae-Grant AD et al. Mult Scler 1999; 5(3):179-83. 1126%1 ~33%2 3553%35 2043% of mastectomy patients6,7 Up to 37%8 Diabetes Cancer HIV Post-surgical Postherpetic neuralgia Chronic low back pain 8%9 75%10 ~55%11 Stroke Spinal cord injury Multiple sclerosis 727% of patients with herpes zoster1 Condition % affected by peripheral neuropathic pain % affected by central neuropathic pain 3 Systemic Disease
  13. 13. 13 DPN The inevitable J Diabetes Invest 2014; 5: 714721 Progressive Almost all patient develops DPN over a time period N = 2006 Indian patients with diabetes 4 Time to diagnosis
  14. 14. 14 Delay in diagnosis of Neuropathy Symptom onset to diagnosis J Peripher Nerv Syst. 2012 May;17 Suppl 2:1-3. 4 Time to diagnosis Less than 30% were given a diagnosis in 1 year and some patients had symptoms for over 15 years before they were diagnosed
  15. 15. 15 1. Is it focal ( involving a particular nerve only) or multifocal (involving many nerves In a single or multiple places, or symmetric ( equal on either portion of the body) 2. If symmetric a. Proximal predominantly motor ( GBS ) except lead neuropathy ,which is distal b. Distal motor or sensory or mixed ( toxic, diabetic, metabolic) Issues in Diagnosis of PN http://www.apiindia.org/pdf/medicine_update_2010/neurology_07.pdf 4 Diagnosis
  16. 16. 16 1 PN can be mimicked by myelopathy, synringomyelia, or tabes dorsalis, and tumors of spinal cord. 2 Not but not the least , but most confusing pictures will be given in hysterical conversion reactions. 3 Early lesions mimic pure sensory neuropathy but , careful examination will reveal subtle motor neuropathy, which is a common feature in diabetic PN. Unless it is observed it is often missed. 4 Symptoms of distal motor weakness are more reliable than our examinations. Diagnostic Cascade - PITFALLS http://www.apiindia.org/pdf/medicine_update_2010/neurology_07.pdf 4 Diagnosis
  17. 17. 17 Diagnosing Neuropathic Pain Is Challenging Harden N, Cohen M. J Pain Symptom Manage 2003; 25(5 Suppl):S12-7; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):1959-64. Diagnostic challenges Multiple, complex mechanisms Diverse symptoms Difficulties in communicating and understanding symptoms Recognition of comorbidities Unmet Need 4 Diagnosis
  18. 18. 18 IASP Definition of Pain IASP : International Association for the Study of Pain Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
  19. 19. 19 Pathophysiological Classification of Pain Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5; Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzacks Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Ross E. Expert Opin Pharmacother 2001; 2(1):1529-30; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15. Multiple types of pain coexist in many conditions (mixed pain)Nociceptive pain - Somatic - Visceral Neuropathic pain - Peripheral - Central Central sensitization/ dysfunctional pain
  20. 20. 20 The International Association for the Study of Pain (IASP) defines neuropathic pain as pain arising as a direct consequence of a lesion or disease or dysfunction affecting the nervous system. Two types Peripheral Neuropathic pain: Lesion in Peripheral Nervous system Central Neuropathic pain: Lesion in Central Nervous system What is Neuropathic pain? http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions
  21. 21. 21 Simplified Pathophysiology of Neuropathic Pain 1. Gilron I et al. Neuropathic pain: a practical guide for the clinician, CMAJ 2006;175:265-75. 2- Ralf Baron, et al, Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.. Lancet Neurol 2010; 9: 80719 NeP Peripheral mechanisms Abnormal discharges Central mechanisms Peripheral neuron hyperexcitability1 Loss of inhibitory controls1,2 Central mechanisms Central neuron hyperexcitability (central sensitization)1 NeP = Neuropathic pain
  22. 22. 22 Classification Neuropathic Pain Pain caused by a lesion or disease of the somatosensory nervous system Peripheral Neuropathic Pain Pain caused by a lesion or disease of the peripheral somatosensory ner