Neuropathic Pain Dr.Husni

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Nociceptive vs Neuropathic Pain

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  • Because of the inherent subjective nature of pain, and the fact that the word “pain” itself connotes multiple meanings, the International Association for the Study of Pain (IASP) has established a standardized definition of pain. The definition makes several important points: Pain is an unpleasant emotional experience as well as an unpleasant sensory experience. This distinction between the sensory aspects of pain and its emotional (or affective) component has had a significant influence on both research and the treatment of chronic pain. Also emphasized by the IASP in defining pain is that pain is always subjective. If patients regard their experience as pain and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. IASP Task Force on Taxonomy. In: Merskey H, Bogduk N, eds. Classification of Chronic Pain . 2nd ed. Seattle, Wash: IASP Press; 1994:209-214.
  • Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli. 1 Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries. Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems. 2 Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain. As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics. Two types of neuropathic pain—PHN and diabetic neuropathy—will be emphasized within this module. These types of pain are being stressed because the great majority of randomized controlled trials of treatments for neuropathic pain have examined these two disorders, and because our understanding of the mechanisms of neuropathic pain is largely derived from those studies. 1. Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:4. 2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9.
  • This slide illustrates the two distinct categories of pain – nociceptive and neuropathic pain. Nociceptive pain is caused by an inflammatory or non-inflammatory response to a noxious stimulus. Neuropathic pain has been defined by the International Association for the Study of Pain (IASP) as that which is “initiated or caused by a primary lesion or dysfunction in the nervous system”. Depending on where the lesion or dysfunction occurs within the nervous system, neuropathic pain can be further classified as either peripheral or central in origin. Reference: Merskey H, Bogduk N, eds. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994:209-212.
  • Nociceptive pain is a response that occurs when specific peripheral sensory neurons (nociceptors) respond to noxious stimuli. Acute nociceptive pain is an appropriate response, which has a protective role because it elicits reflex or behavioral responses that minimise tissue damage. Reference: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.
  • This slide shows the differences between a joint affected by osteoarthritis and a normal joint. Osteoarthritis, a degenerative condition of the joint, is an example of a condition that causes chronic nociceptive pain. Reference 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.
  • This slide gives an overview of neuropathic pain, with examples of common causes. Neuropathic pain has been defined by the IASP as a pain that is “initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system”. Causes of peripheral neuropathic pain include postsurgical and posttraumatic nerve injury, diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN) and radiculopathies. Poststroke pain, multiple sclerosis, and spinal cord injuries are all examples of central neuropathic pain. Neuropathic pain is frequently described as a “shooting”, “electric shock-like”, or “burning” pain – commonly associated with “tingling” and/or “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). In peripheral neuropathic pain, it is in the territory of the affected nerve or nerve root. In central neuropathic pain, it is related to the site of the lesion in the spinal cord or brain. References: Clinical States: Neuropathic Pain. In: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. Merskey H, Bogduk N, eds. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994:209-214.
  • Pain that manifests in diverse diseases may operate through common mechanisms. No pain mechanism is an inevitable consequence of a particular disease process. A given pain mechanism could be responsible for many different symptoms. More than one mechanism can operate in a single patient, and these may change over time. The main neurotransmitter in primary afferents is the excitatory amino acid glutamate. Activation of nociceptors causes the release of glutamate from central terminals; this release acts on the ionotropic glutamate receptor amino-3-hydroxy-5-methylisoxazole-4-proprionic acid postsynaptically to cause a rapid depolarization of dorsal horn neurones and, if threshold is reached, action potential discharge. Transduction: noxious stimuli cause ion channels in the membranes of thermal, mechanical, and chemical receptors located in the skin and tissue to open. Ions enter the receptor and depolarize it. Transmission: a wave of depolarization, or action potential, travels toward the spinal cord via A-beta (thinly myelinated) fibers and C (unmyelinated) fibers and up the ascending pathway. A-beta (light touch) fibers may become sensitized by CNS mechanisms to produce allodynia. Modulation/Perception: the ascending pain pathway carries impulses from the nociceptor to the sensory cortex; thus the sensation of pain is perceived. Interpretation: impulses are carried by 1 st , 2 nd , and 3 rd order neurons. 1 st order neurons carry impulses from the nociceptor to the dorsal horn of the spinal cord. 2 nd order neurons carry impulses from the spinal cord to the thalamus, while 3 rd order neurons carry the impulse from the thalamus to the primary sensory cortex. Crossman AR, Neary D. Neuroanatomy , 2 nd ed. Churchill Livingstone, 2000. Galer B, Gammaitoni A, Alvarez N. 6. Immunology [XIV. Pain]. In: Dale DC, Federman DD, eds. WebMD Scientific American ® Medicine. New York, NY:WebMD Corporation; 2003. Guyton AC, Hall J. Textbook of Medical Physiology, 10 th Ed. Saunders, 2000. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet . 1999;353:1959-1964.
  • Neuropathic pain may result from the concatenation of a number of mechanisms: eg, sodium-channel accumulation, redistribution, and altered expression; increased expression of mRNA for specific neurotransmitters (eg, substance P); central sensitization; sprouting of sympathetic efferents into neuromas and dorsal horn and ganglion cells. Due to this multiplicity of mechanisms, it is unlikely that neuropathic pain corresponds to a unique entity. Each painful symptom may therefore correspond to a distinct mechanism and may only respond to a specific treatment. Spontaneous pain and paraesthesias associated with sodium channel activity, for example, may best respond to sodium channel blockers or antiepileptic agents. Increased transmission and reduced inhibition associated with hyperalgesia and allodynia may best respond to opioids or tricyclic antidepressants. Sensitive and specific diagnostic tools are needed to reveal the particular pathological processes involved in the pain experienced by the individual patient. But accurate diagnosis of pain mechanisms will only occur if the mechanisms can be adequately targeted with appropriate therapies. Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl. 1999;173:12-24. Woolf CJ, Manion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959-1964.
  • In ulnar nerve damage, neuropathic pain is caused by direct trauma or compression of the nerve following elbow fracture. Damaged nerve fibers generate abnormal impulses that are transmitted along the sensory (afferent) nerves to the dorsal roots where they enter the spinal cord to reach the dorsal horn. Abnormal impuls). es over-stimulate the second-order neurons ascending to the cortex through various pathways (brain stem, thalamus, limbic system, and other cortical areas) where pain awareness develops. In neuropathic pain, a lesion or dysfunction of the nervous system may cause an excess of function (positive symptoms) or a deficit of function (negative symptoms): Positive symptoms – spontaneous pain, allodynia (pain due to a stimulus that does not normally provoke pain), dysesthesia, paresthesia, and hyperalgesia Negative symptoms – weakness or loss of sensation (e.g. wrist and hand flexion following ulnar nerve damage Reference McMahon SB, Koltzenburg M, editors. Textbook of Pain, 5th ed. Elsevier Churchill Livingstone; 2006.
  • Approximately 50% of people with diabetes develop some kind of neuropathy. Diabetic peripheral neuropathy (DPN, also referred to as “chronic sensorimotor distal symmetric polyneuropathy”) is the most common form of diabetic neuropathy, being present in 26% of patients with type 2 diabetes. DPN occurs in both type 1 and type 2 diabetes and becomes more common with increasing age and duration of diabetes. Up to half of patients with DPN experience symptoms, most often burning pain, electrical or stabbing sensations, or paraesthesia, hyperparaesthesia, and deep aching pain. Neuropathic pain tends to be intermittent and is typically worse at night. Sensory impairment typically occurs in a “sock-and-glove” pattern, affecting the feet, lower limbs, hands and fingers. Recently, unsteadiness has been recognised as a manifestation of DPN, reflecting disturbed proprioception and possibly abnormal muscle sensory function. This may result in recurrent minor trauma or falls, as well as late complications such as neuroarthropathy. References: World Health Organisation, Diabetes fact sheet. Available at : http://www.who.int/mediacentre/factsheets/fs312/en/index.html. Accessed 20 Jul 2009. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518-22. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care 2004;27:1458–86. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28:956–62. Kumar S, Ashe HA, Parnell LN, et al. The prevalence of foot ulceration and its correlates in type 2 diabetic patients: a population-based study. Diabet Med 1994;11:480-484.
  • The co-existence of pain types has been referred to as “mixed” or “combined” pain. Examples of these conditions include low back pain with associated lumbar radiculopathy, cancer pain and carpal tunnel syndrome. Reference: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.
  • Over the next 3 slides, a typical example of co-existing pain will be demonstrated using low back pain and associated lumbar radiculopathy caused by a herniated disc. These slides will show: a patient image of low back pain caused by a herniated disc a close-up diagram of the area of pain an animated build showing the nervous system involvement in the pain sensation.
  • Nociceptive pain component: Localized, low back pain at the site of the herniated disc is mediated by the release of inflammatory mediators from degrading cartilage cells, activating peripheral nociceptors and sending impulses along the sensory (afferent) nerves to the dorsal horn and then to the brain. Neuropathic pain component: Pain impulses are mediated by nerve damage following compression of the dorsal root and abnormal impulses enter the spinal cord to reach the dorsal horn. These abnormal impulses can over-stimulate the secondary nerves ascending to the cortex through various pathways relaying in the brain stem, thalamus and limbic system where pain awareness develops. Such nerve damage (a lesion or dysfunction at any point of the ascending or descending pathways) can cause: Positive symptoms – spontaneous pain and tingling, radiating down to the lower legs. Negative symptoms – weakness or loss of sensation and numbness, radiating down to the lower legs. Broader analgesic treatment options may be required for the management of co-exisitng pain conditions to encompass both nociceptive and neuropathic elements. Reference: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.
  • Note to speaker: this slide contains an animated build to represent co-presenting pain (herniated disc causing low back pain and lumbar radiculopathy). Clicking on this slide causes subsequent components of the build to appear automatically. Nociceptive pain component: Localized, low back pain at the site of the herniated disc is mediated by the release of inflammatory mediators from degrading cartilage cells, activating peripheral nociceptors and sending impulses along the sensory (afferent) nerves to the dorsal horn and then to the brain. Neuropathic pain component: Pain impulses are mediated by nerve damage following compression of the dorsal root and abnormal impulses enter the spinal cord to reach the dorsal horn. These abnormal impulses can over-stimulate the secondary nerves ascending to the cortex through various pathways relaying in the brain stem, thalamus and limbic system where pain awareness develops. Such nerve damage (a lesion or dysfunction at any point of the ascending or descending pathways) can cause: Positive symptoms – spontaneous pain and tingling, radiating down to the lower legs. Negative symptoms – weakness or loss of sensation and numbness, radiating down to the lower legs. Broader analgesic treatment options may be required for the management of co-exisitng pain conditions to encompass both nociceptive and neuropathic elements. Reference: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.
  • 1. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518-22. 2. International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels (Belgium); 2006. 3. Freynhagen R, Baron R, Gockel U, et al. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911-20. 4. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18(6):350-54.
  • These classic epidemiologic data show that the risk for persistent pain of 1 or more months’ duration (upper line) or 1 or more years (lower line) increases with age in herpes zoster patients. One year after the onset of herpes zoster, only 4.2% of patients younger than 20 years were still experiencing pain, compared with 47% of patients older than 70 years. 1 Although, as shown on the graph, comparatively few patients younger than 40 years report pain 1 month after rash healing, almost 50% of herpes zoster patients older than 70 years continue to experience pain 1 year or more after the onset of their zoster infection. 2 Other risk factors associated with increased risk of PHN include greater severity of acute herpes zoster pain, greater herpes zoster rash severity/greater number of lesions, presence of a painful prodrome, and greater degree of sensory impairment in the affected dermatome. 2 Additional data suggest that the risk of PHN may be slightly increased in patients with ophthalmic zoster. Although the data are inconsistent, some reports suggest that women have a slightly higher incidence of PHN than do men. 3 1. DeMorgas JM, Kierland RR. The outcome of patients with herpes zoster. Arch Dermatol . 1957;75:193-196. 2. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: The McGraw-Hill Companies, Inc; 2000:87-91. 3. Kost RG, Straus SE. Postherpetic neuralgia–pathogenesis, treatment, and prevention. N Engl J Med . 1996;335:32-42.
  • Comprehensive pain assessment is now a regulatory (Joint Commission on Accreditation of Healthcare Organizations) mandate. Important characteristics of a patient’s pain to be documented are listed above. 1,2 Assessment should include an evaluation of a patient’s associated features and associated factors. The features include neurologic deficit and hyperphenomena, and among the associated factors are the psychosocial state (indicated by the patient’s mood and level of emotional distress) and the impairment of functional activities, including activities of daily living, such as the ability to work or sleep. 1 Rational treatment cannot proceed without detailed records of previous treatments, including dosages, duration of therapy, side effects, and reason for stopping treatment. 1 1. Backonja M-M, Galer BS. Pain assessment and evaluation of patients who have neuropathic pain. Neurol Clin . 1998;16:775-789. 2. Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain . 2000;16(suppl 2):S41 S48.
  • Neuropathic sensory symptoms can be classified as either positive or negative and it is important to distinguish between the two. Positive symptoms arise spontaneously or in response to stimuli, while negative symptoms represent decreased responsiveness to stimuli. The major positive sensory symptoms are: Spontaneous pain: Painful sensations felt with no evident stimulus Allodynia: Pain due to a stimulus which does not normally provoke pain. Hyperalgesia: An increased response to a stimulus which is normally painful Dysaesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked. Paraesthesia: An abnormal sensation that is not unpleasant, whether spontaneous or evoked Important points: 1. It is important to recognise that allodynia involves a change in the quality of a sensation, whether tactile, thermal, or of any other sort. The original modality is normally non-painful, but the response is painful. There is thus a loss of specificity of a sensory modality. By contrast, hyperalgesia represents an augmented response in a specific mode. With other cutaneous modalities, hyperaesthesia is the term which corresponds to hyperalgesia, and as with hyperalgesia, the quality is not altered. In allodynia the stimulus mode and the response mode differ, unlike the situation with hyperalgesia. This distinction should not be confused by the fact that allodynia and hyperalgesia can be plotted with overlap along the same continuum of physical intensity in certain circumstances, for example, with pressure or temperature. 2. Hyperalgesia reflects increased pain on suprathreshold stimulation. For pain evoked by stimuli that usually are not painful, the term allodynia is preferred, while hyperalgesia is more appropriately used for cases with an increased response at a normal threshold, or at an increased threshold, e.g., in patients with neuropathy. It should also be recognised that with allodynia the stimulus and the response are in different modes, whereas with hyperalgesia they are in the same mode. Current evidence suggests that hyperalgesia is a consequence of perturbation of the nociceptive system with peripheral or central sensitisation, or both, but it is important to distinguish between the clinical phenomena, which this definition emphasises, and the interpretation, which may well change as knowledge advances. 3. Compare dysaesthesia with pain and with paraesthesia. Special cases of dysaesthesia include hyperalgesia and allodynia. A dysaesthesia should always be unpleasant and a paresthesia should not be unpleasant, although it is recognised that the borderline may present some difficulties when it comes to deciding as to whether a sensation is pleasant or unpleasant. It should always be specified whether the sensations are spontaneous or evoked. 4. After much discussion, it has been agreed to recommend that paraesthesia be used to describe an abnormal sensation that is not unpleasant while dysaesthesia be used preferentially for an abnormal sensation that is considered to be unpleasant. The use of one term (paraesthesia) to indicate spontaneous sensations and the other to refer to evoked sensations is not favoured. There is a sense in which, since paresthesia refers to abnormal sensations in general, it might include dysaesthesia, but the reverse is not true. Dysaesthesia does not include all abnormal sensations, but only those which are unpleasant. References: 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.
  • Neuropathic sensory symptoms can be classified as either positive or negative and it is important to distinguish between the two. Positive symptoms arise spontaneously or in response to stimuli, while negative symptoms represent decreased responsiveness to stimuli. The major negative sensory symptoms are: 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 Important points: 1. Definition of hypoaesthesia excludes the special senses and requires the stimulation and locus to be specified. 2. Hypoalgesia was formerly defined as diminished sensitivity to noxious stimulation, making it a particular case of hypoaesthesia. However, it now refers only to the occurrence of relatively less pain in response to stimulation that produces pain. Hypoaesthesia covers the case of diminished sensitivity to stimulation that is normally painful. 3. For analgesia, as with allodynia, the stimulus is defined by its usual subjective effects. References: 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.
  • Reference 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.
  • References 1. Kavoussi R. Pregabalin: From molecule to medicine. 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. Mechanism of disease: neuropathic pain – a clinical perspective. Nat Clin Pract Neurol. 2006;2(2):95-106. 4. Audette JF, Emenike E, Meleger AL. Neuropathic low back pain. Curr Pain Headache Rep 2005;9(3):168-77. 5 . Freynhagen R, Baron R, Gockel U, Tölle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22:1911-20.
  • References: McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. Schmader KE. Clin J Pain 2002; 18(6):350-54.
  • The 3L approach (Listen, Locate and Look) will facilitate the assessment and successful diagnosis of neuropathic pain in the limited consultation time available in general practice. The 3L approach involves the following steps: Listen to patients’ verbal descriptors of their pain; ask appropriate questions and note their responses. Locate the area of pain and/or determine the nervous system lesion/dysfunction. Look for sensory abnormalities and recognize its distribution pattern. Also look for abnormal behaviour or guarding of the affected area. A differential diagnosis of neuropathic pain is dependent on the combined outcomes from the 3L approach.
  • It is important for the GP to listen carefully to the patient’s verbal descriptions of their pain in addition to assessing the patient’s medical history for important diagnostic clues. Use of a “cluster of terms” may signal neuropathic pain (e.g. shooting, electric shock, burning). The use of one or two typical verbal descriptors is highly suggestive of neuropathic pain, although not pathognomonic.
  • Confirming the presence of neuropathic pain using the 3L approach : Identification of a cluster of common verbal descriptors should lead to the suspicion of neuropathic pain. Finding sensory abnormalities (either a deficit, such as hypoesthesia, or an excess of function such as hyperalgesia) in the painful area adds support for a neuropathic origin of the pain, particularly if the pain and the sensory abnormality are within a neuroanatomical territory. Once neuropathic pain is suspected, the responsible neurological lesion/dysfunction must be identified. Occasionally sensory abnormalities may not be detected and/or the nervous system lesion/dysfunction cannot be easily identified. If neuropathic pain is still suspected, specialist referral should be considered (and appropriate pain treatment initiated in the interim period). Once neuropathic pain diagnosis is confirmed, consider initiating appropriate therapy .
  • The slide lists the various treatments for neuropathic pain in order of invasiveness. 1 However, the efficacy of treatment does not necessarily match its invasiveness. For some patients, behavioral or physical therapy or a topical medication can be at least as effective as an interventional technique. 2,3 While there are many treatment options and combinations for neuropathic pain, this presentation will focus on those meeting three important criteria: 1) efficacy—demonstrated in controlled clinical trials; 2) safety—demonstrated in controlled clinical trials and subsequent clinical experience; 3) favorable tolerability profiles (ie, side effects, drug/drug interactions). Psychological/physical approaches to pain management include relaxation therapy and physical exercise programs. Topical medications consist of the lidocaine patch 5%, capsaicin, and a variety of custom-compounded topical agents of unknown effectiveness. 2,4 Oral medications include anticonvulsants such as gabapentin, tricyclic antidepressants (TCAs), opioids, and miscellaneous agents (eg, mexiletine, baclofen). 1,4 The two types of injections are nerve blocks and local infiltrations that are usually administered with local anesthetics and/or steroids. 5 The interventional techniques that require referral to a specialist are spinal cord stimulation, spinal analgesia, brain stimulation, and various neurosurgical procedures such as dorsal root entry zone lesions. 2,6 1. Mackin GA. J Hand Ther . 1997;10:96-109. 2. Katz N. Clin J Pain . 2000;16:S41-S48. 3. Leland JY. Geriatrics . 1999;54:23-37. 4. Belgrade MJ. Postgrad Med . 1999;106:127-148. 5. Galer BS et al. A Clinical Guide to Neuropathic Pain . 2000:97. 6. Gonzales GR. Neurology . 1995:45(suppl 9):S11-S16.
  • 2
  • Although there are numerous medications for the treatment of neuropathic pain, those listed on this slide have demonstrated efficacy in multiple, consistent, randomized, controlled trials. As such, these agents provide an evidence-based treatment approach for neuropathic pain and will constitute the focus of this program’s discussion on pharmacologic treatment. When selecting a pharmacologic treatment regimen, consideration should also be given to safety and tolerability factors such as side-effect profile and potential for drug interactions. Controlled clinical trials and clinical experience document that the lidocaine patch, because of its nonsystemic mechanism of action, has the least potential for adverse side effects or drug interactions. Among systemic agents, gabapentin, which has no significant side effects, has demonstrated favorable safety and tolerability. Based on these factors, as well as being FDA-approved for the treatment of PHN, the lidocaine patch and gabapentin are often selected as initial treatments for neuropathic pain. 1-6 Nortriptyline, desipramine, tramadol, and controlled-release oxycodone also have demonstrated safety and tolerability profiles which are more favorable than those of earlier agents such as amitriptyline, phenytoin, carbamazepine, and others. 1,2,7-14 1. Backonja M et al. JAMA . 1998;280:1831-1836. 2. Rowbotham M et al. JAMA . 1998;280:1837-1842. 3. Carter GT et al. Phys Med Rehabil Clin N Am. 2001;12:447-459. 4. Rowbotham MC et al. Pain . 1996;65:39-44. 5. Galer BS et al. Clin J Pain. 2002;18:297-301. 6. Galer BS et al. Pain . 1999;80:533-538. 7. Rice AS et al. Prostaglandins Leukot Essent Fatty Acids . 2002;66:243-256. 8. Gorson DM. Diabetes Care . 1998; 21:2190-2191. 9. Max MB et al. N Engl J Med . 1992;326:1250-1256. 10. Watson CPN et al. Neurology . 1998;51:1166-1171. 11. Watson CP. Clin J Pain. 2000;16(suppl 2):S49-S55. 12. Watson CP et al. Neurology . 1998;50:1837-1841. 13. Harati Y et al. Neurology . 1998;50:1842-1846. 14. Sindrup SH et al. Pain. 1999;83:389-400.
  • Only five medications, pregabalin, duloxetine, lidocaine patch 5%, gabapentin, and carbamazepine, have been approved by the FDA for treatment of neuropathic pain—specifically, for treatment of diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and trigeminal neuralgia. The approval of pregabalin was based on the results of six double-blind clinical trials involving more than 9,000 patients, which showed that treatment with pregabalin significantly reduced pain in patients with DPN and PHN. Pain relief was reported as early as the first week of treatment in some patients, and was sustained over the three-month trials. 1 The efficacy of duloxetine for the management of neuropathic pain associated with DPN was established in two randomized, 12-wk, double-blind, placebo-controlled, fixed-dose studies. Treatment with duloxetine at 60 mg qd or bid significantly reduced 24-hour average pain levels compared with placebo. In these trials, 58% of 1074 patient treated with duloxetine reported at least a 30% sustained reduction in pain. 1 On the basis of this data, FDA approved duloxetine for DPN on September 7, 2004. In two double-blind, vehicle-controlled randomized clinical trials, lidocaine patch 5% provided statistically significantly greater pain relief to patients with PHN than did vehicle-control patches without lidocaine. On the basis of those studies, FDA approved lidocaine for treatment of PHN. Anecdotal evidence of a beneficial treatment in patients with other types of neuropathic pain have been published. 2,3 Eight double-blind, placebo-controlled, randomized clinical trials of gabapentin for chronic pain found that, at daily dosages up to 3600 mg, gabapentin significantly reduced pain compared with placebo in patients with PHN, painful diabetic neuropathy (PDN), mixed neuropathic pain syndromes, among other neuropathic disorders. On the basis of two large randomized trials, FDA approved gabapentin for treatment of PHN. ,4,5 Carbamazepine has a well-established beneficial effect in trigeminal neuralgia, and it is approved by the FDA for the treatment of this syndrome. Based on the results of the clinical trials of anticonvulsants in chronic neuropathic pain, carbamazepine can be recommended for patients who have not responded to an adequate trial of gabapentin when treatment with an anticonvulsant is sought. 6,7 Cymbalta. Label and approval history. Available at: http://www.fda.gov/cder/foi/label/2004/21733lbl.pdf. Accessed Sept 10, 2004. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch:double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65:39-44. Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic meuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80:533-538. Rowbotham MC, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837-1842. Rice ASC, Maton S, Postherpetic Neuralgia Study Group: Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215-224. McQuay HJ, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995;311:1047-1052. Loeser JD. Cranial neuralgias. In: Loeser JD, Buutler SH, Chapman CR, Turk DC, eds. Bonicas’s Management of Pain. 3 rd ed. Philadelphia PA: Lippincott Williams & Wilkins;2001:855-866.
  • Available drug treatments for chronic pain currently include simple analgesics such as acetaminophen, salicylates and other nonsteroidal anti-inflammatory drugs, traditional opioid drugs, and adjuvant agents (eg, antidepressants, anticonvulsants). Typically, the choice of a drug is made by balancing the indications for treatment, the clinical efficacy of the drug, and its toxicity. An understanding of the mechanism of action of these drugs helps to establish their role in therapy. Better understanding of the pathophysiology of acute and chronic pain has led to numerous advances in pharmacologic management of painful disorders, including low back pain, migraine headache, fibromyalgia, postherpetic neuralgia, osteoarthritis, rheumatoid arthritis, and cancer-related neuropathic pain. Opioids mimic the actions of endogenous opioid peptides by interacting with mu, delta, or kappa opioid receptors. The opioid receptors are coupled to G1 proteins and the actions of the opioids are mainly inhibitory. They close N-type voltage-operated calcium channels and open calcium-dependent inwardly-rectifying potassium channels. This results in hyperpolarization and a reduction in neuronal excitability. They also decrease intracellular cAMP which modulates the release of nociceptive neurotransmitters (eg, substance P). Inhibition of prostaglandin synthesis by cyclooxygenase is the principal mode of the analgesic and anti-inflammatory actions of NSAIDs. Cyclooxygenase is inhibited irreversibly by aspirin and reversibly by other NSAIDs. The widespread inhibition of cyclooxygenase is responsible for many of the adverse effects of these drugs. NSAIDs also reduce prostaglandin production within the CNS. This is the main action of paracetamol. Argoff CE. Pharmacologic management of chronic pain. J Am Osteopath Assoc. 2002;102(suppl 3):S21-S27. Aronson MD. Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the treatment of chronic pain. Clin Ther. 1997;19:420-32; discussion 367-8. Bovill JG. Mechanisms of actions of opioids and non-steroidal anti-inflammatory drugs. Eur J Anaesthesiol Suppl .1997;15:9-15.
  • Topical treatment is not the same as transdermal treatment. Topical treatment means the drug stays and acts primarily locally, with minimal systemic absorption and effects. Transdermal treatment attempts to have systemic effects by delivering the drug through the skin instead of orally, intravenously, or by other means. Because it is a topical agent, the lidocaine patch 5% achieves insignificant serum levels, even with chronic use. This enhances safety and makes drug interactions unlikely. 1 Clinical trials have shown no statistical difference between lidocaine patch 5% and placebo patch with regard to side effects. 2 The most common adverse event reported with the topical lidocaine patch 5% is transient minor local irritation of the skin. 3 Transdermal therapies for neuropathic pain include the fentanyl patch. Transdermal systems need to be applied to nonirritated skin. They deliver medication systemically, which means a slower onset of action. Patients are advised to use short-acting analgesics until analgesic efficacy with the patch is achieved. Because serum levels of the drug increase correlatively with duration of transdermal patch wear-time, side effects can be significant and problematic. Nausea, mental clouding, and skin irritation are commonly reported. More serious side effects include serious or life-threatening hypoventilation and bradycardia. Drug-drug interactions may also be a problem, especially concomitant use of the transdermal fentanyl patch and central nervous system (CNS) depressants (eg, benzodiazepines). 4 1. Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain . 2000;16(2 suppl):S62- S66. 2. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain . 1999;80:533-538. 3. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:61-64. 4. Duragesic [package insert]. Titusville, NJ: Janssen Pharmaceutica; 1999.
  • Anticonvulsant medications have been used in the treatment of neuropathic pain for many years without FDA approval (except for carbamazepine’s indication for trigeminal neuralgia). Pregabalin, however, as of September 2004 has received approvable letters from the FDA for neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. The slide provides a summary of many of the controlled trials that have been conducted examining the efficacy of anticonvulsant drugs in the treatment of various neuropathic pain syndromes. 1-7 The studies of carbamazepine and phenytoin conducted in the 1960s and 1970s do not meet today’s standards of methodological rigor. 8 The phenytoin studies have produced both successful and unsuccessful results. 9 The two studies of gabapentin are among the largest clinical trials of the treatment of neuropathic pain ever conducted. 8,10 These studies have stimulated a great deal of clinical and research interest in the efficacy and mechanisms of action of anticonvulsant drugs in treating patients with neuropathic pain. First-generation anticonvulsant drugs, which include carbamazepine and phenytoin, sometimes provoke serious side effects and drug-drug interactions that do not occur with second-generation anticonvulsants. 11 We will be focusing on gabapentin because it is the anticonvulsive most commonly used for neuropathic pain and for which there is the most clinical data. 1. Rowbotham M et al. JAMA . 1998;280:1837-1842. 2. Eisenberg E et al. Neurology. 2001;57:505-509. 3. Simpson DM et al. Neurology . 2000;54:2115-2119. 4. Campbell FG et al. J Neurol Neurosurg Psychiatry . 1966;29:265-267. 5. Zakrzewska JM et al. Pain . 1997;73:223-230. 6. Zakrzewska JM et al. J Neurol Neurosurg Psychiatry . 1989;52:472-476. 7. Vestergaard K et al. Neurology . 2001;56:184-190. 8. Rull J et al. Diabetologia . 1969;5:215-218. 9. Chadda VS et al. J Assoc Physicians India . 1978;26:403-406. 10. Backonja M et al. JAMA . 1998;280:1831-1836. 11. Ross EL. Neurology. 2000;55:S41-S46.
  • Gabapentin is an anticonvulsant which has recently been approved for the treatment of PHN, and diabetic neuropathy but it does not have FDA approval for other neuropathic pain syndromes. 1 Its mechanism of action has not been completely identified. Gabapentin has limited intestinal absorption and is usually well tolerated. Among the more common adverse events associated with its use are dizziness and sedation. It has rare serious adverse effects. No clinically significant drug-drug interactions are known. The time to peak concentration is 2 to 3 hours, and the elimination half-life is 5 to 7 hours. Plasma clearance, however, decreases in older patients and in patients with impaired renal function. 2 The effective dose for adjunctive therapy of partial seizures with or without secondary generalization in adults with epilepsy is 900 to 1,800 mg/day, given in divided doses tid and titrated over 3 days. 2 For pain, clinical experience has shown that much higher doses are often necessary and well tolerated; the usual dosage range is up to 3,600 mg/day (tid-qid). 1 1. Backonja M-M. Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain . 2000;16:S67-S72. 2. Neurontin (gabapentin) [package insert]. Morris Plains, NJ: Parke-Davis; 1999.
  • Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Reference: Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-51.
  • Evidence-based guidelines for the pharmacological management of NeP published by the Canadian Pain Society. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications were recommended if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment were based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Reference Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007;12(1):13-21.
  • Pooled analysis to evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN). Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks. Reference: Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008;31(7):1448-54.
  • Background: The aim of this observational open study was to investigate the efficacy and tolerability of pregabalin in patients with peripheral neuropathic pain prospectively under clinical practice conditions. Methods: Physicians of different specialties from 5808 primary care settings and clinics included a total of 15,301 patients with peripheral neuropathic pain. Pregabalin was prescribed for 45 days (median). The majority of patients (78%) received 150 mg daily as a starting dose. Thereafter, a maintenance dose of 300 mg pregabalin daily was given to 43% of the patients. Strength of pain, magnitude of pain-related sleep disturbance, and general well-being were assessed by numeric rating scales (0=best value, 10=worst value) at baseline and after 1, 3 and 6 weeks, respectively. Reference: Mallison R, Tilke C, Brasser M, et al. [Efficacy and tolerability of pregabalin in patients with neuropathic pain. Observational study under clinical practice conditions]. MMW Fortschr Med. 2007(149 Jg.): S13-20.
  • Tricyclic antidepressants (TCAs) act in part by inhibiting the reuptake of norepinephrine and serotonin into presynaptic neurons. They have been used to relieve neuropathic pain, although this indication has not been approved by the FDA. However, many controlled clinical trials and meta-analyses have demonstrated that TCAs (eg, imipramine, amitriptyline, desipramine, nortriptyline, clomipramine) can significantly reduce the pain of diabetic neuropathy and PHN. 1-4 Some, but not all, selective serotonin reuptake inhibitors (SSRIs) have also been shown to be effective for neuropathic pain. Paroxetine and citalopram (slightly) have shown benefit for diabetic neuropathy, 1,2 while fluoxetine has proved to be no more effective than placebo. 3 In general the SSRIs are felt to be, at best, inconsistently effective for neuropathic pain. 4 Some patients who receive antidepressants for neuropathic pain may experience improvement in insomnia, anxiety, and depression. 4,5 Onset of analgesia with antidepressants generally occurs before the onset of the antidepressant effect. The pain-relieving effect of antidepressant agents appears to be independent of their antidepressant effect. 4 Selective norepinephrine reuptake inhibitors (SNRIs) are to be explored for use in neuropathic pain. This module will focus on desipramine and nortriptyline because they are the two antidepressants most commonly used for treatment of neuropathic pain and for which there is the most clinical data. 6-8 1. Sindrup SH et al. Pain . 1990;42:135-144. 2. Sindrup SH et al. Clin Pharmacol Ther . 1992;52: 547-552. 3. Max MB et al. N Engl J Med . 1992;326:1250-1256. 4. Galer BS et al. A Clinical Guide to Neuropathic Pain . 2000:71-72,93. 5. Pappagallo M. Rheum Dis Clin N Am . 1999;25:193-213. 6. Max MB et al. Neurology . 1988;38:1427-1432. 7. Watson CP at al. Neurology . 1998;51:1166-1171. 8. Kishore-Kumar R et al. Clin Pharmacol Ther . 1990;47:305-312.
  • Adverse effects commonly reported with TCAs are anticholinergic effects, which are listed on the left side of the slide. The adverse effects include blurred vision, cognitive changes (such as concentration, memory loss, and confusion), constipation, dry mouth, orthostatic hypotension, sedation, tachycardia, and urinary retention. All TCAs are reported to cause these adverse events in varying degrees of frequency and severity. 1,2 The TCA agents listed on the right side of the slide are organized in descending order of adverse effects, starting with desipramine (fewest adverse effects), nortriptyline, imipramine, doxepin, and amitriptyline (most adverse effects). 2,3 Because of the potential for adverse events and outcomes, amitriptyline should not be prescribed for people older than 65 years. Desipramine would be more appropriate for this population. Of all the drugs that are inappropriate for the elderly, amitriptyline is one of most frequently prescribed. 4 Because the TCAs appear to be almost equally efficacious, a rational approach for clinical practice is to start with the agents with the fewest adverse effects, unless a specific “side effect,” such as nighttime sedation, is desired. 1. Rowbotham MC, Petersen KL, Davies PS, et al. Recent developments in the treatment of neuropathic pain. Proceedings of the 9th World Congress on Pain . Seattle, Wash: IASP Press; 2000:833-855. 2. Mackin GA. Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther . 1997;10:96-109. 3. Tunali D, Jefferson JW, Greist JH. Depression and Antidepressants: A Guide . Madison, Wis: Information Centers, Madison Institute of Medicine; 1999. 4. Piecoro LT, Browning SR, Prince TS, et al. Database analysis of potentially inappropriate drug use in an elderly Medicaid population. Pharmacotherapy . 2000;20:221-228.
  • Opioid therapy entails a number of risks for patients, but these potential problems can be prevented or circumvented. Titration of opioid analgesics should be based on optimizing therapeutic efficacy while minimizing side effects. Regimens of fixed doses are generally preferred over prn regimens. 1 Documentation is critical and should include the initial evaluation, substance abuse history, psychosocial issues, pain/pain relief, side effects, functional outcomes, and continuing monitoring. Regular discussions with family members about the patient’s condition and use of opioids can improve the accuracy of monitoring. 1 The laws on patient monitoring vary from state to state, but the federal government regulates and legislates the use of controlled substances and drugs. Generally, federal laws have priority over state laws. 2 Most opioid side effects can be controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants). 3 Patients on opioids or those who appear to require them also have significant psychosocial rehabilitative issues and are generally best referred to a multidisciplinary center with experience managing chronic pain with opioids. 1 Addiction is referred to by many as psychological dependence. 1. Pappagallo M. Aggressive pharmacologic treatment of pain. Rheum Dis Clin N Am . 1999;25:193-213. 2. Clark HW. Policy and medical-legal issues in the prescribing of controlled substances. J Psychoactive Drugs . 1991;23:321-328. 3. Zenz M. Morphine myths: sedation, tolerance, addiction. Postgrad Med J . 1991;67:S100-S102.
  • Interventional treatments for neuropathic pain include neural blockade, neurolytic techniques, and stimulatory techniques. Neural blockade includes sympathetic blocks for complex regional pain syndrome type I (CRPS-I), which occurs without a definable nerve lesion and is also called reflex sympathetic dystrophy, and complex regional pain syndrome type II (CRPS-II), which occurs when a definable nerve lesion is present; both syndromes are also known as causalgia. 1,2 Neurolytic techniques are primarily employed for pain caused by cancer. 3 Pumps and stimulators are the main interventional techniques in routine clinical use. 2 Stimulatory techniques encompass spinal cord and peripheral nerve stimulation. 4 The main advantage of spinal cord stimulation is that it is a nonpharmacologic intervention that spares patients pharmacy visits, bills, and side effects. 5 Spinal analgesia is widely used for neuropathic pain but is a less conservative therapy than spinal cord stimulation. By acting directly on the spinal cord, spinal analgesia may provide improved pain control with fewer side effects than do systemic drugs. Among these techniques, only spinal analgesia has been shown to be effective in randomized controlled trials (and even this has been studied only short-term). 4 1. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:120,135. 2. MacFarlane BV, Wright A, O’Callaghan J, Benson HAE. Chronic neuropathic pain and its control by drugs. Pharmacol Ther . 1997;75:1-19. 3. Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain . 2000;16(suppl 2):S41-S48. 4. Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:278,293-294,306-307. 5. Gonzales GR. Central pain: diagnosis and treatment strategies. Neurology . 1995;45(suppl 9):S11- S16.
  • There are a number of potential new treatments for neuropathic pain in clinical trials and open-label studies, and results from many of these were presented at the August 2008 World Congress on Pain, . Several of these emerging treatments are listed above and will be discussed in detail on the following slides.
  • Most patients can obtain clinically meaningful relief with appropriate treatment. Given the multiple mechanisms of neuropathic pain, polypharmacy may be required for patients who do not respond adequately to treatment with a single agent. Drugs should be titrated aggressively either to the point where significant pain relief is achieved or intolerable side effects occur. New treatments for neuropathic pain that target specific pathways may help address the underlying mechanisms involved in pain. Treatment should balance efficacy, safety, and tolerability, and progress from the least to the most invasive treatments. More invasive treatments are not necessarily more effective than less invasive ones. The goals of treatment should include not only reducing pain as much as possible but also improving the patient’s QOL. 1 Patients with inadequate pain relief may benefit from referral to multidisciplinary pain treatment centers. 2 1. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: The McGraw-Hill Companies, Inc; 2000:53-55. 2. Cunningham AL, Dworkin RH. The management of post-herpetic neuralgia. BMJ . 2000;321:778-779.
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  • Neuropathic Pain Dr.Husni

    1. 1. Neuropathic Pain and Its Treatment
    2. 3. IASP Definition of Pain <ul><li>“ Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” </li></ul>
    3. 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 .
    4. 5. Nociceptive pain Pain caused by an inflammatory or non-inflammatory response to a noxious stimulus Neuropathic pain &quot; Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system&quot;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
    5. 6. Recognition of Nociceptive Pain <ul><li>Examples </li></ul><ul><li>Pain due to inflammation </li></ul><ul><li>Limb pain after a fracture </li></ul><ul><li>Joint pain in osteoarthritis </li></ul><ul><li>Common descriptors </li></ul><ul><li>Aching </li></ul><ul><li>Throbbing </li></ul>Nociceptive pain Pain caused by an inflammatory or non-inflammatory response to a noxious stimulus <ul><li>Other characteristics </li></ul><ul><li>Pain typically localised at site of injury </li></ul><ul><li>Usually time limited, resolving when damaged tissue heals </li></ul><ul><li>Responds to conventional analgesics </li></ul>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005.
    6. 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.
    7. 8. Recognition of Neuropathic Pain <ul><li>Examples2 </li></ul><ul><li>Postherpetic neuralgia </li></ul><ul><li>Diabetic peripheral neuropathy </li></ul><ul><li>Postsurgical neuropathy </li></ul><ul><li>Post-stroke pain </li></ul><ul><li>Spinal cord injury </li></ul><ul><li>Common descriptors2 </li></ul><ul><li>Burning </li></ul><ul><li>Stabbing (lancinating) </li></ul><ul><li>Tingling </li></ul><ul><li>Electric lightening </li></ul><ul><li>Hypersensitivity to touch or cold (allodynia) </li></ul>Neuropathic pain &quot; Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system&quot;1 <ul><li>Other characteristics2 </li></ul><ul><li>Pain not necessarily at site of lesion </li></ul><ul><li>Usually a chronic condition </li></ul><ul><li>Responds poorly to conventional analgesics </li></ul>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.
    8. 9. COMMON TYPES OF NEUROPATHIC PAIN <ul><li>PERIPHERAL </li></ul><ul><li>Polyradioculopathy </li></ul><ul><li>Alcoholic polyneuropathy </li></ul><ul><li>Entrapment neuropathies (carpal tunnel) </li></ul><ul><li>Nerve compression by tumor </li></ul><ul><li>Diabetic neuropathy </li></ul><ul><li>Phantom limb pain </li></ul><ul><li>Postherpetic neuralgia </li></ul><ul><li>Trigeminal neuralgia </li></ul><ul><li>CENTRAL </li></ul><ul><li>Compressive myelopathy from spinal stenosis </li></ul><ul><li>HIV myelopathy </li></ul><ul><li>MS </li></ul><ul><li>Parkinson disease </li></ul><ul><li>Post ischemic myelopathy </li></ul><ul><li>Poststroke pain </li></ul><ul><li>Posttraumatic spinalcord injury </li></ul>
    9. 10. Physiology of Pain Perception <ul><li>Transduction </li></ul><ul><li>Transmission </li></ul><ul><li>Modulation </li></ul><ul><li>Perception </li></ul><ul><li>Interpretation </li></ul><ul><li>Behavior </li></ul>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 .
    10. 11. Pathophysiologies Involved in Neuropathic Pain <ul><li>Disorders that develop after trauma affecting limbs </li></ul><ul><li>with or without obvious peripheral nerve injury </li></ul><ul><li>Incedents include: </li></ul><ul><ul><li>Crush injuries </li></ul></ul><ul><ul><li>Lacerations </li></ul></ul><ul><ul><li>Fractures </li></ul></ul><ul><ul><li>Occasionally after a MI or CVA </li></ul></ul><ul><li>Burning accompanied by diffuse tenderness and </li></ul><ul><li>pain on light touch </li></ul><ul><li>Autonomic Nervous System dysfunction </li></ul><ul><ul><li>Early changes: </li></ul></ul><ul><ul><ul><li>Warm skin temperature </li></ul></ul></ul><ul><ul><ul><li>Erythema </li></ul></ul></ul><ul><ul><ul><li>Edema </li></ul></ul></ul><ul><ul><li>Late changes: </li></ul></ul><ul><ul><ul><li>Cool and pale or cyanotic appearance </li></ul></ul></ul><ul><ul><ul><li>Dystrophic changes such as smooth, glossy skin and </li></ul></ul></ul><ul><ul><ul><li> bone demineralization </li></ul></ul></ul><ul><ul><ul><li>Stiff, painful joints </li></ul></ul></ul><ul><ul><ul><li>Thermography used to document differences in regional </li></ul></ul></ul><ul><ul><ul><li>blood flow </li></ul></ul></ul>www.aware-rsd.org/ id58.html Source: Stoelting and Miller
    11. 12. <ul><li>NERVE INJURY </li></ul><ul><li>Ectopic Nociceptor Fiber </li></ul><ul><li>discharges sensitization Interactions </li></ul><ul><li>Tonic Activation of C Fibers </li></ul><ul><li>Fixation of SP Release of EAA </li></ul><ul><li>on NK1 Receptor </li></ul><ul><li>ACTIVATION OF NMDA RECEPTORS </li></ul><ul><li>CENTRAL SENSITIZATION </li></ul>
    12. 13. Multiple Pathophysiologies May Be Involved in Neuropathic Pain <ul><li>More than one mechanism of action likely involved </li></ul><ul><li>Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity </li></ul><ul><li>Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids </li></ul><ul><li>In the future, ability to determine the relationship between the pathophysiology and symptoms/signs may help target therapy </li></ul>
    13. 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 <ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>Lesion
    14. 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.
    15. 16. Co-presentation of Nociceptive and Neuropathic Pain Nociceptive pain <ul><li>Examples </li></ul><ul><li>- low back pain with associated lumbar radiculopathy </li></ul><ul><li>cancer pain </li></ul><ul><li>carpal tunnel syndrome </li></ul>Neuropathic pain Both types of pain co-exist in many conditions <ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>
    16. 17. Example of Co-existing Pain Herniated disc causing low back pain and lumbar radiculopathy <ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>
    17. 18. Example of Co-existing Pain Herniated disc causing low back pain and lumbar radiculopathy Lumbar vertebra <ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>Disc herniation Activation of peripheral nociceptors – cause of nociceptive pain component Compression and inflammation of nerve root – cause of neuropathic pain component
    18. 19. Example of Co-existing Pain Patient presents with both types of pain Herniated disc causing low back pain and lumbar radiculopathy <ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>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
    19. 20. Prevalence of Neuropathic Pain <ul><li>Painful Diabetic Neuropathy (PDN) </li></ul><ul><ul><ul><li>Painful diabetic neuropathy occurs in up to 26% of all people with diabetes 1 </li></ul></ul></ul><ul><ul><ul><li>Diabetes is a significant healthcare problem in Africa and the Eastern Mediterranean / Middle East regions, affecting: </li></ul></ul></ul><ul><ul><ul><ul><li>An estimated 35 million people (5% of the adult population) in 2007 2 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>A predicted 63 million people (6% of the adult population) by 2025 2 </li></ul></ul></ul></ul><ul><li>Low back pain </li></ul><ul><ul><ul><li>In patients with chronic low back pain, 35% may have predominantly neuropathic pain 3 </li></ul></ul></ul><ul><li>Postherpetic Neuralgia (PHN) </li></ul><ul><ul><ul><li>Neuropathic pain affects 25-50% of people over 50 who have had herpes zoster 4 </li></ul></ul></ul>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.
    20. 21. Prevalence of Neuropathic Pain
    21. 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
    22. 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
    23. 26. Assessing the Patient With Pain <ul><li>Onset and duration </li></ul><ul><li>Location/distribution </li></ul><ul><li>Quality </li></ul><ul><li>Intensity </li></ul><ul><li>Aggravating/relieving factors </li></ul><ul><li>Associated features or secondary signs/symptoms </li></ul><ul><li>Associated factors </li></ul><ul><ul><li>mood/emotional distress </li></ul></ul><ul><ul><li>functional activities </li></ul></ul><ul><li>Treatment response </li></ul>
    24. 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)
    25. 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
    26. 29. Diabetic Peripheral Neuropathy <ul><ul><li>Numbness or insensitivity to pain or temperature </li></ul></ul><ul><ul><li>Tingling, burning, or prickling sensation </li></ul></ul><ul><ul><li>Sharp pains or cramps </li></ul></ul><ul><ul><li>Extreme sensitivity to touch, even light touch </li></ul></ul><ul><ul><li>Loss of balance and coordination </li></ul></ul><ul><ul><li>Muscle weakness and loss of reflexes </li></ul></ul><ul><ul><li>Symptoms are often worse at night </li></ul></ul>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.
    27. 30. Consider a Neuropathic Component in Low Back Pain <ul><li>Neuropathic symptoms in low back pain may include4: </li></ul><ul><ul><li>Positive sensory symptoms, e.g. tingling or burning pain </li></ul></ul><ul><ul><li>Negative sensory symptoms, e.g. numbness </li></ul></ul>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
    28. 31. Post-herpetic Neuropathy <ul><ul><li>Extreme sensitivity to touch (interferes with dressing, bathing, grooming, eating and mobility) </li></ul></ul><ul><ul><li>Hyperalgesia and allodynia </li></ul></ul><ul><ul><li>Intermittent itching </li></ul></ul><ul><ul><li>Numbness </li></ul></ul><ul><ul><li>Ongoing, spontaneous, burning pain </li></ul></ul><ul><ul><li>Intermittent, sharp, l ancinating pain </li></ul></ul><ul><ul><li>McMahon S, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th ed. Edinburgh: Churchill-Livingstone; 2005. </li></ul></ul>
    29. 32. Quiz Question Give three examples of positive sensory symptoms Answer Spontaneous pain Allodynia Hyperalgesia Dysaesthesia Paraesthesia
    30. 33. Diagnostic Approach
    31. 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
    32. 35. Listen to the Patient Description of Pain <ul><li>Question patients about their pain </li></ul><ul><ul><li>Duration </li></ul></ul><ul><ul><li>Frequency </li></ul></ul><ul><ul><li>Quality </li></ul></ul><ul><ul><li>Intensity </li></ul></ul><ul><li>Be alert and ask for common verbal descriptors of neuropathic pain (e.g. tingling, electric shock-like, numbness, burning, shooting) </li></ul><ul><li>Use analogue or numerical scales to quantify the pain </li></ul><ul><ul><li>Location </li></ul></ul><ul><ul><li>Pattern </li></ul></ul><ul><ul><li>Provokers </li></ul></ul><ul><ul><li>Relievers </li></ul></ul>
    33. 36. Locate the Region of Pain to a Neuroanatomical Area Lumbar radiculopathy Carpal tunnel sequelae Diabetic peripheral neuropathy
    34. 37. Applying the 3L Approach Differentiates Neuropathic from Nociceptive Pain Pain Listen Locate Look Neuropathic &quot;shooting&quot; &quot;electric shock“ &quot;burning&quot; &quot;tingling&quot; &quot;itching&quot; &quot;numbness&quot; 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 &quot;aching&quot; &quot;throbbing&quot; Painful region is typically localised at the site of injury Physical manipulation causes pain in site of injury Sensory abnormalities not indicated
    35. 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?
    36. 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*
    37. 40. Treatment Approach Hx / PE Emergency Non-emergent Pain crisis Chronic Adjuvant analgesics Ketamine etc Optimize opiods Consider regional anesthesia Opioid rotation
    38. 41. PHARMACOLOGIC MANAGEMENT OF NEUROPATHIC PAIN
    39. 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
    40. 43. Neuropathic pain - Therapy Local therapy Antidepressants Anticonvulsants Opioids In the case of inadequate effect: consultation with a pain specialist Causal therapy
    41. 44. Pharmacologic Treatment Options <ul><li>Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain </li></ul><ul><ul><li>topical analgesics (capsaicin, lidocaine patch 5%) </li></ul></ul><ul><ul><li>anticonvulsants (gabapentin, lamotrigine, pregabalin) </li></ul></ul><ul><ul><li>antidepressants (nortriptyline, desipramine) </li></ul></ul><ul><ul><li>opioids (oxycodone, tramadol) </li></ul></ul><ul><li>Consider safety and tolerability when initiating treatment </li></ul>
    42. 45. FDA-Approved Treatments for Neuropathic Pain <ul><li>Carbamazepine </li></ul><ul><ul><li>trigeminal neuralgia </li></ul></ul><ul><li>Duloxetine </li></ul><ul><ul><li>peripheral diabetic neuropathy </li></ul></ul><ul><li>Gabapentin </li></ul><ul><ul><li>postherpetic neuralgia </li></ul></ul><ul><li>Lidocaine Patch 5% </li></ul><ul><ul><li>postherpetic neuralgia </li></ul></ul><ul><li>Pregabalin* </li></ul><ul><ul><li>peripheral diabetic neuropathy </li></ul></ul><ul><ul><li>postherpetic neuralgia </li></ul></ul>*Availability pending based upon controlled substance scheduling by the DEA.
    43. 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
    44. 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)
    45. 48. Anticonvulsant Drugs for Neuropathic Pain Disorders <ul><li>Postherpetic neuralgia </li></ul><ul><ul><li>gabapentin* </li></ul></ul><ul><ul><li>pregabalin * </li></ul></ul><ul><li>Diabetic neuropathy </li></ul><ul><ul><li>carbamazepine </li></ul></ul><ul><ul><li>phenytoin </li></ul></ul><ul><ul><li>gabapentin </li></ul></ul><ul><ul><li>lamotrigine </li></ul></ul><ul><ul><li>pregabalin * </li></ul></ul><ul><li>HIV-associated neuropathy </li></ul><ul><ul><li>lamotrigine </li></ul></ul><ul><li>Trigeminal neuralgia </li></ul><ul><ul><li>carbamazepine* </li></ul></ul><ul><ul><li>lamotrigine </li></ul></ul><ul><ul><li>oxcarbazepine </li></ul></ul><ul><li>Central poststroke pain </li></ul><ul><ul><li>lamotrigine </li></ul></ul>*Approved by FDA for this use. HIV = human immunodeficiency virus.
    46. 49. Pregabalin in Neuropathic Pain Disorders <ul><li>FDA approved for postherpetic neuralgia and diabetic neuropathy </li></ul><ul><li>Anticonvulsant: uncertain mechanism </li></ul><ul><li>Determined intestinal absorption </li></ul><ul><li>Usually well tolerated; serious adverse effects rare </li></ul><ul><ul><li>dizziness and sedation can occur </li></ul></ul><ul><li>No significant drug interactions </li></ul><ul><li>Peak time: 2 to 3 h; elimination half-life: 5 to 7 h </li></ul><ul><li>Usual dosage range for neuropathic pain up to (75 mg –600mg )daily dose </li></ul>
    47. 50. Efficacy of Pregabalin in mechanical allodynia <ul><li>Static Dynamic </li></ul><ul><li>Pregabalin +++ +++ </li></ul><ul><li>Gabapentin +++ +++ </li></ul><ul><li>Morphine +++ - </li></ul><ul><li>Amitriptyline +++ - </li></ul><ul><li>static=pressure (von Frey) </li></ul><ul><li>dynamic=stroking (cotton wool) </li></ul>
    48. 51. Pregabalin binding site <ul><li>Pregabalin and Gabapentin binds specifically on    subunit of Ca ++ channel </li></ul><ul><li>Function needs to be verified </li></ul><ul><li>( Viedeo from pfizer ) </li></ul>
    49. 52. Guidelines for the Treatment of Neuropathic Pain
    50. 53. International Association for the Study of Pain (IASP) Recommendations <ul><li>First line </li></ul><ul><ul><li>Calcium channel α 2- δ (alpha-2- delta) ligands (pregabalin, gabapentin), tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors ( SNRIs), and topical lidocaine </li></ul></ul><ul><li>Second line </li></ul><ul><ul><li>Opioid analgesics or tramadol alone or in combination with one of the first-line medications. </li></ul></ul><ul><li>Third line </li></ul><ul><ul><li>Medications including carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, bupropion, citalopram, mexiletine, Nmethyl-D-aspartate (NMDA) receptor antagonists, and topical capsaicin. </li></ul></ul>Dworkin RH, et al. Pain. 2007 Dec 5;132(3):237-51.
    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
    52. 55. Efficacy in Patients with Diabetic Peripheral Neuropathy <ul><ul><li>Pregabalin significantly reduces pain associated with diabetic peripheral neuropathy1 </li></ul></ul><ul><ul><li>Pain reductions are positively correlated with dosage1 </li></ul></ul><ul><ul><li>Pain-related sleep interference is also significantly improved1 </li></ul></ul>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
    53. 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 <ul><ul><li>Patients with adverse events: 7% </li></ul></ul><ul><ul><li>Most frequently reported adverse events: </li></ul></ul><ul><ul><ul><li>Dizziness 1% </li></ul></ul></ul><ul><ul><ul><li>Fatigue 1% </li></ul></ul></ul><ul><ul><ul><li>Somnolence 1% </li></ul></ul></ul><ul><ul><ul><li>Nausea 0.6% </li></ul></ul></ul><ul><ul><li>Treatment terminated due to adverse events: 4% </li></ul></ul><ul><ul><li>Patients ‘very satisfied’ or ‘satisfied’ with the tolerability of pregabalin: 95% </li></ul></ul><ul><ul><li>Physicians coring tolerability of Pregabalin as ‘very good’ or ‘good’: 95% </li></ul></ul>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
    54. 57. 60%Very satisfied Satisfied 35% Moderately satisfied 3% Un satisfied 2% Safety/Tolerability in Low Back Pain Pain Clinic Central hospital Tripoli
    55. 58. Antidepressants in Neuropathic Pain Disorders* <ul><li>Multiple mechanisms of action </li></ul><ul><li>Randomized controlled trials and meta-analyses demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy </li></ul><ul><li>Onset of analgesia variable </li></ul><ul><ul><li>analgesic effects independent of antidepressant activity </li></ul></ul><ul><li>Improvements in insomnia, anxiety, depression </li></ul><ul><li>Desipramine and nortriptyline have fewer adverse effects </li></ul>*Not approved by FDA for this use.
    56. 59. Tricyclic Antidepressants: Adverse Effects <ul><li>Commonly reported AEs (generally anticholinergic): </li></ul><ul><ul><li>blurred vision </li></ul></ul><ul><ul><li>cognitive changes </li></ul></ul><ul><ul><li>constipation </li></ul></ul><ul><ul><li>dry mouth </li></ul></ul><ul><ul><li>orthostatic hypotension </li></ul></ul><ul><ul><li>sedation </li></ul></ul><ul><ul><li>sexual dysfunction </li></ul></ul><ul><ul><li>tachycardia </li></ul></ul><ul><ul><li>urinary retention </li></ul></ul><ul><li>Desipramine </li></ul><ul><li>Nortriptyline </li></ul><ul><li>Imipramine </li></ul><ul><li>Doxepin </li></ul><ul><li>Amitriptyline </li></ul>Fewest AEs Most AEs AEs = adverse effects .
    57. 60. Principles of Opioid Therapy for Neuropathic Pain <ul><li>Opioids should be titrated for therapeutic efficacy versus effect </li></ul><ul><li>Fixed-dose regimens generally preferred </li></ul><ul><li>Document treatment plan and outcomes </li></ul><ul><li>Consider use of opioid written care agreement </li></ul><ul><li>Opioids can be effective in neuropathic pain </li></ul><ul><li>Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants) </li></ul><ul><li>Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction </li></ul>
    58. 61. Interventional Treatments for Neuropathic Pain <ul><li>Neural blockade </li></ul><ul><ul><li>sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) </li></ul></ul><ul><li>Neurolytic techniques </li></ul><ul><ul><li>alcohol or phenol neurolysis </li></ul></ul><ul><ul><li>pulse radio frequency neural ablative procedures. </li></ul></ul><ul><li>Stimulatory techniques </li></ul><ul><ul><li>spinal cord stimulation </li></ul></ul><ul><ul><li>peripheral nerve stimulation </li></ul></ul><ul><li>Medication pumps </li></ul>CRPS = complex regional pain syndrome.
    59. 62. Summary of Advances in Treatments for Neuropathic Pain* <ul><li>Botulinum toxin: low back pain </li></ul><ul><li>Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related neuropathy, with gabapentin </li></ul><ul><li>CR oxycodone: diabetic neuropathy </li></ul><ul><li>Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others </li></ul><ul><li>Levetiracetam: neuropathic pain and migraine </li></ul><ul><li>Oxcarbazepine: neuropathic pain; diabetic neuropathy </li></ul><ul><li>Bupropion: neuropathic pain </li></ul><ul><li>Transdermal fentanyl: low back pain </li></ul>*Applications not approved by FDA.
    60. 63. Take Home Message <ul><li>Chronic neuropathic pain is a disease, not a symptom </li></ul><ul><li>“ Rational” polypharmacy is often necessary </li></ul><ul><ul><li>combining peripheral and central nervous system agents enhances pain relief </li></ul></ul><ul><li>Treatment goals include: </li></ul><ul><ul><li>balancing efficacy, safety, and tolerability </li></ul></ul><ul><ul><li>reducing baseline pain and pain exacerbations </li></ul></ul><ul><ul><li>improving function and QOL </li></ul></ul><ul><li>New agents and new uses for existing agents offer additional treatment options </li></ul>
    61. 64. Conclusion <ul><li>Several peripheral and central mechanisms underly the various neuropathic pain symptoms. </li></ul><ul><li>Therapeutic options should be more symptom oriented and (ideally) mechanism oriented. </li></ul><ul><li>The multiplicity of mechanisms in the same patient may explain why response to a single intervention is often partial. </li></ul>
    62. 66. http://www.thermogramcenter.com/Images_files/RSD%20arms.jpg
    63. 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.
    64. 68. Current Pharmocological Agents for Neuropathic Pain <ul><li>Sodium channel blockers </li></ul><ul><li>Antidepressant </li></ul><ul><li>Drugs that enhance GABAergic function </li></ul><ul><li>NMDA receptor antagonists </li></ul><ul><li>Others </li></ul>
    65. 69. Na + Channels <ul><ul><li>Na + Channels present in the dorsal root ganglia (DRG) of peripheral afferent fibre (PAF) can be classified into 2 types :- </li></ul></ul><ul><ul><li>1. Tetrodotoxin (TTX) - sensitive </li></ul></ul><ul><ul><li>Low threshold channels which rapidly activate and inactivate; </li></ul></ul><ul><ul><li>2. Tetrodotoxin (TTX) - resistant </li></ul></ul><ul><ul><li>High threshold channels with slower kinetics of activation an inactivation. </li></ul></ul>
    66. 70. Na + Channels modulators <ul><ul><li>Phenytoin </li></ul></ul><ul><ul><li>Carbamazepine </li></ul></ul><ul><ul><li>Sodium valproate </li></ul></ul><ul><ul><li>Lamotrigine </li></ul></ul><ul><ul><li>Topiramate </li></ul></ul><ul><ul><li>Mexiletine </li></ul></ul><ul><ul><li>Lidocaine </li></ul></ul><ul><ul><li>blockade of peripheral TTX sensitive </li></ul></ul><ul><ul><li>Na + channels in damaged PAFs </li></ul></ul><ul><ul><li>Antiallodynic actions </li></ul></ul>
    67. 71. Descending inhibitory pathways and monoamine receptors <ul><ul><li>Receptors Transduction systems Effect </li></ul></ul><ul><ul><li>5-HT 1A Open K + channel - hyperpolarize DH </li></ul></ul><ul><ul><li> - antinociception </li></ul></ul><ul><ul><li>5-HT 2A Activate PLC - depolarize DH </li></ul></ul><ul><li> - nociception </li></ul><ul><li>5-HT 3 Open Ca ++ channel - depolarize DH </li></ul><ul><ul><li> - nociception </li></ul></ul><ul><ul><li> 1 Positively couple with - nociception </li></ul></ul><ul><ul><li> adenylate cyclase </li></ul></ul><ul><ul><li> 2A Negatively couple - inhibit nociception </li></ul></ul><ul><ul><li> with adenylate cyclase </li></ul></ul>Monoamines exert inhibitory or excitatory actions via distinct receptor subtypes differentially coupled to intracellular transduction systems.
    68. 72. Tricyclic antidepressants <ul><ul><ul><li>Inhibit 5-HT and NE reuptake </li></ul></ul></ul><ul><ul><ul><li> 1 antagonist </li></ul></ul></ul><ul><ul><ul><li>muscarinic antagonist </li></ul></ul></ul><ul><ul><ul><li>histamine antagonist </li></ul></ul></ul><ul><li>Amitriptyline </li></ul><ul><li>is also potent 5-HT 2A antagonist. </li></ul>
    69. 73. Inhibitory interneurons in the dorsal horn (DH) <ul><li>Gamma - amino - butyric acid (GABA) is a major inhibitor neurotransmitter in the brain. </li></ul><ul><li>A widespread inhibitory influence of GABA ergic interneurons on nociceptive transmission in the DH and supraspinal structures. </li></ul><ul><li>Drugs which enhance GABA ergic function such as sodium valproate, clonazepam and gabapentin can partially inhibit pain transmission. </li></ul>
    70. 74. Gabapentin pharmacokinetics <ul><li>Rapidly absorbed orally, no effect of foods </li></ul><ul><li>no protein binding </li></ul><ul><li>is not metabolized </li></ul><ul><li>no enzyme induction / inhibition effect </li></ul><ul><li>excreted unchanged via urine </li></ul><ul><li>dose titration in patient with </li></ul><ul><li>renal insufficiency </li></ul><ul><li>t 1/2 ~ 5-7 h </li></ul><ul><li>bid or tid dosing </li></ul>
    71. 75. Gabapentin dosage and side effects <ul><li>600 - 3,600 mg/day </li></ul><ul><li>somnolence, dizziness, ataxia, fatigue, nystagmus and weight gain </li></ul>
    72. 76. Gabapentin binding site <ul><li>Gabapentin binds specifically on    subunit of Ca ++ channel </li></ul><ul><li>Function needs to be verified </li></ul>
    73. 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
    74. 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
    75. 79. Cholecystokinin (CCK) <ul><li>CCK act as an endogenous antiopioid. </li></ul><ul><li>CCK reduces the release of Leuenkephalin </li></ul><ul><li>acting at the  -opioid receptors. </li></ul><ul><li>CCK B antagonist e.g. L365260 and CI-988 enhance the antinociceptive effects of morphine in rats. </li></ul>

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