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Neuropathic pain

The document discusses neuropathic pain, detailing its definitions, classifications, and the underlying mechanisms. It highlights the pathogenesis of neuropathic pain, including peripheral and central sensitization, as well as the various causes and management strategies. The text emphasizes that neuropathic pain is typically chronic, resistant to standard treatments, and characterized by various abnormal sensations and pain responses.

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Amr Hassan, M.D. Associate prof of Neurology - Cairo University Mar 2014 Neuropathic Pain
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Amr Hasan El-Hasany M.D.
What is pain? “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Amr Hasan El-Hasany M.D. Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
Components Motivational-Affective: Emotional Sensory-Discriminative
“Pain is a more terrible lord of mankind than death itself.” Albert Schweitzer
ALLODYNIA Pain due to a stimulus which does not normally provoke pain. ANALGESIA Absence of pain in response to stimulation which would normally be painful. ANESTHESIA DOLORASA Pain in an area or region which is anesthetic. Amr Hasan El-Hasany M.D.
CAUSALGIA A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes. CENTRAL PAIN Pain initiated or caused by a primary lesion or dysfunction in the central nervous system. DYSESTHESIA An unpleasant abnormal sensation, whether spontaneous or evoked. Amr Hasan El-Hasany M.D.
HYPERALGESIA An increased response to a stimulus which is normally painful. HYPERESTHESIA Increased sensitivity to stimulation, excluding the special senses. HYPERPATHIA A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. Amr Hasan El-Hasany M.D.
HYPOALGESIA Diminished pain in response to a normally painful stimulus. NEURALGIA Pain in the distribution of a nerve or nerves. Note: Common usage, especially in Europe, often implies a paroxysmal quality, but neuralgia should not be reserved for paroxysmal pains. NEURITIS Inflammation of a nerve or nerves. Note: Not to be used unless inflammation is thought to be present. Amr Hasan El-Hasany M.D.
NEUROPATHY A disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy. NEUROPATHIC PAIN Pain initiated or caused by a primary lesion or dysfunction in the nervous system. PARESTHESIA An abnormal sensation, whether spontaneous or evoked. Amr Hasan El-Hasany M.D.
Sign/Symptom Description (example) Spontaneous symptoms • Spontaneous pain Persistent burning, intermittent shock-like or lancinating pain • Dysesthesias Abnormal unpleasant sensations e.g. shooting, lancinating, burning • Parasthesias Abnormal, not unpleasant sensations e.g. tingling Stimulus-evoked symptoms • Allodynia Painful response to a non-painful stimulus e.g. warmth, pressure, stroking • Hyperalgesia Heightened response to painful stimulus e.g. pinprick, cold, heat • Hyperpathia Delayed, explosive response to any painful stimulus
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Amr Hasan El-Hasany M.D.
Nociceptive vs neuropathic pain Acute vs chronic pain Stimulus- independent vs stimulus-evoked Hyperalgesia vs allodynia Pain
Nociceptive Pain An appropriate physiologic response to painful stimuli Neuropathic Pain An inappropriate response caused by a primary lesion or dysfunction in the nervous system Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
Neuropathic Pain Muscle/skeletal Pain (nociceptive pain) Chronic pain (months/years) Acute pain (hours or days) Caused by injury or disease to nerves Caused by injury or inflammation that affects both the muscles and joints Mild to excruciating pain that can last indefinitely Moderate to severe pain that disappears when the injury heals Causes extreme sensitivity to touch – simply wearing light clothing is painful Causes sore, achy muscles Sufferers can become depressed or socially withdrawn because they see no relief in sight and may experience sleep problems Sufferers can become anxious and distressed but optimistic about relief from pain Wall PD. Textbook of Pain. 4th ed; 1999; Jude EB. Clin in Pod Med and Surg.1999;16:81-97; Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997: Goldman L. Cecil Textbook of Medicine. 21st ed; 2000
Neuropathic Pain Muscle/Skeletal Pain Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997; Galer BS et al. Diabetes Res Clin Pract. 2000;47:123- 128 Classification of pain
versus A time-based definition Acute Pain  Time limited, <3 months  Results from injury to tissue  Resolves with healing  Example: herpes zoster Chronic Pain  Persistent, ≥3 to 6 months  Continues after initial injury heals  Example: postherpetic neuralgia Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
*Nociceptive; mixed nociceptive and neuropathic; or neuropathic. Cole BE. Hosp Physician. 2002;38:23-30. Insult Resolution <1 month 1 month <6 month 6 months Acute Pain Subacute Pain Chronic Pain*
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Transduction 1. Noxious stimuli (thermal, mechanical, and chemical) - - - - - tissue damage 2. Traumatized tissues release inflam. mediators (PGs, Bradykinin, 5HT, SP, Histamine. 3. Nociceptive free nerve endings sensitized by opening Na + channels - - - - Depolarization 4. So; noxious stimuli are converted to impulse (in milliseconds)
The 1st order neurone  Is the cell of the posterior root ganglion & its axon.  This axon is divided into a lateral & a medial branch.  The lat. branch forms the afferent sensory nerve.  The medial branch enters the spinal cord to ascend a few segments forming Lissauer's tract, and relays in the cells of Substantia Gelatinosa of Rolandi (S.G.R.) capping the post, horn of the gray matter. 2/4/2016 26
The 2nd order neurone  Is the cell of S.G.R. & its axon.  This axon crosses to the OPPOSITE side & ascends in the Lateral Spinothalamic Tract of the spinal cord then in the lateral lemniscus of the brain stem, to relay in the thalamus. 2/4/2016 27 Pathway of Pain
The 3rd order neurone  Starts in the cell of the thalamus, its axon ascends to pass through the posterior limb of the internal capsule conducting the impulse to the cortical sensory area in the parietal lobe. 2/4/2016 28 Pathway of Pain
2/4/2016Neurology for physiotherapist by Prof.Dr Ahmed Aboumousa 30
Transmission  Neural Pathway: First Pain Second Pain Sharp Dull (unpleasant) Initial Later Brief Long – lasting
Spinal cord pathway:  DRG (1st order)  Dorsal horn (2nd order) (laminae I-V) • Wide Dynamic Range Cell (WDR): Glu (AMPA) • Nociceptive specific neurons • SGR (lamina II).
Ascending Pathways:  Spino-Reticulo-Diencephalic: connected to R.F (connected to hypothalamus and Cingulate gyrus “autonomic components”) and medial thalamus  Spinothalamic: VLNT The Thalamus:  The central switching station of the brain.  The lateral nuclei deal with sensory / discriminative aspects.  The medial ones with 'affective' pain.
 Major cortical players are: • Primary sensory cortex, S I • Secondary sensory cortex, S II • Anterior part of the insula • Cingulate gyrus. Cortical structures Tangentially involved in the perception of pain !?!?!
Injury Descending Pathway Peripheral Nerve Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Ascending Pathways Dorsal Horn Brain Spinal Cord Modulation / perception: In cortex. Interpretation
 Descending pathways originate from three main areas: • Cortex • Thalamus • Brainstem: Periaqueductal grey matter (PAG)
 Descending pathways originate from three main areas: 1. The somatosensory cortex 2. The periventricular nucleus of the hypothalamus 3. The pontine reticular formation 4. Raphe nuclei and adjacent medullary reticular formation
From PAG R.F of medulla (raphe nucleus) in ventromedian medulla (5HT) Dorsolateral funiculus of the spinal cord, to end up in Interneurones next to SGR (lamina II) (enkephalin) that inhibit incoming pain impulses.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Pain initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathic pain is usually chronic, difficult to treat, and often resistant to standard analgesic management.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Woolf and Mannion. Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
 Peripheral Mechanisms After a peripheral nerve lesion, neurons become more sensitive and develop abnormal excitability and elevated sensitivity to stimuli [peripheral sensitization] .
Central Mechanisms  As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop an increased background activity, enlarged receptive field and increased responses to afferent impulses, including normal tactile stimuli [central sensitization].
Peripheral Sensitization “ Healthy “ nociceptors Abnormal nociceptors Central Sensitization Normal transmission Central reorganization CNS PNS Neuropathic Pain Nociceptive Pain Physiologic state Pathologic state Peripheral Nervous System Central Nervous System
Peripheral Mechanisms  Membrane hyperexcitability  Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
NEUROPATHIC PAIN  Abnormal sensations are transmitted along myelinated Aβ or A fibers or unmyelinated C fibers
Na+ = sodium ion channels. Injured nerves develop higher number of Na+ channels
Baron, 2001 2. Peripheral Sensitization • Nociceptive C-afferents - Spont. Pain (burning) - evoked pain (allodynia, hyperalgesia). • Non-nociceptive Ab afferents  parasthesias & dysthesia.
Peripheral Mechanisms  Membrane hyperexcitability  Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
•Sensitization of DHC resulting from high frequency stimulation by nociceptive thus  DHC continue to discharge despite cessation of C fiber stimulation.
•Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. •Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors.
Peripheral Mechanisms  Membrane hyperexcitability  Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
2-Central sensitization involves: • Prolonged depolarization of dorsal horn neurons and changes in postsynaptic membrane receptors  Changes in postsynaptic dorsal horn membrane receptors manifest as: • Reduced activation threshold • Increased receptive field • Increased response to suprathreshold stimulus
Peripheral Mechanisms  Membrane hyperexcitability  Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
Dorsal root ganglion C Ab Midline Normal terminations of primary afferents in the dorsal horn After nerve injury Woolf CJ et al. Curr Opin Neurobiol. 1994;4:525-534. Touch Pain
Baron, 2001 Under physiologic circumstances: central terminals of AB low threshold mechanosensetive afferent proeject to dorsal horn laminae ventral to substania gelatinosa (SG) 3-Central Organization
Baron, 2001 3-Central Reorganization Partial degeneration of nociceptive C- fibers: central terminals of AB low threshold mechanosensetive afferent sprout dorsally into (SG) Functional contact with differentiated 2nd order neurone Pathogenesis of neuropathic pain
Baron, 2001 3-Central Reorganization Pathogenesis of neuropathic pain
Peripheral Mechanisms  Membrane hyperexcitability  Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
Baron, 2001 4- Loss of Inhibitory Controls • Neurons in the dorsal horn can facilitate or inhibit transmission of sensation • Inhibition is mediated by GABA and glycine • Experimental peripheral nerve injury in animals decreases GABA and glycine levels and downregulates GABA and opioid receptors • Inhibition is lost and excitatory mechanisms dominate, resulting in the propagation of pain impulses. Pathogenesis of neuropathic pain
Woolf and Mannion. Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
 Dysesthesias  Paresthesias  Spontaneous pain*  Stimulus-evoked pain  Loss / impairment of sensory quality  Numbness and reduced sensation Baron R. Clin J Pain. 2000;16:S12-S20. Positive sensory signs and symptoms Negative sensory signs and symptoms Sensory changes and pain may coexist *Also known as stimulus-independent pain
ALLODYNIA Pain due to a stimulus which does not normally provoke pain. ANALGESIA Absence of pain in response to stimulation which would normally be painful. ANESTHESIA DOLORASA Pain in an area or region which is anesthetic. Amr Hasan El-Hasany M.D.
Woolf and Mannion. Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
Neuropathic pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system Peripheral neuropathic pain Central neuropathic pain Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
 Peripheral causes of neuropathic pain  Trauma – e.g. surgery, nerve entrapment, amputation  Metabolic disturbances – e.g. diabetes mellitus  Infections – e.g. herpes zoster (shingles), HIV  Toxins – e.g. chemotherapeutic agents, alcohol  Vascular disorders – e.g. polyarteritis nodosa  Nutritional deficiencies – e.g. niacin, thyamine, pyridoxine  Direct effects of cancer – e.g. metastasis, infiltrative  Central causes of neuropathic pain  Stroke.  Spinal cord lesions.  Multiple sclerosis.  Tumors. Wall PD, Melzack R (Eds).Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical guide to neuropathic pain. 2000:Woolf CJ et al. Lancet. 1999;353:1959-1964.
 Painful Diabetic Neuropathy (PDN)  Low back pain Neuropathic pain affects up to 55% of patients with chronic low back pain.  Postherpetic Neuralgia (PHN) Neuropathic pain affects 25 to 50% of people over 50 who have had herpes zoster.  Cancer Neuropathic pain affects about 33% of cancer patients.  Spinal cord injury Neuropathic pain affects 75% of patients with spinal cord injury.  Stroke Neuropathic pain affects 8% of post-stroke patients.  Multiple sclerosis Neuropathic pain affects approximately 55% of patients with multiple sclerosis. Neuropathic Pain is highly prevalent among a number of different patients
Woolf and Mannion. Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27 Pain Sleep disturbances Anxiety & Depression Functional impairment
Social Consequences  Marital/family relations  Intimacy/sexual activity  Social isolation Socioeconomic Consequences  Healthcare costs  Disability  Lost workdays Quality of Life Physical functioning Ability to perform activities of daily living Work Recreation Psychological Morbidity Depression Anxiety, anger Sleep disturbances Loss of self-esteem 1.U.S. News & World Report.Washington, DC: U.S. News & World Report L.P.; March 17, 1997:55-57, 60-62, 65, 67. 2.Becker N, Sjogren P, Bech P, Olsen AK, Eriksen J.Treatment outcome of chronic non-malignant pain patients managed in a Danish multidisciplinary pain centre compared to general practice: a randomized controlled trial. Pain. 2000;84:203-211.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
•Definitions and glossary •Classification of pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
• Type, distribution and location of pain  Character of complaints  e.g. burning, shock-like, pins and needles etc.  Based on anatomic drawing  Dermatomal  Non-dermatomal • Duration of complaints • Average intensity of pain in the last day/week (0-10) • Extent of interference with daily activity (0-10) 1. Jensen and Baron. Pain. 2003;102:1-8 Identify the following:1 Areas of further exploration • Previous medical history • Exposure to toxins or other drug treatment e.g. radiation • Use of pain medications • Associated psychological and mood disturbance
EMG-NCV  To localise pain- generator/nerve or root lesion  To rule out : - Axonal Vs focal segmental demyelination - Underlying small-fiber or mixed polyneuropathy
 Nerve ( eg, sural nerve ) : to diagnose vasculitis, amyloidosis, sarcoidosis, etc.  Skin : to evaluate density of unmyelinated fibers within dermis and epidermis
Bennett. Pain. 2001;92:147-57
• Completed by physician in office • Differentiates neuropathic from nociceptive pain • 5 pain questions and 2 skin sensitivity tests • Validated
• Completed by physician in office • Differentiates neuropathic from nociceptive pain • 2 pain questions (7 items) • 2 skin sensitivity tests (3 items) • Validated DN4: Douleur Neuropathique en 4 questions Bouhassira et al. Pain. 2005;114:29-36
Diagnosis Treat underlying condition/symptomatic treatment Reduce Pain Prevention (if applicable) Reduce psychological distress Improve physical functioning Improve overall quality of life
Level of Risk Most invasive Least invasive Interventional techniques Oral medications Topical medications Psychologic/ physical approaches Injections Treatment should begin at an appropriate point along the risk continuum
 Cognitive-behavioral strategies • Meditation • Biofeedback • Relaxation therapy  Physical rehabilitation  Acupuncture  TENS
 Anticonvulsants: GBP, CBZ, OXC, LTG  Lidocaine patch 5%  Opioid analgesics  Tramadol  Tricyclic antidepressants, SSRIs, SNRIs  Recently approved agents • Duloxetine • Pregabalin
*: FDA approved in various neuropathic pain disease +: FDA approved for use in severe chronic pain
Currently available treatment options for neuropathic pain and possible sites of action within the nervous system.
Mechanism Symptom Molecular targets Drugs Na+ channels Accumulation Redistribution Altered expression Spontaneous pain Paresthesias Neuroma sign Na+ channels TTX-sensitive TTX-resistant Carbamazepine Lamotrigine Mexilitine Tricyclic antidepressants Central sensitization Hyperalgesia Tactile Cold Pin-prick NMDA receptors Neurokinin-1 receptors nNOS Protein kinase γ antagonists NMDA Ketamine Dextramethorphan Amantidine
Mechanism Symptom Molecular targets Drugs Peripheral sensitization Hyperalgesia Pressure Thermal Spontaneous pain Neurogenic inflammation Vanilloid receptor-1- desensitization Neurokinin 1 Na +channels: TTX- resistant Nerve growth factor Capsaicin Sympathetic stimulation Spontaneous pain α-receptor antagonists Nerve growth factor/trKA Phentolamine Guanethidine
Mechanism Symptom Molecular targets Drugs Increased transmission Reduced inhibition Spontaneous pain Hyperalgesia Calcium channels, N- type Receptors Conotoxin Opiates Gabapentin Clonidine Tricyclic antidepressants SNRIs
Consider nonpharmacologic treatmentsFirst Step Second Step Initiate first-line drug monotherapy (Pregabalin or Gabapentin or TCA or SNRI) Third Step Partial response: add No response: Switch to alternate first-line Forth Step Partial response: add No response: Switch to tramadol/oxycodone Fifth Step Ineffective/not-tolerated: pain specialty clinic
THANK YOU
• Pregabalin binding affinity for α2-δ -subunit, and potency, is six times more than that of gabapentin.
• Pregabalin modulates the hyperexcited neuron by: -High affinity binding the α2-δ subunit of voltage-gated calcium channels. -Attenuating calcium influx into presynaptic terminals. -Reducing excessive release of excitatory neurotransmitters.
• Pregabalin has linear pharmacokinetics Pregabalin Pharmacokinetic •Bockbrader H, Hunt T, Strand J, Posvar E, Sedman A. Pregabalin pharmacokinetics and safety in healthy volunteers: results from two phase 1 studies. Neurology 2000; 54:A421 •Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004; 45:13–8 • Pregabalin monograph. Pregabalin Gabapentin Time to the effective dose 1 day 9 days
• Gabapentin monograph. • Pregabalin monograph. Indications Pregabalin Gabapentin Neuropathic pain associated with diabetic peripheral neuropathy √ Neuropathic pain associated with postherpetic neuralgia √ √ Fibromyalgia √ FDA approved indications for Pregabalin and Gabapentin
• The recommended dosage scheme  Dosing should begin at 50 mg three times / day increased to 100 mg three times / day, based on efficacy and tolerability. The recommended dosage in the treatment of Fibromyalgia 300 – 450 mg / day.
 Since Pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement.  In vitro and in vivo studies showed that Pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions.
Amr Hasan El-Hasany M.D.
THANK YOU

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Neuropathic pain

  • 1.
    Amr Hassan, M.D. Associateprof of Neurology - Cairo University Mar 2014 Neuropathic Pain
  • 2.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 3.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 4.
  • 5.
    What is pain? “Anunpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Amr Hasan El-Hasany M.D. Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
  • 6.
  • 7.
    “Pain is amore terrible lord of mankind than death itself.” Albert Schweitzer
  • 8.
    ALLODYNIA Pain due toa stimulus which does not normally provoke pain. ANALGESIA Absence of pain in response to stimulation which would normally be painful. ANESTHESIA DOLORASA Pain in an area or region which is anesthetic. Amr Hasan El-Hasany M.D.
  • 9.
    CAUSALGIA A syndrome ofsustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes. CENTRAL PAIN Pain initiated or caused by a primary lesion or dysfunction in the central nervous system. DYSESTHESIA An unpleasant abnormal sensation, whether spontaneous or evoked. Amr Hasan El-Hasany M.D.
  • 10.
    HYPERALGESIA An increased responseto a stimulus which is normally painful. HYPERESTHESIA Increased sensitivity to stimulation, excluding the special senses. HYPERPATHIA A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. Amr Hasan El-Hasany M.D.
  • 11.
    HYPOALGESIA Diminished pain inresponse to a normally painful stimulus. NEURALGIA Pain in the distribution of a nerve or nerves. Note: Common usage, especially in Europe, often implies a paroxysmal quality, but neuralgia should not be reserved for paroxysmal pains. NEURITIS Inflammation of a nerve or nerves. Note: Not to be used unless inflammation is thought to be present. Amr Hasan El-Hasany M.D.
  • 12.
    NEUROPATHY A disturbance offunction or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy. NEUROPATHIC PAIN Pain initiated or caused by a primary lesion or dysfunction in the nervous system. PARESTHESIA An abnormal sensation, whether spontaneous or evoked. Amr Hasan El-Hasany M.D.
  • 13.
    Sign/Symptom Description (example) Spontaneoussymptoms • Spontaneous pain Persistent burning, intermittent shock-like or lancinating pain • Dysesthesias Abnormal unpleasant sensations e.g. shooting, lancinating, burning • Parasthesias Abnormal, not unpleasant sensations e.g. tingling Stimulus-evoked symptoms • Allodynia Painful response to a non-painful stimulus e.g. warmth, pressure, stroking • Hyperalgesia Heightened response to painful stimulus e.g. pinprick, cold, heat • Hyperpathia Delayed, explosive response to any painful stimulus
  • 14.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 15.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 16.
  • 17.
    Nociceptive vs neuropathic pain Acutevs chronic pain Stimulus- independent vs stimulus-evoked Hyperalgesia vs allodynia Pain
  • 18.
    Nociceptive Pain An appropriate physiologicresponse to painful stimuli Neuropathic Pain An inappropriate response caused by a primary lesion or dysfunction in the nervous system Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
  • 19.
    Neuropathic Pain Muscle/skeletalPain (nociceptive pain) Chronic pain (months/years) Acute pain (hours or days) Caused by injury or disease to nerves Caused by injury or inflammation that affects both the muscles and joints Mild to excruciating pain that can last indefinitely Moderate to severe pain that disappears when the injury heals Causes extreme sensitivity to touch – simply wearing light clothing is painful Causes sore, achy muscles Sufferers can become depressed or socially withdrawn because they see no relief in sight and may experience sleep problems Sufferers can become anxious and distressed but optimistic about relief from pain Wall PD. Textbook of Pain. 4th ed; 1999; Jude EB. Clin in Pod Med and Surg.1999;16:81-97; Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997: Goldman L. Cecil Textbook of Medicine. 21st ed; 2000
  • 20.
    Neuropathic Pain Muscle/SkeletalPain Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997; Galer BS et al. Diabetes Res Clin Pract. 2000;47:123- 128 Classification of pain
  • 21.
    versus A time-based definition AcutePain  Time limited, <3 months  Results from injury to tissue  Resolves with healing  Example: herpes zoster Chronic Pain  Persistent, ≥3 to 6 months  Continues after initial injury heals  Example: postherpetic neuralgia Merskey H et al, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
  • 22.
    *Nociceptive; mixed nociceptiveand neuropathic; or neuropathic. Cole BE. Hosp Physician. 2002;38:23-30. Insult Resolution <1 month 1 month <6 month 6 months Acute Pain Subacute Pain Chronic Pain*
  • 23.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 24.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 25.
    Transduction 1. Noxious stimuli(thermal, mechanical, and chemical) - - - - - tissue damage 2. Traumatized tissues release inflam. mediators (PGs, Bradykinin, 5HT, SP, Histamine. 3. Nociceptive free nerve endings sensitized by opening Na + channels - - - - Depolarization 4. So; noxious stimuli are converted to impulse (in milliseconds)
  • 26.
    The 1st orderneurone  Is the cell of the posterior root ganglion & its axon.  This axon is divided into a lateral & a medial branch.  The lat. branch forms the afferent sensory nerve.  The medial branch enters the spinal cord to ascend a few segments forming Lissauer's tract, and relays in the cells of Substantia Gelatinosa of Rolandi (S.G.R.) capping the post, horn of the gray matter. 2/4/2016 26
  • 27.
    The 2nd orderneurone  Is the cell of S.G.R. & its axon.  This axon crosses to the OPPOSITE side & ascends in the Lateral Spinothalamic Tract of the spinal cord then in the lateral lemniscus of the brain stem, to relay in the thalamus. 2/4/2016 27 Pathway of Pain
  • 28.
    The 3rd orderneurone  Starts in the cell of the thalamus, its axon ascends to pass through the posterior limb of the internal capsule conducting the impulse to the cortical sensory area in the parietal lobe. 2/4/2016 28 Pathway of Pain
  • 30.
    2/4/2016Neurology for physiotherapistby Prof.Dr Ahmed Aboumousa 30
  • 31.
    Transmission  Neural Pathway: FirstPain Second Pain Sharp Dull (unpleasant) Initial Later Brief Long – lasting
  • 32.
    Spinal cord pathway: DRG (1st order)  Dorsal horn (2nd order) (laminae I-V) • Wide Dynamic Range Cell (WDR): Glu (AMPA) • Nociceptive specific neurons • SGR (lamina II).
  • 33.
    Ascending Pathways:  Spino-Reticulo-Diencephalic:connected to R.F (connected to hypothalamus and Cingulate gyrus “autonomic components”) and medial thalamus  Spinothalamic: VLNT The Thalamus:  The central switching station of the brain.  The lateral nuclei deal with sensory / discriminative aspects.  The medial ones with 'affective' pain.
  • 34.
     Major corticalplayers are: • Primary sensory cortex, S I • Secondary sensory cortex, S II • Anterior part of the insula • Cingulate gyrus. Cortical structures Tangentially involved in the perception of pain !?!?!
  • 35.
  • 36.
     Descending pathwaysoriginate from three main areas: • Cortex • Thalamus • Brainstem: Periaqueductal grey matter (PAG)
  • 37.
     Descending pathwaysoriginate from three main areas: 1. The somatosensory cortex 2. The periventricular nucleus of the hypothalamus 3. The pontine reticular formation 4. Raphe nuclei and adjacent medullary reticular formation
  • 38.
    From PAG R.Fof medulla (raphe nucleus) in ventromedian medulla (5HT) Dorsolateral funiculus of the spinal cord, to end up in Interneurones next to SGR (lamina II) (enkephalin) that inhibit incoming pain impulses.
  • 41.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 42.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 43.
    Pain initiated orcaused by a primary lesion or dysfunction in the nervous system. Neuropathic pain is usually chronic, difficult to treat, and often resistant to standard analgesic management.
  • 44.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 45.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 46.
    Woolf and Mannion.Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
  • 47.
     Peripheral Mechanisms Aftera peripheral nerve lesion, neurons become more sensitive and develop abnormal excitability and elevated sensitivity to stimuli [peripheral sensitization] .
  • 48.
    Central Mechanisms  Asa consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop an increased background activity, enlarged receptive field and increased responses to afferent impulses, including normal tactile stimuli [central sensitization].
  • 49.
    Peripheral Sensitization “ Healthy“ nociceptors Abnormal nociceptors Central Sensitization Normal transmission Central reorganization CNS PNS Neuropathic Pain Nociceptive Pain Physiologic state Pathologic state Peripheral Nervous System Central Nervous System
  • 50.
    Peripheral Mechanisms  Membrane hyperexcitability Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 51.
    NEUROPATHIC PAIN  Abnormalsensations are transmitted along myelinated Aβ or A fibers or unmyelinated C fibers
  • 52.
    Na+ = sodiumion channels. Injured nerves develop higher number of Na+ channels
  • 53.
    Baron, 2001 2. PeripheralSensitization • Nociceptive C-afferents - Spont. Pain (burning) - evoked pain (allodynia, hyperalgesia). • Non-nociceptive Ab afferents  parasthesias & dysthesia.
  • 55.
    Peripheral Mechanisms  Membrane hyperexcitability Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 56.
    •Sensitization of DHCresulting from high frequency stimulation by nociceptive thus  DHC continue to discharge despite cessation of C fiber stimulation.
  • 57.
    •Wind-up is afrequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. •Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors.
  • 59.
    Peripheral Mechanisms  Membrane hyperexcitability Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 60.
    2-Central sensitization involves: •Prolonged depolarization of dorsal horn neurons and changes in postsynaptic membrane receptors  Changes in postsynaptic dorsal horn membrane receptors manifest as: • Reduced activation threshold • Increased receptive field • Increased response to suprathreshold stimulus
  • 62.
    Peripheral Mechanisms  Membrane hyperexcitability Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 63.
    Dorsal root ganglion C Ab Midline Normalterminations of primary afferents in the dorsal horn After nerve injury Woolf CJ et al. Curr Opin Neurobiol. 1994;4:525-534. Touch Pain
  • 64.
    Baron, 2001 Under physiologic circumstances:central terminals of AB low threshold mechanosensetive afferent proeject to dorsal horn laminae ventral to substania gelatinosa (SG) 3-Central Organization
  • 65.
    Baron, 2001 3-Central Reorganization Partialdegeneration of nociceptive C- fibers: central terminals of AB low threshold mechanosensetive afferent sprout dorsally into (SG) Functional contact with differentiated 2nd order neurone Pathogenesis of neuropathic pain
  • 66.
  • 67.
    Peripheral Mechanisms  Membrane hyperexcitability Ectopic discharges  Peripheral sensitization Central Mechanisms  Wind up  Central sensitization  Central reorganization of Ab fibers  Loss of inhibitory controls Attal N et al. Acta Neurol Scand. 1999;100(suppl):12-24; Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 68.
    Baron, 2001 4- Lossof Inhibitory Controls • Neurons in the dorsal horn can facilitate or inhibit transmission of sensation • Inhibition is mediated by GABA and glycine • Experimental peripheral nerve injury in animals decreases GABA and glycine levels and downregulates GABA and opioid receptors • Inhibition is lost and excitatory mechanisms dominate, resulting in the propagation of pain impulses. Pathogenesis of neuropathic pain
  • 69.
    Woolf and Mannion.Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
  • 71.
     Dysesthesias  Paresthesias Spontaneous pain*  Stimulus-evoked pain  Loss / impairment of sensory quality  Numbness and reduced sensation Baron R. Clin J Pain. 2000;16:S12-S20. Positive sensory signs and symptoms Negative sensory signs and symptoms Sensory changes and pain may coexist *Also known as stimulus-independent pain
  • 73.
    ALLODYNIA Pain due toa stimulus which does not normally provoke pain. ANALGESIA Absence of pain in response to stimulation which would normally be painful. ANESTHESIA DOLORASA Pain in an area or region which is anesthetic. Amr Hasan El-Hasany M.D.
  • 74.
    Woolf and Mannion.Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
  • 75.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 76.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 77.
    Neuropathic pain Pain initiatedor caused by a primary lesion or dysfunction in the nervous system Peripheral neuropathic pain Central neuropathic pain Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
  • 78.
     Peripheral causesof neuropathic pain  Trauma – e.g. surgery, nerve entrapment, amputation  Metabolic disturbances – e.g. diabetes mellitus  Infections – e.g. herpes zoster (shingles), HIV  Toxins – e.g. chemotherapeutic agents, alcohol  Vascular disorders – e.g. polyarteritis nodosa  Nutritional deficiencies – e.g. niacin, thyamine, pyridoxine  Direct effects of cancer – e.g. metastasis, infiltrative  Central causes of neuropathic pain  Stroke.  Spinal cord lesions.  Multiple sclerosis.  Tumors. Wall PD, Melzack R (Eds).Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical guide to neuropathic pain. 2000:Woolf CJ et al. Lancet. 1999;353:1959-1964.
  • 79.
     Painful DiabeticNeuropathy (PDN)  Low back pain Neuropathic pain affects up to 55% of patients with chronic low back pain.  Postherpetic Neuralgia (PHN) Neuropathic pain affects 25 to 50% of people over 50 who have had herpes zoster.  Cancer Neuropathic pain affects about 33% of cancer patients.  Spinal cord injury Neuropathic pain affects 75% of patients with spinal cord injury.  Stroke Neuropathic pain affects 8% of post-stroke patients.  Multiple sclerosis Neuropathic pain affects approximately 55% of patients with multiple sclerosis. Neuropathic Pain is highly prevalent among a number of different patients
  • 80.
    Woolf and Mannion.Lancet 1999;353:1959-64 Neuropathic pain Spontaneous pain Stimulus-evoked pain Mechanisms Metabolic Traumatic ToxicIschemic Hereditary Compression Infectious Immune-related Syndrome Symptoms Pathophysiology Etiology Nerve damage
  • 81.
    Nicholson and Verma.Pain Med. 2004;5 (suppl. 1):S9-S27 Pain Sleep disturbances Anxiety & Depression Functional impairment
  • 82.
    Social Consequences  Marital/family relations Intimacy/sexual activity  Social isolation Socioeconomic Consequences  Healthcare costs  Disability  Lost workdays Quality of Life Physical functioning Ability to perform activities of daily living Work Recreation Psychological Morbidity Depression Anxiety, anger Sleep disturbances Loss of self-esteem 1.U.S. News & World Report.Washington, DC: U.S. News & World Report L.P.; March 17, 1997:55-57, 60-62, 65, 67. 2.Becker N, Sjogren P, Bech P, Olsen AK, Eriksen J.Treatment outcome of chronic non-malignant pain patients managed in a Danish multidisciplinary pain centre compared to general practice: a randomized controlled trial. Pain. 2000;84:203-211.
  • 83.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 84.
    •Definitions and glossary •Classificationof pain •Pathways of pain •Neuropathic pain Pathogenesis of neuropathic pain Causes of neuropathic pain Management of neuropathic pain Amr Hasan El-Hasany M.D.
  • 85.
    • Type, distributionand location of pain  Character of complaints  e.g. burning, shock-like, pins and needles etc.  Based on anatomic drawing  Dermatomal  Non-dermatomal • Duration of complaints • Average intensity of pain in the last day/week (0-10) • Extent of interference with daily activity (0-10) 1. Jensen and Baron. Pain. 2003;102:1-8 Identify the following:1 Areas of further exploration • Previous medical history • Exposure to toxins or other drug treatment e.g. radiation • Use of pain medications • Associated psychological and mood disturbance
  • 86.
    EMG-NCV  To localisepain- generator/nerve or root lesion  To rule out : - Axonal Vs focal segmental demyelination - Underlying small-fiber or mixed polyneuropathy
  • 87.
     Nerve (eg, sural nerve ) : to diagnose vasculitis, amyloidosis, sarcoidosis, etc.  Skin : to evaluate density of unmyelinated fibers within dermis and epidermis
  • 88.
  • 89.
    • Completed byphysician in office • Differentiates neuropathic from nociceptive pain • 5 pain questions and 2 skin sensitivity tests • Validated
  • 90.
    • Completed byphysician in office • Differentiates neuropathic from nociceptive pain • 2 pain questions (7 items) • 2 skin sensitivity tests (3 items) • Validated DN4: Douleur Neuropathique en 4 questions Bouhassira et al. Pain. 2005;114:29-36
  • 91.
    Diagnosis Treat underlying condition/symptomatictreatment Reduce Pain Prevention (if applicable) Reduce psychological distress Improve physical functioning Improve overall quality of life
  • 92.
    Level of Risk Mostinvasive Least invasive Interventional techniques Oral medications Topical medications Psychologic/ physical approaches Injections Treatment should begin at an appropriate point along the risk continuum
  • 93.
     Cognitive-behavioral strategies •Meditation • Biofeedback • Relaxation therapy  Physical rehabilitation  Acupuncture  TENS
  • 94.
     Anticonvulsants: GBP,CBZ, OXC, LTG  Lidocaine patch 5%  Opioid analgesics  Tramadol  Tricyclic antidepressants, SSRIs, SNRIs  Recently approved agents • Duloxetine • Pregabalin
  • 95.
    *: FDA approvedin various neuropathic pain disease +: FDA approved for use in severe chronic pain
  • 96.
    Currently available treatment optionsfor neuropathic pain and possible sites of action within the nervous system.
  • 97.
    Mechanism Symptom Molecular targets Drugs Na+channels Accumulation Redistribution Altered expression Spontaneous pain Paresthesias Neuroma sign Na+ channels TTX-sensitive TTX-resistant Carbamazepine Lamotrigine Mexilitine Tricyclic antidepressants Central sensitization Hyperalgesia Tactile Cold Pin-prick NMDA receptors Neurokinin-1 receptors nNOS Protein kinase γ antagonists NMDA Ketamine Dextramethorphan Amantidine
  • 98.
    Mechanism Symptom Molecular targets Drugs Peripheral sensitization Hyperalgesia Pressure Thermal Spontaneous pain Neurogenic inflammation Vanilloidreceptor-1- desensitization Neurokinin 1 Na +channels: TTX- resistant Nerve growth factor Capsaicin Sympathetic stimulation Spontaneous pain α-receptor antagonists Nerve growth factor/trKA Phentolamine Guanethidine
  • 99.
    Mechanism Symptom Molecular targets Drugs Increased transmission Reduced inhibition Spontaneous pain Hyperalgesia Calcium channels,N- type Receptors Conotoxin Opiates Gabapentin Clonidine Tricyclic antidepressants SNRIs
  • 100.
    Consider nonpharmacologic treatmentsFirstStep Second Step Initiate first-line drug monotherapy (Pregabalin or Gabapentin or TCA or SNRI) Third Step Partial response: add No response: Switch to alternate first-line Forth Step Partial response: add No response: Switch to tramadol/oxycodone Fifth Step Ineffective/not-tolerated: pain specialty clinic
  • 101.
  • 103.
    • Pregabalin binding affinityfor α2-δ -subunit, and potency, is six times more than that of gabapentin.
  • 104.
    • Pregabalin modulatesthe hyperexcited neuron by: -High affinity binding the α2-δ subunit of voltage-gated calcium channels. -Attenuating calcium influx into presynaptic terminals. -Reducing excessive release of excitatory neurotransmitters.
  • 106.
    • Pregabalin haslinear pharmacokinetics Pregabalin Pharmacokinetic •Bockbrader H, Hunt T, Strand J, Posvar E, Sedman A. Pregabalin pharmacokinetics and safety in healthy volunteers: results from two phase 1 studies. Neurology 2000; 54:A421 •Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004; 45:13–8 • Pregabalin monograph. Pregabalin Gabapentin Time to the effective dose 1 day 9 days
  • 107.
    • Gabapentin monograph. •Pregabalin monograph. Indications Pregabalin Gabapentin Neuropathic pain associated with diabetic peripheral neuropathy √ Neuropathic pain associated with postherpetic neuralgia √ √ Fibromyalgia √ FDA approved indications for Pregabalin and Gabapentin
  • 108.
    • The recommendeddosage scheme  Dosing should begin at 50 mg three times / day increased to 100 mg three times / day, based on efficacy and tolerability. The recommended dosage in the treatment of Fibromyalgia 300 – 450 mg / day.
  • 109.
     Since Pregabalinis predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement.  In vitro and in vivo studies showed that Pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions.
  • 110.
  • 111.